eLife assessment

This study presents valuable findings on a cleaved form of METTL3 that may play an essential role in regulating the assembly of the METTL3-METTL14-WTAP complex. The evidence supporting the claims of the authors is solid, but the model and assays can be improved. The work will be of interest to biologists working on RNA epigenetics and cancer biology.

eLife assessment

This study provides potentially important, new information about the combination of information from the two eyes in humans. The data included frequency tagging of each eye's inputs and measures reflecting both cortical (EEG) and sub-cortical processes (pupillometry). Binocular combination is of potentially general interest because it provides -in essence- a case study of how the brain combines information from different sources and through different circuits. The strength of supporting evidence appears to be solid, showing that temporal modulations are combined differently than spatial modulations, with additional differences between subcortical and cortical pathways. However, the manuscript's clarity could be improved, including by adding more convincing motivations for the approaches used.

eLife assessment

This study offers new fundamental information on a role for the sodium/potassium pump in sleep regulation. Elegant methods were used to provide compelling evidence supporting the claim. The work will be of interest to sleep researchers in zebrafish as well as in other species.

eLife assessment

Yang et al. investigate whether distinct sources of conflict are represented in a common cognitive space. The study uses an interesting task that mixes two different sources of difficulty and reports that the brain appears to represent these sources as a mixture on a continuum, in the prefrontal areas involved in resolving task difficulty. While these results are useful, they overlap with previous findings, leave open several design and logical concerns, and rely on novel statistical analyses that may require further validation, so they are currently incomplete.

eLife assessment

This is an important study demonstrating that vitamin D-bound VDR both increases SIRT1 expression and directly interacts with SIRT1 to cause auto-deacetylation on Lys610, thereby regulating activation of SIRT1 catalytic activity. The data presented to support the presented conclusions are convincing, and the findings are particularly relevant to the actions of VDR on colorectal cancer.

eLife assessment

This study presents valuable findings on a potential positive feedback loop between ZEB2 and ACSL4 that regulates lipid metabolism and breast cancer metastasis. The evidence supporting the claims of the authors is solid, but more appropriate validation for ACSL4 interacting with ZEB2 would have strengthened the study. The work will be of particular interest to colleagues working on breast cancer.

eLife assessment

This important study uses calcium imaging in mice to advance our understanding of the effect of antipsychotic drugs on neural functioning. The evidence supporting the conclusions is solid, although the statistical testing of the data may be improved. This work will be of interest to neuroscientists working on visual processing and psychosis researchers.

eLife assessment

This study will be of interest and valuable to scientists of many different subareas in the study of eukaryotic extracellular vesicles. The authors' efforts to improve the way we analyze EVs are highly appreciated and their results are convincing: they not only used appropriate and validated methodologies in line with current state-of-the-art but also presented alternatives to improve these approaches.

eLife assessment

This valuable study reports a complete in vitro system where different steps and direct interactions between different components of MHCI maturation can be monitored, hence leading to a better mechanistic understanding of MHC I maturation. The evidence supporting the findings is currently incomplete and would benefit from clarification of some key issues. This work will be of interest to immunologists and biochemists.

Globin Gene Switching is a process of sequential activation and inactivation of globin genes during development. Here's how it works:

1. Transcription factors along with epigenetic elements such as DNA methyltransferases and demethylases interact with enhancers "upstream" of the β-globin gene cluster that contact globin gene promoters.
2. This process silences the embryonic and fetal genes.
3. Activation of fetal globin gene repressors during development allows expression of the adult genes.
4. Developmental factors such as RNA-binding factors and microRNAs also impact hemoglobin switching.

β-Globin Gene Switching:

1. An upstream super-enhancer called the β-globin locus control region (LCR) binds erythroid-specific and ubiquitous transcription factors.
2. The LCR interacts directly with globin gene promoters.
3. Transcription factors that silence and activate genes also interact with elements of the globin genes.
4. Competition among the β-like genes for the LCR and autonomous silencing of the embryonic and fetal globin genes depends on transcription factors.
5. Silencing, first of HBE and then of HBG2 and HBG1, favors the interaction of the LCR with HBB.
6. When HBG2 or HBG1 is upregulated by rare point mutations in their promoters, expression of the linked HBB is downregulated.
7. Deletions of the HBB promoter remove competition for the LCR, increasing the expression of HBG2, HBG1, and HBD.
8. The transcription factors BCL11A and ZBTB7A silence the HbF genes.
9. BCL11A binds to the HbF gene promoters, repressing them and silencing transcription; ZBTB7A binds upstream of BCL11A with similar repressive effects.
10. Mutations in these binding sites abolish the normal silencing of the HbF genes, leading to hereditary persistence of fetal hemoglobin (HPFH).
11. Disruption of the BCL11A regulatory elements or the binding sites for BCL11A by gene editing is a prime therapeutic target for HbF induction.

α-Globin Gene Switching:

1. A less complex switch takes place in the α-globin gene cluster.
2. A regulatory locus of four elements termed R1-R4 is present within introns of the gene NPRL3 that is upstream of HBA2.
3. A developmental switch from embryonic ζ- to adult α-globin gene expression occurs at about 6 weeks’ gestation.

Modulation of HbF Level:

1. Variations in three quantitative trait loci (QTL), BCL11A, MYB, and a locus linked to the HBB cluster, account for a major portion of HbF variation among normal individuals and patients with sickle cell anemia and β thalassemia.
2. BCL11A, a zinc finger protein that represses HbF genes, binds TGACCA motifs, the most important at position –115 in the promoter of each γ-globin gene.
3. ZBTB7A binds 85 nucleotides upstream of these BCL11A binding sites; its binding also represses γ-globin gene transcription.
4. When binding of either BCL11A or ZBTB7A is disrupted, silencing of HBG2 and HBG1 is abrogated.
5. The MYB gene is essential for hematopoiesis and erythroid differentiation.
6. MYB inhibits HbF expression directly by activation of KLF1 and other repressors and indirectly through alteration

Here are the major points summarizing the text on globin gene clusters and hemoglobin:

Globin Gene Clusters:

• Globin is encoded in two nonallelic gene clusters: β-globin gene cluster on chromosome 11 and α-globin gene cluster on chromosome 16.
• The β-globin gene cluster contains an embryonic ε-globin gene, two fetal γ-globin genes, a major adult β-globin gene, and a minor adult δ-globin gene.
• The α-globin gene cluster contains an embryonic ζ-globin gene and duplicated α-globin genes with identical proteins.
• Hemoglobin production begins with embryonic hemoglobins: Gower I, Gower II, Portland I, and Portland II.
• Fetal hemoglobin (HbF) production starts at 6-8 weeks of gestation, peaks during mid-gestation, and falls to <1% of total hemoglobin during the first 6 months of extrauterine life.
• Adult hemoglobin A (HbA) production follows a pattern reciprocal to that of HbF.
• Hemoglobin composition of normal adults is >95% HbA, ~1% HbF, and 2-3% HbA2.
• Hemoglobin is subject to posttranslational modifications, the most important being the nonenzymatic glycosylation of HbA forming the adduct HbA1c.

Hemoglobin Structure:

• All globin polypeptides have similar but not identical primary structures. α-Globins contain 141 amino acids, and β-like globins have 146 amino acids.
• The primary structure dictates the secondary structure of globin into α-helical sections joined by small nonhelical stretches.
• Each globin chain folds into a tertiary conformation known as the globin fold, where charged amino acid residues face the exterior of the molecules and uncharged residues face the hydrophobic interior.
• The iron-containing tetrapyrrole heme moiety is protected from oxidation and located between two of the helical segments; O2 loading and unloading occur when heme iron is in its reduced ferrous form.
• Globin gene mutations affecting critical heme-binding amino acid residues allow iron to be oxidized, forming methemoglobin, which has high O2 affinity and does not release O2 in tissues.
• Dimers of α- and non-α-globin chains reversibly assemble into tetramers, forming a quaternary structure.

Hemoglobin Function:

• Hemoglobin transports O2 from lungs to tissues and carbon dioxide (CO2) from tissues to lungs.
• Hemoglobin is a nitrate reductase that releases nitric oxide (NO) from nitrite to promote vasodilation.
• Oxygen binding is defined by the sigmoidal shape of the hemoglobin-O2 dissociation curve.
• The P50 is a point on this curve that indicates the partial pressure of O2 where hemoglobin is half saturated.
• The P50 is influenced by the binding of 2,3-bisphosphoglycerate, pH, and temperature.
• The conformation of hemoglobin fully saturated with O2 is known as the R or relaxed state; desaturated hemoglobin is in the T or tense state.
• Hemoglobin variants that decrease P50 are characterized by isolated erythrocytosis as compensation for hypoxia.
• Variants with increased P50 sometimes are accompanied by cyanosis and anemia as hemoglobin becomes unsaturated and O2 delivery is enhanced.
• Mutations of residues critical for heme binding, R-T transitions, or tetramer stability cause hemoglobinopathies characterized by hemolytic anemia

eLife assessment

This work aims to discover the mechanisms governing the switch between conventional DNA replication and telomeric end-replication that requires a specialized mechanism. Genetic and biochemical assays for protein modifications and interactions suggest an interplay between sumoylated PCNA and chromosome terminal capping proteins. The results address an important question that would have implications for several fields interested in genome stability questions. However, several claims, even some that form the basis of the proposed molecular models, are incompletely supported by the data.

eLife assessment

This study presents convincing evidence of the correlation between social tolerance and communicative complexity in a comparison of three macaque species. Notably, the authors use an innovative, detailed methodology for quantifying facial expressions during social interactions that provides a valuable framework for future comparative research in animal communication. These findings would be further strengthened with some conceptual clarity regarding the basis of the hypotheses being tested and the addition of an interobserver reliability test.

eLife assessment

This study provides valuable information on the biogenesis of eccDNAs during spermatogenesis, i.e., eccDNAs in spermatogenic cells are not derived from miotic recombination hotspots but represent oligonucleosomal DNA fragments from apoptotic male germ cells, whose ends are ligated through microhomology-mediated end-joining. The study is currently incomplete because the method of bioinformatics needs more details and data interpretation should take the amplification bias into consideration.

Sure, here's a summary of the causes of secretory diarrhea presented in the text:

Causes of secretory diarrhea:

1. Medications: Regular ingestion of drugs and toxins, including prescription and over-the-counter medications, may produce diarrhea. Stimulant laxatives and chronic ethanol consumption may also cause secretory-type diarrhea.

2. Bowel resection, mucosal disease, or enterocolic fistula: These conditions may result in secretory-type diarrhea because of inadequate surface for reabsorption of secreted fluids and electrolytes.

3. Partial bowel obstruction, ostomy stricture, or fecal impaction: These may paradoxically lead to increased fecal output due to fluid hypersecretion.

4. Hormones: Secretory diarrhea may be caused by hormones, including those released by metastatic gastrointestinal carcinoid tumors, gastrinomas, VIPomas, medullary carcinoma of the thyroid, and systemic mastocytosis.

5. Bacterial infections: Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea.

6. Environmental toxins: Inadvertent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute forms of diarrhea.

7. Idiopathic bile acid malabsorption (BAM): Reduced negative feedback regulation of bile acid synthesis in hepatocytes by fibroblast growth factor 19 (FGF-19) produced by ileal enterocytes results in a degree of bile-acid synthesis that exceeds the normal capacity for ileal reabsorption, producing BAD. An alternative cause of BAD is a genetic variation in the receptor proteins (β-klotho and fibroblast growth factor 4) on the hepatocyte that normally mediate the effect of FGF-19.

8. Colonic transit: Genetic variation in the bile acid receptor (TGR5) in the colon may result in accelerated colonic transit.

It's worth noting that some of these causes may overlap or occur in conjunction with each other.

Points:

The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool.

Workup includes cultures for bacterial and viral pathogens; direct inspection for ova and parasites; and immunoassays for certain bacterial toxins (C. difficile), viral antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica).

Clinical and epidemiologic associations may assist in focusing the evaluation.

If a particular pathogen or set of possible pathogens is implicated, either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate.

Molecular diagnosis of pathogens in stool can be made by identification of unique DNA sequences, and evolving microarray technologies have led to more rapid, sensitive, specific, and cost-effective diagnosis.

Persistent diarrhea is commonly due to Giardia, but additional causative organisms that should be considered include C. difficile, E. histolytica, Cryptosporidium, Campylobacter, and others.

Flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated if stool studies are unrevealing.

Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomography (CT) scanning may be appropriate in patients with uncharacterized persistent diarrhea to exclude IBD or as an initial approach in patients with suspected noninfectious acute diarrhea.

Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea.

Oral sugar-electrolyte solutions (iso-osmolar sport drinks or designed formulations) should be instituted promptly with severe diarrhea to limit dehydration, which is the major cause of death.

Profoundly dehydrated patients, especially infants and the elderly, require IV rehydration.

In moderately severe nonfebrile and nonbloody diarrhea, antimotility and antisecretory agents such as loperamide can be useful adjuncts to control symptoms.

Such agents should be avoided with febrile dysentery, which may be prolonged by them, and should be used with caution with drugs that increase levels due to cardiotoxicity.

Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients or those with renal impairment because of the risk of bismuth encephalopathy.

Judicious use of antibiotics is appropriate in selected instances of acute diarrhea and may reduce its severity and duration.

Many physicians treat moderately to severely ill patients with febrile dysentery empirically without diagnostic evaluation using a quinolone, such as ciprofloxacin (500 mg bid for 3–5 d).

Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d).

Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens, geographic patterns of resistance, and conditions found.

Newer agents such as nitazoxanide may be required for Giardia and Cryptosporidium infections because of resistance to first-line treatments.

Antibiotic coverage is indicated, whether or not a causative organism is discovered, in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly.

Bismuth subsalicylate may reduce the frequency of traveler’s diarrhea.

Antibiotic prophylaxis is only indicated for certain patients traveling to high-risk countries in whom the likelihood or seriousness of acquired diarrhea would be especially high.

Use of ciprofloxacin, azithromycin, or rifaximin may reduce bacterial diarrhea in such travelers by 90%, though rifaximin is not suitable for invasive disease but rather as treatment for uncomplicated traveler’s

Sure, here are some additional sub points for each category of infectious agents:

1. Travelers:
2. Enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC)
3. Campylobacter
4. Shigella
5. Aeromonas
6. Norovirus
7. Coronavirus
8. Salmonella

9. Vibrio cholerae

10. Consumers of certain foods:

11. Salmonella (from chicken, eggs)
12. Campylobacter (from undercooked hamburger)
13. Shigella (from undercooked pork)
14. Enterohemorrhagic E. coli (EHEC) O157:H7 (from undercooked hamburger)
15. Bacillus cereus (from fried rice or other reheated food)
16. Staphylococcus aureus (from mayonnaise or creams)
17. Listeria monocytogenes (from fresh or frozen uncooked foods, mushrooms, or dairy products)

18. Vibrio species (from seafood, especially if raw)

19. Immunodeficient persons:

20. Mycobacterium species
21. Cytomegalovirus
22. Adenovirus
23. Herpes simplex virus
24. Cryptosporidium
25. Isospora belli
26. Microsporidia
27. Blastocystis hominis
28. Neisseria gonorrhoeae
29. Treponema pallidum

30. Chlamydia

31. Daycare attendees and their family members:

32. Shigella
33. Giardia
34. Cryptosporidium
35. Rotavirus
36. Adenovirus

37. Norovirus

38. Institutionalized persons:

39. Clostridioides difficile (C. difficile)
40. Norovirus
41. Rotavirus
42. Adenovirus
43. Salmonella
44. Shigella
45. Campylobacter
46. Vibrio cholerae

Additionally, some infectious agents may cause specific clinical features: - Small-bowel hypersecretion: preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens (resulting in profuse, watery diarrhea) - Marked vomiting and minimal or no fever: preformed bacterial toxins and enterotoxin-producing bacteria - Abdominal cramping or bloating, higher fever: enteroadherent pathogens - High fever and abdominal pain: cytotoxin-producing and invasive microorganisms - Bloody diarrhea (dysentery): invasive bacteria and Entamoeba histolytica - Severe abdominal pain with tenderness mimicking acute appendicitis: Yersinia invades the terminal ileal and proximal colon mucosa

Here's a simplified list of causes of different types of gastrointestinal symptoms:

1. Heartburn: Opportunistic fungal or viral esophageal infections, GERD, hiatal hernia, peptic ulcer disease, and gastritis.

2. Odynophagia (painful swallowing): Opportunistic fungal or viral esophageal infections.

3. Upper abdominal pain: Biliary colic, pancreatic disease (chronic pancreatitis, malignancy), hepatocellular carcinoma, Ménétrier’s disease, infiltrative diseases (sarcoidosis, mastocytosis, eosinophilic gastroenteritis), mesenteric ischemia, thyroid and parathyroid disease, and abdominal wall strain.

4. Nausea and vomiting: Gastroparesis, viral or bacterial gastroenteritis, chemotherapy-induced nausea and vomiting, motion sickness, and vestibular disorders.

5. Gas, bloating, and discomfort: Intestinal lactase deficiency, intolerance of other carbohydrates (e.g., fructose, sorbitol), and small-intestinal bacterial overgrowth.

6. Dyspepsia (indigestion): Peptic ulcer disease, gastritis, GERD, celiac disease, nonceliac gluten sensitivity, pancreatic disease (chronic pancreatitis, malignancy), hepatocellular carcinoma, Ménétrier’s disease, infiltrative diseases (sarcoidosis, mastocytosis, eosinophilic gastroenteritis), mesenteric ischemia, thyroid and parathyroid disease, and abdominal wall strain.

7. Other causes of indigestion: Congestive heart failure and tuberculosis.

Sure, here are some variants and examples of the conditions mentioned in the text:

Intraperitoneal Disorders: - Ulcers: peptic ulcers, stress ulcers - Malignancy: stomach cancer, colon cancer - Benign or malignant tumors: intestinal tumors, colon polyps - Inflammatory diseases: Crohn's disease, ulcerative colitis - Superior mesenteric artery syndrome: Wilkie's syndrome - Median arcuate ligament syndrome: Dunbar syndrome - Biliary colic: gallstones, cholecystitis - Enteric infectious causes: norovirus gastroenteritis, bacterial food poisoning (e.g. Staphylococcus aureus, Bacillus cereus), cytomegalovirus enteritis

Gut sensorimotor dysfunction: - Gastroparesis: diabetic gastroparesis, idiopathic gastroparesis, postsurgical gastroparesis - Intestinal pseudoobstruction: Ogilvie's syndrome, chronic idiopathic intestinal pseudoobstruction, secondary pseudoobstruction (e.g. from scleroderma, amyloidosis, small-cell lung carcinoma) - Gastroesophageal reflux: GERD - Irritable bowel syndrome: IBS - Chronic constipation: functional constipation, slow-transit constipation

Other functional gastroduodenal disorders: - Chronic nausea vomiting syndrome: functional nausea vomiting disorder - Cyclic vomiting syndrome: CVS - Cannabinoid hyperemesis syndrome: CHS - Rumination syndrome: regurgitation disorder

Extraperitoneal Disorders: - Myocardial infarction: heart attack - Congestive heart failure: CHF - Postoperative emesis: postoperative nausea and vomiting (PONV) - Increased intracranial pressure: intracranial hypertension, pseudotumor cerebri - Anorexia nervosa: restrictive eating disorder - Bulimia nervosa: binge-eating disorder

Medications and Metabolic Disorders: - Analgesics: opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) - Antibiotics: macrolides, fluoroquinolones, tetracyclines - Cardiac antiarrhythmics: amiodarone - Antihypertensives: calcium channel blockers, ACE inhibitors, beta blockers - Oral hypoglycemics: sulfonylureas, meglitinides - Antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) - Smoking cessation drugs: varenicline, nicotine replacement therapy (NRT) - Contraceptives: combined oral contraceptives (COCs), progestin-only contraceptives (POCs) - Cancer chemotherapy: cisplatin, carboplatin, paclitaxel, docetaxel, doxorubicin - Metabolic disorders: pregnancy (nausea of pregnancy, hyperemesis gravidarum), uremia, diabetic ketoacidosis, Addison's disease, hypoparathyroidism, hyperthyroidism, hypothyroidism - Circulating toxins: fulminant liver failure, enteric bacterial infections (e.g. Salmonella, Shigella, Escherichia coli), ethanol intoxication.

Start | |---Brainstem nuclei (including the nucleus tractus solitarius; dorsal vagal and phrenic nuclei; medullary nuclei regulating respiration; and nuclei that control pharyngeal, facial, and tongue movements) | |---Coordinate initiation of emesis | |---Neurokinin NK1 pathway | |---Serotonin 5-HT3 pathway | |---Endocannabinoid pathway | |---Vasopressin pathway | |---Activators of emesis | |---Emetic stimuli act at several sites | | | |---Unpleasant thoughts or smells (brain) | | | |---Motion sickness and inner ear disorders (labyrinthine pathways) | | | |---Gastric irritants and cytotoxic agents (gastroduodenal vagal afferent nerves) | | | |---Nongastric afferents (bowel obstruction and mesenteric ischemia) | | | |---Bloodborne stimuli (area postrema) | |---Neurotransmitters mediating vomiting are selective for different sites | |---Vestibular muscarinic M1 and histaminergic H1 receptors (labyrinthine disorders) | |---5-HT3 receptors (vagal afferent stimuli) | |---5-HT3, M1, H1, and dopamine D2 subtypes (area postrema) | |---NK1 receptors in the CNS (nausea and vomiting) | |---Cannabinoid CB1 pathways (cerebral cortex and brainstem) | |---Somatic and visceral muscles respond stereotypically during emesis | |---Inspiratory thoracic and abdominal wall muscles contract | |---Distally migrating gut contractions are abolished | |---Orally propagating spikes evoke retrograde contractions to facilitate expulsion of gut contents | |---Therapies for vomiting act on receptor-mediated pathways End

• Nausea: the sensation or feeling of an urge to vomit.
• Vomiting (emesis): the act of expelling the contents of the stomach through the mouth due to the contraction of the gastrointestinal and thoracoabdominal muscles.
• Regurgitation: the effortless movement of food or liquid from the stomach back into the mouth without the forceful contractions seen in vomiting.
• Rumination: the repeated regurgitation of food residue, which may be rechewed and reswallowed voluntarily.
• Indigestion: a collection of symptoms that includes nausea, vomiting, heartburn, regurgitation, and dyspepsia. Dyspepsia is a group of symptoms that originate in the gastroduodenal region and include postprandial fullness, early satiety, bloating, eructation, and anorexia. Epigastric burning or pain may also be present.
• Avoidant/restrictive food intake disorder: a condition in which individuals have difficulty consuming certain types of food or food in general, leading to weight loss or nutritional deficiencies. Nausea, vomiting, and dyspepsia have been associated with this disorder.

summary Oropharyngeal Dysphagia: - Poor bolus formation and control, drooling, and difficulty initiating swallowing are characteristic signs. - May result in premature spillage of food into the hypopharynx, aspiration into the trachea, or regurgitation into the nasal cavity. - Causes include neurologic, muscular, structural, iatrogenic, infectious, and metabolic factors, with iatrogenic, neurologic, and structural pathologies being the most common. - Iatrogenic causes include head and neck cancer treatments such as surgery and radiation. - Neurogenic dysphagia resulting from cerebrovascular accidents, Parkinson’s disease, and amyotrophic lateral sclerosis is a major cause of morbidity related to aspiration and malnutrition. - Asymmetry in the cortical representation of the pharynx provides an explanation for the dysphagia that occurs as a consequence of unilateral cortical cerebrovascular accidents. - Structural lesions causing dysphagia include Zenker’s diverticulum, cricopharyngeal bar, and neoplasia. - Rapid-sequence fluoroscopy is necessary to evaluate for functional abnormalities. - Adequate fluoroscopic examination requires that the patient be conscious and cooperative. - Timing and integrity of pharyngeal contraction and opening of the UES with a swallow are analyzed to assess both aspiration risk and the potential for swallow therapy. - Structural abnormalities of the oropharynx should be assessed by direct laryngoscopic examination.

Esophageal Dysphagia: - The adult esophagus measures 18-26 cm in length and is anatomically divided into the cervical esophagus and the thoracic esophagus. - Solid food dysphagia becomes common when the lumen is narrowed to <13 mm. - The most common structural causes of dysphagia are Schatzki’s rings, eosinophilic esophagitis, and peptic strictures. - Propulsive disorders leading to esophageal dysphagia result from abnormalities of peristalsis and/or deglutitive inhibition, potentially affecting the cervical or thoracic esophagus. - Rapid-sequence fluoroscopy is necessary to evaluate for functional abnormalities. - Adequate fluoroscopic examination requires that the patient be conscious and cooperative. - High-resolution manometry is used to measure pressure changes along the length of the esophagus during swallowing. - Structural abnormalities of the esophagus should be assessed by endoscopic examination.

Here's a table summarizing the information:

| Category | Oropharyngeal Dysphagia | Esophageal Dysphagia | | --- | --- | --- | | Signs and Symptoms | Poor bolus formation and control, drooling, difficulty initiating swallowing | Solid food dysphagia, potentially accompanied by altered esophageal sensation, reduced distensibility, or motor dysfunction | | Causes | Neurologic, muscular, structural, iatrogenic, infectious, metabolic | Structural causes include Schatzki’s rings, eosinophilic esophagitis, and peptic strictures; propulsive disorders due to abnormalities of peristalsis and/or deglutitive inhibition | | Iatrogenic Causes | Head and neck cancer treatments such as surgery and radiation | N/A | | Diagnosis | Rapid-sequence fluoroscopy, direct laryngoscopic examination | Rapid-sequence fluoroscopy, high-resolution manometry, endoscopic examination |

1. Iron is transported in the blood by the iron-transferrin complex.
2. The complex interacts with specific transferrin receptors on the surface of cells that express transferrin receptors, such as developing erythroblast cells.
3. The iron-bearing transferrin is internalized via clathrin-coated pits and transported to an acidic endosome.
4. Iron is released from the transferrin at the low pH of the endosome.
5. Iron is made available for heme synthesis.
6. The transferrin-receptor complex is recycled to the surface of the cell.
7. The bulk of the transferrin is released back into circulation, and the transferrin receptor re-anchors into the cell membrane.
8. Iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin.
9. Senescent red cells are recognized by the cells of the reticuloendothelial system and undergo phagocytosis.
10. Hemoglobin is broken down, and the iron is shuttled back to the surface of the RE cell.
11. Iron is presented to circulating transferrin via the iron export channel, ferroportin.
12. Iron is then available for reutilization for hemoglobin synthesis

eLife assessment

This work explores how centrosomes, which function as the primary microtubule organizing center in animal cells, regulate cell division by examining the process in cells in which centrosome formation has been inhibited. The carefully conducted experiments provide convincing support for the important observation that elongated, but successful, mitosis observed in cells lacking centrosomes is due to delays in cell cycle progression, though the reviewers highlight some caveats that merit further discussion.

eLife assessment

This important work provides evidence that artificial recurrent neural networks can be used to investigate neural mechanisms underlying reversible remapping of spatial representations. Authors perform convincing state of the art analyses showing how population activity preserves the encoding of spatial position despite remappings due to the tracking of an internal variable. This paper will be of interest to neuroscientists studying contextual computations, neural representation of space and links between artificial neural networks and the brain.

eLife assessment

This behavioral modeling study investigates how humans make decisions on the difficulty of perceptual categorization tasks. The study finds that such judgments are best described by an evidence-accumulation model that includes a dynamic comparison of difficulty-related evidence, which terminates when the difference in evidence between two tasks reaches a predetermined bound - a valuable finding for research in perceptual decision-making. The paper provides solid behavioral evidence for the proposed model, but reviewers noted some potential improvements in the model selection procedure and the relation of the optimal model of the task to the human data, and to the best-fitting model.

eLife assessment

This paper presents an important finding that Styxl2, a poorly characterized pseudo-phosphatase, plays a role in the sarcomere assembly by promoting autophagic degradation of non-muscle myosins. The evidence supporting the conclusions is convincing. This work will be of interest to biologists working on muscle development, cell biology, and proteolysis.

eLife assessment

This valuable work fills a gap in the mapping of gene expression patterns in the early embryo of C. elegans. The presented data are solid and provides a resource for future analysis. The manuscript can still be improved in order to strengthen some of the conclusions made.

eLife assessment

In this important study, the authors provide convincing evidence that current DNA-based microbial genomics for skin bacteria cannot always detect the source of sequenced DNA and whether it originated from viable or non-viable bacteria. Additionally, the authors demonstrated in humans and mice that most of the viable bacteria reside inside hair follicles rather than the surface of the skin per se. Overall, the work has significance beyond a single discipline and will be of interest to those studying microbiomes.

eLife assessment

This important study provides exciting first-time evidence linking palmitate-induced insulin resistance to ceramide accumulation within the mitochondrial compartment and subsequent depletion of CoQ, an essential component of mitochondrial respiration. Whereas the results and interpretations are generally solid, the mechanistic aspect of the work and conclusions put forth rely heavily on in vitro studies performed in cultured L6 myocytes, which are highly glycolytic and generally not viewed as a good model for studying muscle metabolism and insulin action. Nonetheless, the findings offer intriguing new insights into mechanisms that connect ceramides to both insulin resistance and mitochondrial dysfunction, and are likely to open new avenues of preclinical/clinical research with broad therapeutic implications.

eLife assessment

The authors provide a new powerful tool as well as a large database that should be useful to the neuroscience community, but not only. The authors developed and applied a methodology to automatically estimate the volume, cell number, and density of mice brains from multiple regions, by detecting the native fluorescence of the cell nuclei. Using this platform, they analyzed an existing dataset containing multiple mouse brains, available in the Allen Mouse Connectivity project. The data provides a comprehensive neuroanatomical comparison of brain nuclei between males and females, between hemispheres, and between 2 strains of lab mice.

eLife assessment

In its current form, the reviewers felt that the work describing the use of a CycleGAN for alignment of neural activity from a neural interface across sessions was useful, with solid evidence showing that it improved performance over similar-concept previous approaches.

eLife assessment

This is an interesting and valuable study describing the importance of a focal adhesion protein vinculin in osteocytes in controlling bone formation by regulating the expression of sclerostin, which inhibits bone formation. The data are generally convincing and support the conclusions. Some additional investigation and discussions are required to further strengthen the conclusion and interpretation.

eLife assessment

Small subthreshold dendritic-somatic depolarizations can propagate to presynaptic nerve endings and may modulate transmitter release, but the mechanisms of this modulation remain poorly understood because the technical challenge of recording from small bouton synapse. Here the authors directly record from small cerebellar bouton terminals In paired somatic and presynaptic recordings, they demonstrate that small synaptic potentials can travel within 2 to 3 ms to the bouton and arrive there with an amplitude attenuated by 20 to 70% with respect to the somatically recorded potential. As expected, this amplitude attenuation depends on axon length. In recordings of MLI-Purkinje cell pairs the authors further demonstrate that small somatic subthreshold depolarizations of about 20 mV size can enhance AP-triggered IPSCs recorded in the Purkinje cells and change synaptic plasticity during AP trains. In order to address mechanisms of such presynaptic modulation, the authors measure presynaptic AP waveforms via cell attached recordings and found these very stable. On the other hand, presynaptic ICa(V) directly recorded in voltage-clamped MLI boutons facilitated in response to small pre-depolarizations and such facilitated ICa(V) produced larger IPSCs in paired recordings of MLI boutons and coupled Purkinje cells. The authors propose that an accumulation of partially gated channels during small presynaptic depolarizations is able to produce more rapid gating of VGCCs during the AP waveform on arrival of an invading presynaptic AP.

eLife assessment

The phenomenon of summit disease, where complex animal behaviours are controlled by single-celled parasites, captivates biologists and non-scientists alike. In this valuable study, the authors use a laboratory model (Drosophila melanogaster infected with Entomophthora muscae) for this disease to provide compelling evidence for the neuroanatomical and physiological underpinnings of summit disease. This is an excellent example of how seemingly intractable questions in behavioural ecology can be effectively addressed in laboratory settings using decades of work in creating 'models' for biology.

eLife assessment

This is an important report on the discovery of a strong sensitizing effect of cannabidiol on the activation of TRPV2 channels by 2-APB. The conclusions are convincingly supported by solid electrophysiological recordings and cryo-EM structures, but identification of a clear molecular mechanism will require additional structural work. The paper will be of interest to the ion channel research community.

eLife assessment

This valuable paper uses a cohort of SARS-CoV-2 infected people to link immune signatures 3 months post-infection with persistent, long COVID-19 symptoms. The strength of the evidence presented is solid based on a wide array of immunologic assays and a strategically designed cohort, with some claims that are incomplete based on a lack of specifically designed endpoints, lack of analysis of regulatory signals, and incomplete use of control samples. A couple of findings are novel and will be of interest to clinicians and immunologists, particularly that degree of inflammation at 3 months does not impair the generation of SARS-CoV-2 humoral and cellular memory responses and that cellular immune signatures are only somewhat correlated with long COVID-19 symptoms.

eLife assessment

Protein abundance is the result of many layers of regulation, including at the levels of transcription, mRNA stability, translation and protein degradation. Many transcripts contain short upstream ORFs (uORFS), but their effects on the translation of the main ORFs are difficult to predict as they are sometimes negative, positive and of different magnitudes. Here, the authors identify features of uORFs using massively parallel reporter assays, and these features help predict uORF effects on translation of main ORFs. The results will be an important resource for the community of researchers using this model organism and for the molecular and cell biology community in general as they allow to better understand how genes are regulated. There are also areas in which the authors' claims or conclusions are not fully justified and require either additional statistical analysis or new experimentation.

eLife assessment

This important study was designed to examine the bypass of Ras/Erk signaling defects that enable limited regeneration in a mouse model of hepatic regeneration. This hepatocyte proliferation is associated with the expression by groups of cells of mRNA-loaded CD133+ intracellular vesicles that mediate an intercellular signaling pathway that supports proliferation. These are new observations, supported by convincing data, that have broad significance to the fields of regeneration and cancer.

eLife assessment

This valuable study presents a novel and theoretically interesting model to account for viral diversity within hosts in evolutionary and genomic analyses of pathogens. The simulation results presented are solid, although there are some aspects of the methodology that require further investigation in order to establish their validity. The application to SARS-CoV-2 shows promise, but would benefit from further evaluation.

eLife assessment

This study presents the important finding that gene editing could be used to activate delta-globin expression to treat disorders of red blood cell synthesis. The evidence supporting the claims of the authors is solid, particularly in the immortalized cell lines, although inclusion of a larger number of donor patient samples may have strengthened the conclusions that were able to be drawn from the primary cell experiments. The data show this approach to have promise and identify avenues of effort that could be pursued to advance it to a clinical strategy for hemoglobinopathy treatment.

eLife assessment

Early life stress can have profound effects on animal behavior, including potential influences on individuality. In this valuable work, the authors use a rich new dataset to solidly demonstrate that the behavioral consequences of early life stress in C. elegans can be buffered by neuromodulators previously implicated in patterns of individuality. While much remains to be learned about the mechanisms by which stress might influence individuality, these studies provide an important entry point that will be of interest to neurobiologists studying interactions between behavior, neuromodulation, stress, and individuality.

eLife Assessment:

In addition to identifying several components regulated by checkpoint kinases, the authors identify a novel non-canonical activation mode for the central checkpoint kinase Rad53, a phosphorylation event that does not depend on Mec1 and instead depends on proteins involved in retrograde signaling through Rtg3. The study thus reveals unanticipated complexities in the DNA replication stress response. Overall, the work is well done and the data support the main conclusions.

eLife assessment

Reao et al. investigate a question that has long puzzled neuroscientists: what features of ongoing brain activity predict trial-to-trial variability in responding to the same sensory stimuli? The data demonstrate that the outcome of the previous trial, specifically a miss, allows these associations to be seen - while a correct response appears less likely to do so. and this is a valuable advance in our understanding of the relationship between brain state, behavioral state, and performance. Technically, the study is solid, ie, the methods, data and analyses broadly support the claims, with some weaknesses remaining.

This entire comment is gold

eLife assessment

The important study by Barreat and Katzourakis examines the evolutionary history of eukaryotic viruses (and related mobile elements) in the Bamfordvirae kingdom, and evaluates potential alternative scenarios regarding the origin of different lineages in this highly diverse kingdom. Through convincing phylogenetic analyses, the authors propose a new evolutionary model for the origin of this kingdom where their last common ancestor is inferred to have been an exogenous, non-virophage DNA virus with a small genome. This work advances our understanding of the deep evolutionary history of viruses, the interaction between viruses and the first eukaryotes, and the diversification of viral lineages.

eLife assessment

ZMYM2 is a transcriptional corepressor but little was known about how it is recruited to chromatin. This study reveals that ZMYM2 homes to distinct classes of retrotransposons bound by the TRIM28 and ChAHP complexes in human cells, an important finding in the field of transcriptional regulation. The evidence supporting the claims of the authors is solid, although inclusion of more functional data would have strengthened the original model proposed.

eLife assessment

This study represents a valuable mechanistic contribution towards understanding how ribosomal RNA is processed during ribosome biogenesis. The biochemical evidence supporting the major conclusions is solid, but the structural biology data is incomplete and would benefit from more rigorous analysis. After further strengthening, this work would be of interest to cell biologists and biochemists working on ribosome biogenesis.

eLife assessment

Caveney et al. overexpressed an engineered construct of the human membrane receptor guanyl cyclase GC-C in Hamster cells, co-purified it with endogenous HSP90 and CDC37 proteins and determined the cryo-EM structure of this complex. This important work shows that the pseudo-kinase domain of GC-C associates with CDC37 and HSP90 similarly to how the bona fide protein kinases CDK4, CRAF and BRAF have been shown to interact. The methodology used is state of the art and the evidence presented is convincing.

eLife assessment

This valuable study links natural variation in a steroidal glycoalkaloid to disease and insect resistance in potato species. The study design is straightforward and thorough, and the evidence supporting the main conclusions is solid; however, other relevant studies are not discussed with enough context. The work will be of interest to plant biologists and breeders.

eLife assessment

In this important study, the authors provide compelling evidence that the interplay between alternative polyadenylation (APA) of mRNA encoding Aurora Kinase A (AURKA) and hsa-let-7a miRNA governs AURKA protein levels. The authors show that short 3'UTR isoform of mRNA encoding AURKA is efficiently translated throughout the cell cycle, while the long 3'UTR isoform is suppressed by hsa-let-7a miRNA in a cell cycle-dependent manner. These findings delineate post-transcriptional mechanisms regulating AURKA expression that may be implicated in increase in AURKA protein that is frequently observed across a variety of cancers.

eLife assessment

This valuable paper sheds new light on the growth trajectory of bonobos (Pan paniscus), with explicit contributions to discussions of the exclusivity of certain aspects of growth in modern humans, most specifically with respect to components of the adolescent growth spurt, which may be less human-specific among primates than presumed to this point. The results are solid, based on the largest sample ever considered in the study of bonobo growth and include both morphometric and endocrinological data. This work will be of interest to human evolutionary biologists, primatologists, and researchers studying the ontogeny and evolution of growth and development in general.

eLife assessment

This study reports useful information on the limits of the organotypic culture of neonatal mouse testes, which has been regarded as an experimental strategy that can be extended to humans in the clinical setting for the conservation and subsequent re-use of testicular tissue. The evidence that the culture of testicular fragments of 6.5-day-old mouse testes does not allow optimal differentiation of steroidogenic cells is compelling and would be useful to the scientific community in the field for further optimizations.

eLife assessment

This important study functionally characterizes hemoglobin from Steller's sea cow, a cold-water adapted sirenian that went extinct ~250 years ago. Using ancestral sequence reconstruction, site-directed mutagenesis and biochemical assays to compare Steller's hemoglobin to those from (sub)tropical extant sea cows (all of which are proficient divers despite lacking massive muscle oxygen storage), the authors build a solid case for the molecular basis of cold adaptation, centered around an increased solubility and higher oxygen carrying capacity. Remarkably, a single amino acid replacement would explain most of the distinctive functional features of this hemoglobin, which include a hitherto unknown resistance to DPG. Overall, this work will be of interest to evolutionary biologists, physiologists, and biochemists, as well as an enjoyable and informative read for the general public.

eLife assessment

This important study identifies more than 1500 genes that are differentially transcribed over the cell cycle of the single-celled eukaryotic pathogen, Trypanosoma brucei. Analysis of the two major developmental stages of these pathogens suggests that a core set of genes are similarly regulated in both stages, while many cell cycle-related changes in gene expression were unique to one stage. Intriguingly, the levels of far fewer proteins are differentially regulated over the trypanosome cell cycle, indicating that protein levels are primarily regulated by post-transcriptional processes. The study represents a significant technical advance in analyzing gene expression at the single-cell level in unfractionated trypanosome cultures.

eLife assessment

This is a fundamental study of the activation process of Nurr1, an orphan nuclear receptor that may be a significant target for the treatment of neurodegenerative disorders. Nurr1 functions as a monomer, but may also heterodimerize with RXR which represses Nurr1 transcriptional activation. The authors provide compelling evidence for Nurr1 activation through ligand-induced dissociation of an inactive Nurr1-RXRa heterodimer. These data will be important for biochemists and cell biologists working on regulatory / activation mechanisms of nuclear hormone receptors.

eLife assessment

This manuscript is of big interest to physicians and geneticists who may struggle with interpreting the clinical significance of novel or rare missense variants in the TNFAIP3 gene in patients with systemic inflammatory diseases. There is also much debate about the potential mechanisms by which these missense mutations might be pathogenic. El Khour et al. addressed these questions by using a combination of in silico analysis and in vitro functional assays. However, their conclusions require additional experimental support and should be expanded to include other reported likely pathogenic missense variants.

eLife assessment

This interesting and important work shows that diacety, a volatile organic compound released by yeast in fermenting fruit, can act as a histone deacetylase (HDAC) inhibitor and trigger wide changes in gene expression, together with suppression neurotoxicity in a Drosophila model of Huntington's disease. While the effects on gene expression changes and degenerative phenotypes are convincingly shown, additional data are required to connect olfactory sensory neurons and odorant receptors with the demonstrated physiological effects of diacetyl.

eLife assessment

Genome-wide association studies on asthma have been challenging due to innate heterogeneity and the syndromic nature of asthma, variable accuracy in phenotyping, and potential gene-environment interactions. Here, the authors identified genetic loci associated with subtypes of childhood wheezing in combined data of multiple birth cohorts, by coupling latent class analysis of clinical phenotypic data with GWAS discovery. A mechanistically plausible genetic locus close to annexin 1 (ANXA1) was associated exclusively with early-onset persistent wheeze and provides new translatable molecular insight into asthma pathogenesis.

eLife assessment

The findings in this manuscript have important theoretical and practical implications within the fields of bacterial morphogenesis, peptidoglycan, and cytoskeletal function. The evidence presented is convincing and uses validated methodology in line with current state-of-the-art. This manuscript will be of interest to cell biologists studying the cytoskeleton and bacterial morphogenesis.

eLife assessment

This valuable study reports on the role of transposable elements in gene expression variation in rice and how TE-associated expression changes could have been selected during domestication. The combination of evidence from linkage studies and selection scans for a subset of insertions is convincing, although it is currently unclear how large the contribution of TEs to gene expression variability compared to other variants is, which should be reflected in the title. The work will be of interest to colleagues working on the role of transposable elements in adaptation and to biologists working on domestication.

eLife assessment

Necarsulmer et al describe an interesting new mouse model of TDP-43 proteinopathy in which gene editing was used to introduce a K145Q acetylation-mimic mutation previously shown to impair RNA-binding capacity and induce downstream misregulation of target genes. Mice homozygous for this mutation are convincingly shown to display cognitive/behavioral impairment, TDP-43 phosphorylation and insolubility, and changes in gene expression and splicing. This novel mouse model replicates some important hallmarks of human frontotemporal lobar degeneration and will be an important contribution to the field after several points are adequately addressed.

eLife assessment

This fundamental work reports the unique finding that specific ligands and receptors in the natriuretic peptide signaling pathway act during early embryogenesis to discriminate between neural crest and cranial placode fates using two distinct mechanisms. This work will be of broad interest to both developmental and cell biologists.

eLife assessment

Rapan et al. report a new multi-modal parcellation of the macaque frontal cortex based on cytoarchitectural division complemented with functional connectivity and neurochemical data. This builds on prior highly influential maps that subdivide the cortex based on anatomical fingerprints, both confirming these prior reports and defining new subdivisions. As such, this is a fundamental contribution with compelling results that can guide future neuroscientific research into the function of the frontal lobes.

eLife assessment

This is a valuable study, carried out in a solid and comprehensive manner. The results advance the understanding of one of the steps of the HIV life cycle, via a better description of the mechanisms underlying Gag-Pol dimerization.

eLife assessment

This study by Mohebi, Collins, and Berke presents valuable findings on the control of the neurotransmitter dopamine by cholinergic interneurons, a sparse but important subclass of neurons with the ventral striatum, a key brain region involved in motivational behaviors. The evidence supporting the claims of the authors is solid, although the inclusion of a key experiment presenting causality between cholinergic neuron activity and dopamine release during behavior is needed. The work will be of broad interest to neuroscientists in the fields of motivation and decision-making.

eLife assessment

This important paper compares the neural basis for different calling songs in five species of clawed Xenopus frogs using neural activity recordings combined with lesions of pathways and stimulation of specific parts of the circuit. The evidence supporting the claims is mostly solid but in part incomplete. The work will be of broad interest to neurophysiologists beyond the vocalization topic.

eLife assessment

In the DNA damage response (DDR) pathway, single-stranded DNAs (ssDNAs) activate a downstream kinase cascade with ATR/Chk1. Replication protein A (RPA) is believed to be essential for DDR activation by recruiting an ATR-partner protein, ATRIP, to RPA-coated ssDNAs through direct protein-protein interaction. This important paper provides convincing results, showing that an AP endonuclease, APE1 (APEX1), plays a role not only in RPA-dependent but also in RPA-independent recruitment of ATRIP on ssDNAs for DDR activation.

eLife assessment

This study provides a clearly presented and thoughtfully analyzed single cell-resolution dataset of gene expression in wildtype and mutant zebrafish skin. These data are used by the authors to develop and test hypotheses about cell lineage relationships and signaling interactions between cell types in the skin, allowing them to identify roles for several signaling pathways and the hypodermis in scale and pigment cell development. The reviewers have suggestions for clarifications and acknowledging caveats to some experiments, but overall assess the significance of the manuscript to be fundamental and the quality of the data compelling.

eLife assessment

This study presents valuable findings on the changes of immune cell populations and stromal cells occurring at the CNS borders in a neonatal bacterial meningitis model, focusing on fibroblasts, macrophages and endothelial cells. The study provides solid snRNA-seq dataset and high quality immune fluorescence images of dissected brain border regions, that will be useful for the community. These observations and datasets will be of interest to the neuro-immunology community.

eLife assessment

This study represents a valuable body of work in which the authors assemble a molecular description of colorectal cancer and classification into subtypes. Overall, the evidence supporting the findings is solid and could be improved with more detail. Consensus over a diverse range of data from publicly available sources is convincing. When added to existing knowledge this work may contribute to future biomarker discoveries for colorectal cancer.

eLife assessment

This important study advances our understanding of the metabolic and hemodynamic underpinnings of different brain networks. The evidence is convincing, drawn from multiple datasets and including simultaneous fMRI and PET, although the authors should make clear which claims are supported by their evidence and which are speculation based on the literature. The study will be of interest to neuroscientists and researchers who use functional neuroimaging tools to study brain activity.

eLife assessment

This study presents useful information on the environmental and epigenomic associations of obesity in children and adolescents. The data were collected and analyzed using a solid and validated methodology and can be referenced at the clinics and health authorities to make a guideline and a policy strategy.

eLife assessment

This manuscript presents an exciting set of experiments on the mechanisms through which PSD proteins induce actin bundle formation. The work included deep mechanistic analyses which determine the necessity of upper vs. lower levels of PSD proteins for actin bundle formation, identify the domains and interactions of these proteins that are necessary and sufficient to induce actin bundles, and provide a first assessment in neurons of potential roles of the newly discovered mechanisms.

eLife assessment

This paper presents a valuable cross-validation study of mesoscopic measurements of axonal orientations from three different modalities: x-ray tomography, scattered light imaging, and diffusion MRI. The authors show convincing similarities and differences in fibre orientations from all three methods over partial ex vivo brain samples, though as only a single diffusion method is investigated, there is inadequate evidence to support conclusions about diffusion MRI reconstruction methods in general. As a first example of work comparing these three modalities, it is of interest to researchers who want to apply x-ray tomography or scattered light imaging to image the white matter ex vivo or use these methods for future validation of diffusion MRI methods.

eLife assessment

This study has important implications for the impact of sexual conflict on population viability under different temperatures. The authors propose that male harm to females in sexual conflict can be reduced as a function of temperature within the optimal reproductive range of a species. The evidence for this proposal is currently incomplete because there is methodological detail that needs to be further clarified. The results could have implications for the likelihood of the evolutionary rescue of species facing the climate crisis.

eLife assessment

The authors use computational modeling of the mammalian visual system to address an important and understudied problem: how precise temporal properties of synaptic transmission might impact the kinds of neuronal correlations that instruct development. The present description of the simulations provides mixed evidence for the authors' conclusions. That slow NMDA currents help to minimize rapid timescale correlations is compelling, but other aspects of the simulations, such as neuronal heterogeneity may also contribute.

eLife assessment

In this important study, the authors generate and analyse single-cell datasets for the human parasitic nematode Brugia malayi. The new resource has the potential to uncover new details of the biology of secretory systems in this filarial nematode but the main claims are only partially supported and strengthening them would require additional experimental support and new analyses. With the methodological part strengthened, the new resource would be of broad interest to parasitologists and nematode biologists and would have the potential to accelerate research in the search of new anthelmintics and vaccines.

eLife assessment

We believe this study has the potential to be fundamental for the field of microbial communication and compelling evidence with the chance of changing the current state-of-the-art in this area has been presented. This is will be of natural interest to the field of parasitology, but scientists in the general area of cell-to-cell communication will certainly benefit from this contribution too. A major strength of this manuscript is the clear demonstration of the role of cytoneme-like structures and extracellular vesicles in parasite communication using the Trichomonas vaginalis model. Given the potential of these findings, the authors could deepen their discussion and perspectives for other areas.

eLife assessment

This study reports a cutting-edge set of experiments examining evolutionary models of paralog function differentiation for the mammalian ribosomal proteins eS27 and eS27L. No differentiated roles were identified for either paralog, but the paralogs are differentially expressed, and they preferentially associate with different transcript classes. Reciprocal switching of their coding sequences yielded no detectable phenotypes, but loss of either paralog resulted in lethality at different developmental stages, suggesting that subfunctionalized expression patterns underlie the retention of these paralogs. The work will be of interest to colleagues studying the evolution and diversification of ribosomes.

eLife assessment

The authors show that tunneling nanotubes or TNTs are used by cells to transfer full-length mRNAs. The data show that as much as 1% of the endogenous mRNA are passed between cells by this procedure. The transferred mRNA affect the transcriptome of the acceptor cells thus highlighting the significance of this nanotube mediated trafficking of mRNA between cells. We appreciate the difficulty of this exercise. The strength of the presented evidence could be questioned based on technical limitations.

eLife assessment

After mating, animals show a repertoire of behavioural changes. In flies, this includes an increase in egg-laying, salt, and food (particularly protein) consumption, and a concomitant decrease in sexual receptivity. This valuable study compellingly shows that flies also have an increased sugar appetite and they identify the central brain circuitry that controls this increase in the mated condition.

eLife assessment

The large genetic association studies conducted in East Africa have shown that the Dantu blood group provides substantial protection against severe malaria since it increases the surface tension of red blood cells making it harder for malaria parasites to invade. In this important work, the authors show that parasite growth is indeed restricted in vivo by testing this hypothesis in adult Kenyan volunteers infected with P. falciparium under careful monitoring. They were able to show convincingly that indeed, parasite growth was reduced amongst Dantu adults.

eLife assessment

Seelbinder et al. describe a new method for perturbing chromatin in living cells by local heating. Employing this approach, the authors uncover interesting behaviors that underscore the variability in the mechanical response of subnuclear domains and structures. The study is timely, and if some conceptual and technical aspects are improved, it should be of broad interest to both the cell biophysics and cell biology communities, in particular since the method can also be applied to study mechanical relationships of subcellular compartments in other cellular and multicellular systems.

eLife assessment

This study presents a useful inventory of chromatin modifications and genes that are up- and down-regulated during cerebellar development in vivo and in primary culture. The main claims were incomplete and would benefit from further analysis and/or additional experiments. The work will be of interest to biologists working on brain development.

eLife assessment

This study presents important findings regarding the quantification of dynamics in fish communities in changing ecosystems by combining a large-scale environmental DNA metabarcoding time series with novel statistical approaches. The methods are convincing, with controlled experiments, thorough statistical analyses, and a substantial dataset covering two years of detailed observation, which can provide sufficient power to detect fine-scale ecological interactions. This work is relevant for informing future research on assessing community stability under climate change.

eLife assessment

The authors use a combination of structural and MD simulation approaches to characterize phospholipid interactions with the pentameric ligand-gated ion channel, GLIC. The general agreement between structures and simulations increases confidence in the description of the lipid interaction poses, and provides a solid basis for the prediction of a state dependent interaction site where lipids could dynamically modulate channel gating. The results will be very useful to understand the nature of phospholipid interactions with pentameric ligand-gated ion channels, although the functional or structural significance of these lipid interactions remains unclear.

eLife assessment

This interesting study builds on previous work by the PI implicating Greatwall/MASTLKinase in recovery from DNA damage in cultured human cells. This study identifies a ubiquitin ligase that may regulate the stability of Greatwall/MASTL protein stability, and the authors propose that this constitutes a molecular "timer" that controls recovery from DNA damage. Should this be validated it would be an important advance for the field, but the data presented are currently incomplete and do not yet fully support this claim.

eLife assessment

The authors have uncovered a new target that may be exploited to selectively kill BRCA2 mutant cancer cells. Strengths of the study include the novel pathway uncovered (ROCK kinases) and the strong data in support of the findings. Weaknesses include limited detail regarding the mechanism of BRCA2-specific cell death by ROCK kinase inhibitors, limited information on why some ROCK kinase inhibitors are not effective, as well as whether the cell killing in BRCA2 wild-type cells by ROCK kinase inhibitors is the same mechanism but just attenuated. The work will be of interest to cancer biologists and colleagues studying kinases.

eLife assessment

This manuscript is of interest to readers in the field of neural development. The study is important as it examines two mutations within a homeodomain transcription factor called Cone-Rod Homeobox (CRX) that cause retinopathy in humans. The data are solid, and the work contributes to our understanding of the underlying pathogenetic mechanisms.

eLife assessment

This study combines experiments in developing embryos and embryo extracts to investigate a fundamental relationship in biology - how the size of mitotic chromosomes scales with changes in cell size during development. By combining the unique tools available in the Xenopus system with modern genomic approaches, the authors convincingly demonstrate that mitotic chromosome scaling is mediated by differential loading of maternal chromatin remodeling factors during interphase. Although it remains unclear exactly how these factors impact chromosome size, the findings reported here will be of broad interest to the cell biology community and are likely to spawn new avenues of experimental inquiry aimed at understanding intracellular scaling relationships.

eLife assessment

This study provides important estimates from international cancer screening data repository about the impact of the COVID-pandemic related disruptions on cancer screening programs in selected low- and middle-income countries. The evidence supporting the study is solid and relies on national-level screening program attendee volumes and assessments of screen positives during 2019 (pre-pandemic) and 2020 (during the pandemic). The study provides real-world data estimates of proportions/volumes of missed screenings due to pandemic control measures (lockdowns and closures) and may contribute to future modelling efforts for measuring the impact on late/advanced stage detection and excess case burden and mortality.

eLife assessment

This paper addresses an important clinical concern which is how the antidepressant ketamine exerts its effects acts rapidly. The authors suggest the reason is that ketamine increases glutamatergic transmission in the hippocampus. The strengths are the data are mostly very good, and the limitations are a lack of compelling evidence that the hippocampus is the location where effects occur, as well as several other issues.

eLife assessment

This important study will be of interest to those working on mycobacterial signal transduction. A combination of experiments provides convincing evidence to show how universal stress proteins bind to cAMP and function by direct sequestration of the second messenger. Although the methods, data and analyses broadly support the conclusions, the main claims are only partially supported and can be strengthened through further analytic approaches.

eLife assessment

Villalobos-Cantor et. al. describe a new technique for cell-type specific in vivo labeling of nascent peptides, which they call POPPi. POPPi is based on sequence-independent incorporation of the puromycin analog OPP into an elongating peptide, which also simultaneously terminates the growing peptide. To achieve cell-type-specific labeling, the authors used an OPP derivative, PhAc-OPP, as the labeling substrate. The method is potentially interesting but needs further characterization to be able to assess its use.

eLife assessment

This important study combines a screen of known N6-methyladenine (m6A)-dependent RNA modifying factors to identify ALKBH5 as critical in crush injury response. They demonstrate through gain and loss of function an effect on ALKBH5 m6A-dependent Lpin2 mRNA stability during injury-induced axon regeneration in both dorsal root ganglia nerve and optic nerve regeneration. The results provide new insight into the role of RNA modification on neural injury. However, the limitations of the experimental design on the conclusions drawn require additional consideration. With additional control experiments and further consideration of the limitations, the paper will provide a link between N6-methyladenine and neurotrauma.

eLife assessment

This study describes important results and convincing evidence linking myofibroblast senescence in the aged heart with a pro-arrhythmogenic phenotype. This is in turn related to higher mortality after myocardial infarction in the aged rabbit heart. These constitute important empiric as opposed to detailed findings. They nevertheless will be of interest to clinician scientists studying cardiac function and disease.

eLife assessment

Non-communicable diseases (NCDs) are rising rapidly in urbanizing populations in many parts of the developing world, including in sub-Saharan Africa. Temba and colleagues show important evidence that healthy Tanzanians display a pro-inflammatory phenotype with enrichment of specific immune-metabolic pathways. Dood-derived metabolites were identified as an important driver of inflammation-related molecules. These findings provide solid evidence that the dietary transition that occurs in urbanizing areas in sub-Saharan Africa may contribute significantly to the increased incidence of non communicable diseases in this part of the world.

eLife assessment

This important interdisciplinary study substantially advances our understanding of the prolactin receptor interactions with the membrane lipids and the effect of these interactions on cell signaling. The authors use a combination of state-of-the-art NMR structural analysis, simulations, and cellular assays to provide compelling experimental evidence for protein complexes being regulated by IDR-membrane interactions. The work will be of broad interest to structural biologists and biochemists, and the results presented herein are likely relevant for other non-tyrosine kinase receptors.

eLife assessment

This important study demonstrates that the transcription factor Chinmo is a master regulator that maintains larval growth and development as part of the metamorphic gene network in Drosophila. Chinmo does so in part by regulating Broad expression in imaginal tissues (exemplified in the wing disc) and in a Broad-independent manner in other larval tissues such as the salivary gland. Finally, they demonstrate that the role of Chinmo in promoting larval development is conserved between holometabolous insects and hemimetabolous insects, which lack a pupal stage. The data were collected and analyzed using solid and validated methodology and will be of interest to a broad audience including those interested in development and evolution.

eLife assessment

Using surface micropatterning, optical activation, and theoretical analysis, the authors provide compelling evidence that adjacent cells actively propagate mechanical stress in epithelial tissues. The response of the receiver cell is active and enhanced when the principal stress direction is perpendicular to the orientation of actin fibers. This work is important and a must-read for everybody wanting to understand tissue mechanics.

eLife assessment<br /> <br /> This is an important study that uses the song system in a bird model to understand the transcriptional mechanisms underlying neuronal adaptations to sensory deprivation. The manuscript offers compelling data in support of their hypothesis that these transcriptional changes are related to song plasticity. The work will be of interest to biologists who study neuronal plasticity mechanisms.

eLife assessment

Inferior olivary neurons drive complex spiking activity in Purkinje neurons of the cerebellar cortex, ultimately playing critical roles in controlling motor coordination and plasticity. Using transgenic mice or optogenetic techniques to independently control a major excitatory and inhibitory pathway to the inferior olive, the authors show that the probability and phase of olivary neuron output depend critically on the relative timing of excitation and inhibitory inputs. Network models predict that appropriately timed excitatory and inhibitory input patterns efficiently synchronize larger clusters of inferior olivary neurons, raising the possibility that input timing can gate the output of the motor commands. These valuable findings have the potential to impact the field's understanding of sensorimotor processing, but the strength of evidence is currently incomplete.

eLife assessment

The study provides evidence that the hormone PTH increases bone mass by, at least in part, regulating the factor Zfp467. In turn, Zfp67 controls expression of the receptor for PTH, thus creating a feedback loop that overall augments bone mass. The findings are novel and of potential great interest. Overall, the study is of interest to a broad audience and significant as it unveils a novel feedback loop involving PTH, a critical endocrine regulator of calcium, phosphate, and bone mass.

eLife assessment

This paper describes a new method to investigate Staphylococcus aureus intracellular virulence that has produced important insights into the mechanisms of staphylococcal pathogenesis. The results are convincing and the methodology is state-of-the-art. This paper will be of interest to scientists studying microbial intracellular pathogenesis and cell biology.

eLife assessment

This paper demonstrates the genetic architecture of heart mitochondrial proteome that influences cardiac hypertrophy, using a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). The HDM panel is a very powerful tool to study the genetic basis of various physiological and pathological processes in mice. The authors have used this panel extensively before, and in this paper, they extend their proteomic studies to demonstrate the genetic basis of cardiac hypertrophy. The studies will allow us to better understand the genetics of hypertrophic cardiomyopathy.

eLife assessment

This important study greatly expands our knowledge of the fossil record of Mermithid nematodes, modern members of which are ecologically important parasitoids of arthropods, annelids and mollusks today. The most important finding, convincingly presented, is that mermithids parasitized a number of insect clades in the Cretaceous that they are not known to infect today or in Cenozoic amber. The evidence for a shift in exploited hosts from heterometabolous insects in the Cretaceous to holometabolous ones in the Miocene is solid but could be made exceptional by adding a small quantitative analysis with confidence intervals and bar plots from the data already compiled in the supplementary material; potential collection bias should be addressed as well.

eLife assessment

This fundamental work uses deep neural networks to simulate activity evoked by a wide range of stimuli and demonstrates systematic differences in latent population representations between hearing-impaired and normal-hearing animals that are consistent with impaired representations of speech in noise. While the evidence supporting the conclusions is compelling, additional analyses would facilitate the generalizability of the neural-network approach. The research will be of interest to auditory neuroscientists and computational scientists.

eLife assessment

This manuscript provides valuable data gathered using a new video fluoroscopy method by which movements of artificial joints can be visualized in real time. These solid data add to the understanding of the links between symptoms of unstable joints after total knee replacement and actual joint instability. The paper should be of interest to those who study biomechanics after total joint replacement.

eLife assessment

In this study, Li and al describe valuable insights into the mechanisms underlying sex-differences diet-induced obesity in mice, with a role of macrophage-derived RELMa secretion in female-specific protection. They provide solid evidence for the impact of RELMa signaling in eosinophil recruitment for diet-induced obesity protection in female mice. Single-cell RNA-seq analysis of the stromal vascular fraction of control and RELMa deficient animals methods were used to investigate molecular mechanisms underlying the protection as a powerful method, although the analysis of this data is difficult to evaluate with incomplete methodological information.

eLife assessment

In vertebrates, ciliary motility is powered by axonemal dyneins, known as OADs, tethered to doublet microtubules by a pentameric docking complex including the Armc4 and Calaxin subunits. This valuable study combines zebrafish genetics with cryo-electron tomography to convincingly show that Armc4 plays a critical role in the docking of OAD and that Calaxin stabilizes the molecular interaction. The work will be of interest to those studying the structure and function of the axoneme, and motile cilia in general.

eLife assessment

This important study combines behavior, computational modelling and magnetic resonance spectroscopy to address the question whether age-related declines in learning are driven by declines in working memory or deficiencies of the RL system. The general approach is solid, but the presented evidence to support the papers' main claims could be stronger. With additional analyses and adaptation of the main claims, the paper could be of high interest for researchers in the field of cognitive aging and decision making.

eLife assessment

The authors present a manuscript aiming to understand the mechanism(s) underlying myeloid bias in HSCs, specifically focused on the role of Pcgf1, and therefore PRC1.1, in the regulation of hematopoiesis. This important work is of interest to the community of researchers interested in myeloid differentiation, lineage fate decisions in hematopoietic stem cells, and the molecular mechanisms that contribute to the initiation of myeloid malignancies. The methods are rigorous and the results convincingly support the authors' conclusions.

eLife assessment

This is a valuable paper describing an attempt to reconstruct the evolution of Dicer. Using ancestral reconstruction approaches, the authors carefully examine the biochemical characteristics of reconstructed proteins at various junction points in the animal lineage. They provide solid evidence that the deepest ancestrally reconstructed protein has double-stranded RNA stimulated ATPase activity and that this characteristic was lost along the vertebrate lineage. This paper will be of interest to scientists in the RNA-protein interaction and protein evolution fields.

eLife assessment

The authors have established new formulas to predict maximum oxygen uptake for cyclists and runners based on submaximal exercise testing and anthropometric characteristics. This is an important study with a large and comprehensive dataset, which may be helpful for many exercise labs. The work is convincing, using appropriate and validated methodology in line with the current state-of-the-art, as shown by references to common exercise books.

eLife assessment

In the current manuscript, the authors study the effects of hypoxia or genetic and pharmacologic modulation of the hypoxic pathways on T cells. The findings about T cells sense hypoxia and how hypoxia affects T cell (and CAR T cell) differentiation and function are significant and interesting for the field. The data supporting these findings are mostly robust, yet some questions remain open and some statements seem unsupported by evidence.

eLife assessment

This fundamental work substantially advances our understanding of polymer physics underpinnings of genome folding, organization, and regulation. The conclusions are supported by both convincing computer simulations and analytical theory. The work will be of significant interest to the genome folding community.

eLife assessment

This manuscript will be of interest to scientists in the field of tissue injury and repair. It provides novel molecular mechanisms of a transcription factor, Prrx1, in fibroblast activation following lung injury. Overall, the work suggests that PRRX1 plays a functional role downstream of TGFb1 to elicit some aspects of the fibrotic response and that PRRX1 could represent an important therapeutic target to treat fibrosis. The strengths of this work are the multiple approaches applying human and mouse lung tissue used by the authors to test the role of PRRX1 in lung fibrosis, however, in its current form, major limitations need to be addressed.