eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. The strength of the evidence supporting the claims is solid, although many computational details are still missing, and the are concerns about the repeatability of the results across replicates, the dynamics of evaporation in their experiment, and the termites' ability to sense humidity.

eLife assessment

This paper describes a useful analysis tool for quantitative assessment of sarcomere structures in healthy and perturbed cardiomyocytes. The work is solid, and the methods, data and analyses broadly support the claims with only minor weaknesses. The tool will be of interest to biologists working on sarcomere structure, function and development.

eLife assessment

This useful manuscript challenges the utility of current paradigms for estimating brain-age with magnetic resonance imaging measures, but presents inadequate evidence to support the suggestion that an alternative approach focused on predicting cognition is more useful. The paper would benefit from a clearer explication of the methods and a more critical evaluation of the conceptual basis of the different models. This work will be of interest to researchers working on brain-age and related models.

eLife assessment

This study presents important findings that set a new standard for generating and maintaining monosomic yeast lines, and is the first, to our knowledge, to assess gene expression in yeast monosomies. The research offers an innovative approach to evaluate epistasis between genes on the same chromosome; however, the strength of evidence supporting the conclusions on positive epistasis for fitness is still incomplete due to the need for clarification for the exact calculation method of expected fitness without epistasis, as well as due to a lack of molecular mechanisms. Additionally, the interpretation of transcriptome results would benefit from a more comprehensive consideration of previous studies on genomic balance and the inclusion of further analyses and experiments.

eLife assessment

This valuable manuscript provides a single-cell RNA sequencing analysis of adult pig skin from different species and anatomical regions. The evidence supporting the conclusions is compelling, with identification molecular and cellular differences in pig skin, yet the analyses are incomplete in the analysis of regional- or species-based differences.

eLife assessment

This is an important study that defines cell type changes upon the expression of a mutant tau protein and put it into context of human postmortem tissue. Technically, the single cell mRNA sequencing data are convincing but the loss of neurons already at the earliest stages assessed in this model may rather suggest there are also elements of developmental toxicity.

eLife assessment

This fundamental study substantially advances our understanding of how aging and stress resilience across an organism is determined by identifying a new player in this process and uncovering its mode of action. The evidence is solid as the methods, data and analyses broadly support the claims with only minor weaknesses. The work will be of broad interest to the field of aging and protein homeostasis.

eLife assessment

Studies of prey behavior have the potential to provide insight into the chemical encoding of stress in the brain and the mechanisms by which this generates behavioral plasticity. In this important work, the authors identify a novel predation-evoked behavior in the nematode C. elegans and implicate dopamine in its implementation. While the support for some claims in the current paper is incomplete, this work provides an exciting foundation for future studies of behavioral plasticity in this powerful system.

eLife assessment

The toxin mycolactone is produced by mycobacterium ulcerans which is responsible for the Buruli ulcer. The authors performed a valuable study showing the effects of mycolactone on blood vessels integrity. This convincing data provide new therapeutic targets to accelerate healing of Buruli ulcers.

eLife assessment

This paper is of interest to neuroscientists studying the effects of sex hormones on neural and behavioral plasticity, and more specifically to researchers studying the neural mechanisms underlying birdsong plasticity. The experimental design is excellent, and the work provides a comprehensive resource for understanding the intersection between testosterone's influence on gene expression and behavior. However, the work also makes claims concerning cellular effects and gene regulatory mechanisms that extend beyond the data and under the current analyses are not rigorously supported.

eLife assessment

This study is an excellent example of how one can use high-throughput technologies to address animal evolution from a cell-type perspective. The authors present a beautiful analysis of single-nucleus RNA-seq data from three embryonic stages in a sea star; this is the first single-cell data from this large group of echinoderms and the first single-nucleus transcriptomic study in any echinoderm. The authors demonstrate the presence of unique as well as previously unnoticed homologous cell types between a sea star and a sea urchin, discovery very intriguing to echinoderm developmental biologists, which will also be of great interest to scientists in the broad fields of evolution and development.

eLife assessment

The findings of this study yield important new insights into the relationship between the number of close friends and mental health, cognition, and brain structure. Due to the large sample sizes, the evidence is solid but would have been improved if both of the analyzed datasets contained more closely matched measures. This work advances our understanding of how the friendship network relates to young adolescents' mental well-being and cognitive functioning and their underlying neural mechanisms.

eLife assessment

This potentially important work proposes a novel approach, based on co-evolution analysis, machine-learning protocols and molecular dynamics simulations, to predict structures and energetics of the main states of the alternating access cycle of a family of membrane transporters, the sugar porters. The approach is compelling, especially the application of co-evolution and Alphafold to generate highly accurate models in different conformational states of a given protein, but the work is currently incomplete due to shortcomings in the calculation of the energy landscape. With this aspect strengthened, the manuscript will be of interest to the transporter and computational modeling communities.

eLife assessment

This study presents useful structural and functional connectivity profiles of patients receiving deep brain stimulation in the posterior hypothalamus for severe and refractory aggressive behavior. The inclusion of data from multiple centers is compelling. However, the imaging analysis is incomplete and the interpretation of the findings is not solid.

eLife assessment

This study reports a joint experimental and computational investigation of the structural features of biomolecular condensates formed by a specific intrinsically disordered protein. The authors also adapt emerging rules to discuss and physico-chemical determinants of these structures of condensates. Specifically, the authors adapt the analysis of fractal structures, co-opted from the field of colloidal chemistry / physics, and generate important insights regarding the network-like organization of disordered proteins within in silico facsimiles of condensates. The usage of these analyses in the context of studying all atom models for multi-chain assemblies intended to mimic the internal organization of condensates is very interesting. The work is of relevance to cell biology and structural biology.

eLife assessment

The study of Thiery et al. details the heterogeneous expression of a very large number of genes presumably associated with cell fate decisions in the ectoderm at the neural plate border in early avian embryos. The authors mostly succeed in presenting their very complex strategy of data analysis in a clear way but the work is incomplete with some conceptual weaknesses in how the authors describe and interpret their results. By focusing on one of the earliest cell fate decisions in the ectoderm of a vertebrate embryo, this study will be valuable to a broad range of developmental biologists.

eLife assessment

This study presents a useful application of a prior model published by the authors to a new dataset. The results from this approach were interesting and solid but the conclusions that one can make from the application of the model to only one paper are limited in scope and would depend on further probing to know if the model itself has face validity as a model of ventral visual stream function.

eLife assessment

Protein and lipid homeostasis are important for maintaining cellular functions but their crosstalk remains largely unknown. This important manuscript deals with this interesting topic and applies the powerful unbiased tools of somatic cell genetics to discover evidence suggesting a link between sphingolipids/cholesterol ester metabolism and lysosomal protein aggregation. However, in our view the experimental evidence in support of the paper's stated conclusions remains incomplete and measures that (i) go beyond reliance on the ProteoStat stain as the sole metric for aggregation and proteostatic challenge, (ii) biochemically back up the results and provide plausible mechanistic insights into the connection of lysosomal lipid handling and protein aggregation are needed.

eLife assessment

This paper introduces the python software package Pynapple and a separate package of more advanced routines (Pynacollada) to the Neuroscience/Neural Engineering community. Pynapple provides a set of data objects and methods that have the potential to simplify data analysis for neural and behavioral data types. This represents a valuable contribution to the field. The evidence was judged to be incomplete due to the fact that key details were missing.

eLife assessment

This is an important paper that revises the canonical model of how olfactory sensory neurons choose which odor receptor to express. The data presented in the paper are convincing and the model proposed is provocative and likely to enable important future work.

eLife assessment

This important study combines state-of-the art proteomics and genetic manipulation of Chlamydia trachomatis to study the function of a chlamydial effector, Cdu1, with deubiquitination and acetylation activities. Solid evidence is provided to show that Cdu1 is able to protect itself and three other chlamydial effectors, which are involved in the control of chlamydial egress from host cells, from ubiquitin-mediated degradation, and that this depends on the acetylation activity of Cdu1, but not on its deubiquitination activity. This work should be of interest to microbiologists and cell biologists studying host cell-pathogen interactions.

eLife assessment

This valuable work describes a novel role of Vangl2, a core planar cell polarity protein, in mechanistically linking the inflammatory NF-kB pathway to selective autophagic protein degradation. Using solid methods, the authors also establish the functional significance of the proposed mechanism in sepsis, a biomedically important human ailment. The work may advance our understanding of NF-kB control, particularly in the context of aberrant inflammation. However, some gaps remain, and additional studies are needed to unequivocally establish the role of Vangl2 in regulating NF-kB signaling.

eLife assessment

This work presents an important methodological advance for single-molecule force spectroscopy of membrane proteins providing a new robust design of the linkage between a target single molecule and solid support. The data provide compelling evidence of the improved mechanical stability of the pulling system. Allowing more statistically reliable force measurements of biomolecules, this method may be broadly applicable in the field of single-molecule biophysics.

eLife assessment

The authors present an exciting idea about how to integrate morphogens into a gene regulatory network with the dynamics of morphogenesis and cell movement. It represents a novel methodology, but in its current form the hypotheses, data and relationships described do not provide a sufficiently compelling model to disentangle cause and effect or elucidate the impact of cell movements on differentiation dynamics the zebrafish mesoderm.

eLife assessment

This important work investigates how two distinct processes, morphological changes and synaptic plasticity, contribute to the final shape of neuronal dendrites and the spatial structure of their synaptic inputs. The modelling is solid and could be broadly applied to other similar questions. Some of the findings are a direct result of how the model is constructed, which limits the impact. The work will be of interest to neuroscientists studying dendritic development and connectivity at a single-cell level.

eLife assessment

This paper presents important findings on the hexametric structure of MCM8/9, which potentially explain its role as a DNA helicase in homologous recombination. Due to the lack of DNA in the complex and the invisibility of HROB the current data only provide an incomplete model of the function of the MCM8/9 complex. This work will be of interest to biologists studying DNA transactions.

eLife assessment

The authors present a useful analysis of different factors that are required for release of the lipid-linked morphogen Shh from cellular membranes. The evidence is currently still incomplete as experiments rely on over-expression of Shh in a single cell line and are sometimes of a correlative nature. The study confirms and extends previous findings and will be of interest to developmental biologists who work on Hedgehog signaling.

eLife assessment:

This study introduces a valuable paradigm in the filed of adipose biology field: blocking triglyceride storage in adipose tissue does not lead to lipodystrophy and impaired glucose homeostasis but instead improves metabolic health. The evidence supporting these claims are convincing, with the authors providing a comprehensive metabolic analysis. However, mechanistic studies, which are currently incomplete, would strengthen the study and its impact. Regardless, this study will be of high interest to those in the adipose tissue biology and metabolism fields.

eLife assessment

This study presents an important open-source resource for high-throughput behavioral screening. The protocols employ inexpensive, off the shelf hardware, and carry out real-time analysis of hundreds of behaving flies. Although these protocols were developed using Drosophila melanogaster, they could easily be applied to other model systems. The evidence in support of the conclusions is solid although more details on the algorithms used for phenotyping would be helpful in order to better assessing the overall robustness of the platform.

Within the pantheon of types of notes there are: - paraphrasing notes, which one can use to summarize ideas for later recall and review as well as to check one's own knowledge and understanding of what an author has said. - commentary notes, which take the text and create a commentary on them, often as part of having a conversation with the text. These can be seen historically in the Midrashim tradition of commenting on Torah.

[23:12 - 24:47]

separately also: - productivity notes - to do lists, reminders of work to be done, often within or as part of a larger complex project

eLife assessment

This valuable work provides new insights into history-dependent biases in human perceptual decision-making. It provides compelling behavioral and MEG evidence that humans adapt their history-dependent to the correlation structure of uncertain sensory environments. Further neural data analyses would strengthen some of the findings, and the studied bias would be more accurately framed as a stimulus- or outcome-history bias than a choice-history bias because tested subjects are biased not by their previous choice, but by the previous feedback (indicating the category of the previous stimulus).

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

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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This entire comment is gold

eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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eLife assessment

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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.