bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Lipinskis Rule of 5 and Machine Learning Based Prediction of Fraction Absorbed for Assessing Oral Absorption in Humans
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Ekmefjord Morgan , Spjuth Ola
Published: August 2024

Background - The influential Lipinskis Rule of 5 (Ro5) describes molecular properties important for oral absorption in humans. According to Ro5, poor absorption is more likely when 2 or more of its criteria (molecular weight (MW) above 500 g/mol, calculated octanol-water partition coefficient (clog P) above 5, above 5 hydrogen bond donors (HBD) and above 10 hydrogen bond acceptors (HBA)) are violated. Earlier evaluations have shown that many drugs are sufficiently well absorbed into the systemic circulation despite many Ro5-violations. No evaluation of Ro5 vs fraction absorbed (fa) has, however, been done. Methods - Datasets of orally administered drugs violating and not violating Ro5 and with available human clinical fa-values were assembled, and contrasted to machine learning based predictions using the ANDROMEDA prediction software having a major MW-domain of 150-750 g/mol. Results - 129 Ro5-violent compounds (29 with MW above 1000 g/mol) were found, 59 of which had fa-values (42 % mean fa). 34 % and 66 % of compounds were predicted as having fa below 10 % and above 10-30 % respectively, which was in good agreement with measured fa of 37 % and 63 %. The fa for all compounds with fa above 5 % and above 10 % were correctly predicted. For compounds with fa above 30 %, 81 % were predicted to have a fa above 30 %, but none were predicted to have a fa below 10 %. The Q2 for predicted vs observed fa was 0.64. For a set of 77 compounds without Ro5 violation (80 % mean fa), all compounds were correctly predicted to have a fa below or above 30 % (Q2=0.56). Among these are compounds with poor uptake (below 1 % to 7 %). Conclusion - We show that machine learning based predictions of fa are superior to Ro5 for assessing oral absorption obstacles in humans. Too strict reliance on Ro5 may hence constitute a risk. ANDROMEDA predicts fa well, easily and quickly, and also differentiates well between poor and adequate oral uptake for compounds violating and not-violating Ro5. This makes it a valid and useful tool capable of predicting oral absorption in humans with good accuracy and replacing Ro5 for oral absorption assessments.
Anti-NMDAR encephalitis alters intrinsic spatiotemporal coding by enhancing neuronal coupling and clustering
Authors: Rahmati Vahid , Graf Jürgen , Ceanga Mihai , Rivera Dario Cuevas , Haselmann Holger , Liebscher Sabine , Prüss Harald , Holthoff Knut , Kirmse Knut , Geis Christian
Published: August 2024

Autoimmune anti-NMDA-receptor encephalitis is characterized by severe neuropsychiatric symptoms including memory dysfunction and seizures. However, it remains enigmatic what functional changes at the multi-neuronal level mediate network dysfunction. We used two-photonin vivorecording in a passive-transfer mouse model with patient’s monoclonal anti-GluN1-autoantibodies during slow-wave sleep-like conditions, a critical phase for memory processing. We find enhanced functional coupling and clustering between hippocampal CA1 pyramidal neurons (PNs), which intrinsically expose the network to hypersynchrony. These connectivity changes are associated with a selective preservation of strong excitatory synapses despite overall reduced excitation, thus enhancing hub-like properties of functionally connected PNs. Furthermore, we find abnormal PN firing characteristics, decreased transmission failure, and increased similarity of spontaneous spatiotemporal activity patterns, all affecting CA1 intrinsic neuronal coding. Collectively, the functional rewiring of hippocampal networks and altered intrinsic information processing provide new mechanistic insights into the NMDAR-hypofunction consequences and pathomechanisms of anti-NMDAR encephalitis symptomatology.
Distinct roles of prefrontal cortex neurons in set shifting
Authors: Nigro Marco , Tortorelli Lucas Silva , Yang Hongdian
Published: August 2024

Cognitive flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies, requires adaptive processing of internal states and contextual cues to guide goal-oriented behavior, and is dependent on prefrontal cortex (PFC) functions. However, the neurophysiological underpinning of how the PFC supports cognitive flexibility is not well understood and has been under active investigation. We recorded spiking activity from single PFC neurons in mice performing the attentional set-shifting task, where mice learned to associate different contextually relevant sensory stimuli to reward. We identified subgroups of PFC neurons encoding task context, choice and trial outcome. Putative fast-spiking neurons were more involved in representing outcome and choice than putative regular-spiking neurons. Regression model further revealed that task context and trial outcome modulated the activity of choice-encoding neurons in rule-dependent and cell type-dependent manners. Together, our data provide new evidence to elucidate PFC’s role in cognitive flexibility, suggesting differential cell type-specific engagement during set shifting, and that both contextual rule representation and trial outcome monitoring underlie PFC’s unique capacity to support flexible behavioral switching.
Interventions for burnout and well-being in homelessness staff: a systematic scoping review
Authors: Ng L , Adams E , Henderson D , Donaghy E , Mercer SW
Published: August 2024

Background

Homelessness staff often experience high job demands, limited resources, and significant emotional strains; with high levels of burnout, stress, and trauma being common within the workforce. Despite growing recognition of these issues, limited information exists regarding interventions to address this.

Aim

To conduct a systematic scoping review of interventions aimed at improving well-being and reducing burnout among homelessness staff.

Methods

All eligible studies needed to include an intervention addressing burnout and/or well-being in homelessness staff, published in English with primary data. Evidence sources were left open with no data restrictions. Following a registered protocol (available at osf.io/jp5yx), a systematic search of five electronic databases (Medline, APA PsychInfo, Global Health, ASSIA, CINAHL) and Google Scholar was conducted. Studies were double-screened for inclusion. Methodological quality was assessed using the Mixed Methods Appraisal Tool.

Results

Out of 5,775 screened studies, six met the inclusion criteria: two peer-reviewed and four non-peer-reviewed publications. No studies were retrieved from Google Scholar. The included studies comprised four quantitative non-randomised designs, one randomised controlled trial, and one mixed-methods study, with four being complex interventions. Three were therapy-based, two included supervision, and two comprised one-time educational sessions. Most were conducted in the United States (n=4), with two in the United Kingdom. The total pooled sample was 347 participants, though four studies were missing demographic data (age and gender). The studies used heterogenous measures and outcomes. Limitations included restrictions to English-only publications, potential gaps in capturing well-being measures, and a limited grey literature scope.

Conclusion

There is a lack of research on well-being and burnout interventions in frontline homelessness staff. Identified studies were generally of low quality with a heterogeneity of measures and outcomes used to assess well-being and burnout, limiting generalisability of findings. More robust study designs, along with standardised measures and outcomes, are needed going forwards.
Assessing fecal contamination from human and environmental sources using Escherichia coli as an indicator in rural eastern Ethiopian households - a study from the EXCAM project
Authors: Deblais Loic , Usmael Ahmedo Belisa , Ojeda Amanda , Mummed Bahar , Wang Yuke , Terefe Mekonnen Yitagele , Demisie Weldesenbet Yenenesh , Hassen Kedir , Brhane Mussie , McKune Sarah L , Havelaar Arie , Liang Song , Rajashekara Gireesh
Published: August 2024

Enteric pathogens are a leading causes of diarrheal deaths in low- and middle-income countries. The Exposure Assessment of Campylobacter Infections in Rural Ethiopia (EXCAM) project, aims to identify potential sources of bacteria in the genus Campylobacter and, more generally, fecal contamination of infants during the first 1.5 years of life using Escherichia coli as indicator. A total of 1,310 samples (i.e., hand rinses from the infant, sibling and mother, drinking and bathing water, food and fomite provided to or touched by the infants, areola swabs, breast milk and soil) were collected from 76 households between May 2021 and June 2022. Samples were assigned to two groups by infant age: TP1 (time point 1), infants between 4 and 8 months of age, and TP2, infants between 11 and 15 months of age. Fluorometric and semi-selective colorimetric approaches were used to quantify E. coli in the field samples. Overall, E. coli was ubiquitous within selected households (56.8% across the study). E. coli was more frequently detected than average (>53%) with high concentration (>2-log CFU) in soil (g) and per pair of hand, while the opposite trend (<33%; <1.5-log CFU) was observed in food provided to the infants (g or ml), per areola, and breast milk (ml; P<0.01). E. coli was frequently detected in fomites touched by the infants, drinking and bathing water (>51%), but at low concentration (<1.5-log CFU). Correlation analysis between E. coli concentration in different sample types suggested that the mother hands might play a key role in the transmission of E. coli between the environment (i.e., soil, bathing water and fomites) and other family members (i.e., infant and sibling; P<0.04; r2>0.3). Using E. coli as surrogate, our study identified mother (hands and areola) as reservoirs likely to be involved in frequent transmission of fecal contaminants to infants within rural Ethiopian households.
PriMAT: A robust multi-animal tracking model for primates in the wild
Authors: Vogg Richard , Nuske Matthias , Weis Marissa A. , Lüddecke Timo , Karakoç Elif , Ahmed Zurna , Pereira Sofia M. , Malaivijitnond Suchinda , Meesawat Suthirote , Wörgötter Florentin , Kappeler Peter M. , Gail Alexander , Ostner Julia , Schülke Oliver , Fichtel Claudia , Ecker Alexander S.
Published: August 2024

Detection and tracking of animals is an important first step for automated behavioral studies in videos. Nowadays, animal tracking is mostly done using deep learning frameworks based on keypoints, which show remarkable results in lab settings with fixed cameras, backgrounds, and lighting. In contrast, multi-animal tracking in the wild is currently underexplored as it presents numerous challenges such as high background variability, lighting conditions, complex motion, and occlusion.

We propose a multi-animal tracking model, PriMAT, for nonhuman primates in the wild. The model learns to detect and track primates and other objects of interest from labeled videos or single images using bounding boxes instead of keypoints. Using bounding boxes significantly facilitates data annotation and allows for more robust results. Our one-stage model is conceptually simple but highly flexible, and we add a classification branch that allows us to train individual identification.

To evaluate the performance of our model, we applied it in two case studies with Assamese macaques and redfronted lemurs in the wild. We show that with only a few hundred frames labeled with bounding boxes, we can achieve robust tracking results. Combining these results with the classification branch, our model shows an accuracy of 83% in predicting lemur identities.

Our approach presents a promising solution for accurately tracking and identifying animals in the wild using deep learning based bounding box tracking, offering researchers a tool to study animal behavior in their natural habitats. Our code, models, training images, and evaluation video sequences are publicly available (https://github.com/ecker-lab/PriMAT-tracking), facilitating its use for animal behavior analyses and future research in this field.
Brewery Waste as a Sustainable Protein Source for the Banded Cricket (Gryllodes sigillatus)
Authors: Kasdorf Sophie Y , Muzzatti Matthew J , Haider Fouzia , Bertram Susan M , MacMillan Heath A
Published: August 2024

Crickets, like other edible insects, can convert organic by-products of the food and agricultural industries into high-value protein. Waste products high in protein like brewer's spent grain and brewer's spent yeast are particularly attractive replacements for unsustainable protein sources in cricket feed like fishmeal or soy. Such replacement will only be advantageous, however, if feeding on these waste products does not impact, or only minimally impacts, cricket survival, growth, and body composition. In this study, a farmed cricket species, Gryllodes sigillatus, was reared in isolation on experimental diets in which fishmeal was wholly or partially replaced with either brewer's spent grain or brewer's spent yeast. Cricket survival, development and macromolecular composition were not different across diets. However, wholly replacing fishmeal with brewer's spent yeast or brewer's spent grain reduced cricket adult body mass by approximately 16%. To extend these findings toward a farm environment, a second cohort of crickets were reared communally on diets in which fishmeal, and fishmeal and soy (a secondary protein source), were replaced by brewer's spent grain. We found that in a communal environment, crickets reared on both diets performed equally as well as the control. Therefore, brewing waste products are promising candidates for use as a primary protein source in the feed of G. sigillatus. In addition to contributing towards the goals of a circular bioeconomy through the repurposing of waste, the use of brewing waste in cricket feed may have a positive impact of the cricket farming industry as a cost-effective and sustainable alternative to traditional feed.
Joint Impacts of Nutrition and Socioeconomic Status on SARS-CoV-2 Antibody Titer in a Prospective Birth Cohort in Brazil
Authors: Vahora Moin , Leão Otávio , da Silveira Mariângela Freitas , Domingues Marlos Rodrigues , Hallal Pedro , Kraay Alicia N.M.
Published: August 2024

Purpose

In this study, we examine the joint effects of stunting and socioeconomic status (SES) on COVID-19 serostatus in Brazil and whether these patterns vary by COVID-19 vaccine status.

Methods

We use data from birth through the 7-year follow-up of the Pelotas 2015 birth cohort, including anthropometry, demographics, vaccination status, and COVID-19 antibody test results. We use linear regression models to examine the associations between SES (exposure) and stunting (effect modifier) on COVID-19 antibody titer among children who had not been vaccinated for COVID-19 (n=1,103) and among children who had been vaccinated (n=1,875).

Results

All SES strata had a statistically identical probability of testing positive. While not statistically significant, stunted children who were unvaccinated tended to have lower COVID-19 titers (difference -0.10, 95% CI: -0.21,0.004) compared with children who were not stunted, and this difference was attenuated among stunted children who were vaccinated. Duration of school enrollment was associated with increased antibody titer, with each month being associated with a 0.17 unit higher increase in OD titer (95% CI: 0.15, 0.18).

Conclusions

This result may suggest that stunted children have poorer immune responses to natural infection and thus lower immunity, but vaccination can overcome this deficit. Future recommendations include population-wide follow-up vaccination, particularly for stunted children. Given increasing antibody titer with a longer duration of school attendance, primary COVID-19 vaccination and potential boosters may be useful for children prior to school entry to reduce the risk of natural infection.
Effect of intermittent pringle manipulation on serum potassium concentration during laparoscopic hepatectomy: a self-controlled study protocol
Authors: Weng Yan , Shang Ziqi , Wang Yan , Liu Xiaojuan , Tang Yuling , Zhang Hua , Wu Chunmei , Mao Wenjie , Zhong Qing
Published: August 2024

Background Intermittent Pringle Manipulation (IPM) is among the most common methods used for controlling blood loss during hepatectomy. Ischaemia–reperfusion injury has also been associated with IPM. Ischaemic injury exposes the liver cells to hypoxia, adenosine triphosphate depletion, pH changes, and cellular metabolic stress, all of which can lead to cell damage and death. Reperfusion injury is caused by microcirculatory dysfunction, hypoxia, oxidative stress, and apoptosis. The pathophysiological mechanism of ischaemia-reperfusion injury is hyperkalaemia. Hyperkalaemia is closely related to the electrophysiological activity of the myocardium. Acute hyperkalaemia is associated with life-threatening ventricular arrhythmia and sudden cardiac arrest. Therefore, it is necessary to observe changes in patient serum potassium concentrations during IPM to provide a reference for developing a secure anaesthesia management approach. Methods and analysis This was a single-centre, open, non-interventional, self-controlled study. All eligible consecutive patients were recruited from a regional medical centre and scheduled for elective hepatectomy. There was no control group; all participants were continuously enrolled from 1 September 2023 to 31 August 2024. The primary outcome was the perioperative serum potassium concentration during IPM. Secondary outcomes included perioperative electrocardiogram changes, lactic acid status, postoperative serum potassium concentration, alanine amine transferase, and aspartate amine transferase peaks, adverse events, serious adverse events, and postoperative hospital stay. These parameters were statistically compared. Subgroup analysis will be performed according to liver disease type and duration of IPM. Discussion Our finding will provide a reference for developing a secure anaesthesia management approach for anesthesiologists. Ethics and dissemination The Biomedical Ethics Review Committee of the People’s Hospital of Jianyang City approved the study protocol (ethics reference: JY202383). All relevant ethical guidelines were followed in this study. The findings will be disseminated in peer-reviewed journals, publicly available reports to be published online, and academic conferences.
Explainable, federated deep learning model predicts disease progression risk of cutaneous squamous cell carcinoma
Authors: Pisula Juan I. , Helbig Doris , Sancéré Lucas , Persa Oana-Diana , Bürger Corinna , Fröhlich Anne , Lorenz Carina , Bingmann Sandra , Niebel Dennis , Drexler Konstantin , Landsberg Jennifer , Thomas Roman , Bozek Katarzyna , Brägelmann Johannes
Published: August 2024

Predicting cancer patient disease progression is a key step towards personalized medicine and secondary prevention. The ability to predict which patients are at an elevated risk of developing local recurrences or metastases would allow for tailored surveillance of these high-risk patients as well as enhanced and timely interventions.

We developed a deep learning transformer-based approach for prediction of progression of cutaneous squamous cell carcinoma (cSCC) patients based on diagnostic histopathology slides of the tumor. Our model, trained in a federated manner on patient cohorts from three clinical centers, reached an accuracy of AUROC=0.82, surpassing the predictive power of clinico-pathological parameters used to assess progression risk. We conducted an interpretability analysis, systematically comparing a broad range of spatial and morphological features that characterize tissue regions predictive of patient progression. Our findings suggest that information located at the tumor boundaries is predictive of patient progression and that heterogeneity of tissue morphology and organization are characteristic of progressive cSCCs. Trained in a federated fashion exclusively on standard diagnostic slides obtained during routine care of cSCC patients, our model can be deployed and expanded across other clinical centers. This approach thereby offers a potentially powerful tool for improved screening and thus better clinical management of cSCC patients.
Baseline drug treatments and long-term outcomes in COVID-19-hospitalized patients: results of the 2020 AUTCOV study
Authors: Graf Alexandra Christine , Reichardt Berthold , Wagenlechner Christine , Krotka Pavla , Traxler-Weidenauer Denise , Mildner Michael , Mascherbauer Julia , Aigner Clemens , Auer Johann , Wendt Ralph , Ankersmit Hendrik Jan
Published: August 2024

Limited data are available on long-term morbidity and mortality after COVID-19 hospitalization. In this population-based study, we investigated the long-term mortality and morbidity after COVID-19 hospitalization and associations with baseline drug treatments. Data were provided on hospitalized COVID-19 patients in 2020 and matched controls by the Austrian Health Insurance Funds. The primary outcome was all-cause mortality. Secondary outcomes were all-cause mortality conditional on COVID-hospital survival and re-hospitalization due to any reason. The median follow-up was 600 days. 22 571 patients aged >18 years were hospitalized in Austria in 2020 due to COVID-19. The risk of all-cause mortality was significantly higher with polypharmacy. With the exception of the youngest age group (19-40 years), antiepileptics, antipsychotics and the medicament group of iron supplements, erythropoietic stimulating agents, Vitamin B12, and folic acid were significantly associated with a higher risk of death (all p<0,001). For Non-steroidal anti-inflammatory drugs and other anti-inflammatory drugs, significantly increased survival was observed (all p<0,001). Patients had a higher drug prescription load than the control population. Long-term mortality and the risk of re-hospitalization due to any reason were also significantly greater in the patients. Antipsychotics are assumed to be an underrecognized medication group linked to worse outcomes after COVID-19 hospitalization.
Lung functions among children and adolescents with sickle cell disease receiving care at Jaramogi Oginga Odinga Teaching and Referral Hospital Kisumu, Kenya
Authors: Olewe Fredrick O. , Tenge Constance N. , Marete Irene K.
Published: August 2024

Sickle cell disease is a genetic disorder associated with lifelong symptoms of anemia, vaso-oclusive crisis and organ damage. Pulmonary complications and declining lung functions are contributors to morbidity and mortality. Determination of lung functions can enable early diagnosis and institution of appropriate intervention.

The objectives were; To determine the prevalence, patterns, and the factors associated with abnormal lung functions in children and adolescents aged 6-17 years with confirmed diagnosis Sickle Cell Disease.

This was a cross sectional study done at Jaramogi Oginga Odinga Teaching and Referral Hospital in Kisumu, Kenya. A total of 138 participants were recruited. A structured data collection tool was used to collect Socio-demographics and clinical characteristics. The spirometry was done using NDD Easy-On PC spirometer and results entered into database, cleaned and analyzed for proportions, frequency, mean, range and odds ratio at 95% confidence level.

Females were 65(47%), males 73(53%), and the mean age was 10.99 years with SD of 3.15. A total of 79(57%) were from rural and fuel used was fired wood 41%. Hospital admission were 84(61%), vaso-oclusive crisis 104 (75%), acute chest syndrome 61(44%) and blood transfusions 56(40%) in the last 12 months. Prevalence of abnormal lung functions was 28 % (39), restrictive pattern 26(67%) and obstructive pattern 13(33%). Urban setting (OR 24.101 p value 0.163), being female (OR 18.911 p value 0.069), and blood transfusion (OR 11.683 p value 0.195) had high odds ratio while, stable hydroxyurea use (OR 0.525 p value 0.678) and hospital admission (OR 0.048 p value 0.121) had low odds ratio, but not statistically significant.

One third had abnormal lung function mostly restrictive followed by obstructive pattern. Residence in urban setting, being female and blood transfusion had high odds ratio, while stable hydroxyurea use and hospital admission had low odds ratio but no statistically significant.
Comparison of Peripheral Nerve Injury Outcomes Between COVID-19 Survivors and Non-COVID Rehabilitation Inpatients: A Retrospective Study
Authors: Mondríguez-González Antonio , Rothemich Brian M. , Sheth Manasi , Swong Kevin N. , Franz Colin K.
Published: August 2024

Introduction

Peripheral nerve injury (PNI) is associated with severe Coronavirus disease 2019 (COVID-19) survivorship. The diagnosis of PNI is often made by a physiatrist during a detailed functional assessment during an inpatient rehabilitation stay. COVID-19 patients have elevated rates of medical comorbidities, including risk factors for acquired PNI, such as diabetes mellitus and obesity. It is not known if the functional prognosis from PNI in COVID-19 survivors differs substantially from PNI in other inpatient rehabilitation populations.

Objective

To determine the prognosis of PNI associated with severe COVID-19 survivorship and compare it to PNI associated with other inpatient rehabilitation populations.

Design

Retrospective chart review study.

Setting

Single-center inpatient rehabilitation hospital in a large urban city.

Patients

Adult patients admitted to an inpatient rehabilitation hospital with PNI(s).

Interventions

Not applicable.

Main Outcome Measures

The primary outcome was the change in manual muscle testing (MMT) over time. Secondary outcomes included the rate of peripheral nerve surgery and the number of distinct PNI sites per patient.

Results

The analysis consisted of 60 subjects with PNI. We identified 30 subjects who had PNI associated with COVID-19 and were matched with 30 subjects with PNI not associated with COVID-19 who were diagnosed during their inpatient rehabilitation admission. The data collected included basic demographics, COVID-19 status immediately before inpatient rehabilitation admission, medical comorbidities, acute rehabilitation inpatient diagnosis, nerve injury location and mechanism of injury, muscles affected, and change in serial MMT, plus documentation of any surgical intervention. No significant difference was found between the improvement of MMT, surgery rate, or number of nerve injuries and COVID-19 status.

Conclusion

PNIs associated with severe COVID-19 survivorship have similar recovery patterns as those of other etiologies. This data is reassuring that PNI associated with COVID-19 may be managed similarly to other types of PNI.
Risk factors and cognitive domain markers of progression in subjective cognitive decline
Authors: Bubu Omonigho M , Mbah Alfred K , Bernard Mark Anthony , Briggs Anthony Q , Faustin Arline , Gurin Lindsey , Rao Julia A , Ouedraogo Tall Sakina , Osorio Ricardo S , Masurkar Arjun V
Published: August 2024

We evaluated risk factor differences and cognitive domain markers associated with progression in subjects with subjective cognitive decline (SCD) at baseline from the NYU Alzheimer Disease Research Center. We included SCD non-decliners (n = 27), who remained stable, and decliners (n = 24), who progressed to mild cognitive impairment or worse, between the second to sixth yearly follow-up visits. Adjusted mixed-effects models examined group differences and associations between demographic, APOE status, psychometric test performance and comorbidities with longitudinal-decline. Overall, mean (SD) age was 67.4 (9.2) and total follow-up time was 5.1 (1.8) years. Lower education (14.9 (3.2) vs. 17.3 (2.1)), Hispanic ethnicity (50.0% vs. 11.0%), and hypercholesterolemia (aOR: 6.67), p ≤ 0.05 for all, were risk factors for progression in SCD, whereas APOE status was not. Notably, SCD decliners were at increased risk for both amnestic and non-amnestic cognitive-decline with psychometric changes in memory, executive, and language domains (p < 0.001 for all). These findings inform further work on SCD outcomes and related biomarkers, as well as preventive studies that target modifiable risk factors for SCD progression.
SERS Analysis Of Sialic Acid In Single Dendritic Cells Within The Tumor Microenvironment
Authors: Li Xingrui , Ma Lingling , Yang Xiaofei , Wang Nian , Bai Shiyu , Zhao Qiongzhen , Yang Yu , Huang Weidong , Su Zhengding , Li Jinyao
Published: August 2024

The crucial role of Dendritic Cells (DCs) in anti-tumor immune responses depends on surface Sialic Acid (SA). The regulation of DC surface sialic acid in the Tumor Microenvironment (TME) remains underexplored. Current methods struggle to provide highly sensitive, multiplex analyses of SA and other immune protein changes in single DCs within the tumor microenvironment. Here, we employed a SERS tags method for specific and highly sensitive analysis of SA, MHCII, CD86, and CD40 in DCs using a single DC analysis microfluidic platform. We also explored the differential regulatory effects of various immune-modulating drugs and tumor supernatant on multiple immunophenotypes of DCs in different immune states. The expanded two-cell microfluidic system further allows for phenotypic analysis of DCs at different time points within the tumor microenvironment. Given this method enables highly sensitive single-cell analysis of DCs, further development of this technology for tumor microenvironment applications will aid in deeply understanding the tumor-induced suppression of DC immune function, providing valuable insights for DC-mediated tumor immunotherapy research.
SOI: Robust identification of orthologous synteny with theOrthology Indexand broad applications in evolutionary genomics
Authors: Zhang Ren-Gang , Shang Hong-Yun , Milne Richard Ian , Almeida-Silva Fabricio , Chen Hengchi , Zhou Min-Jie , Shu Heng , Jia Kai-Hua , Van de Peer Yves , Ma Yong-Peng
Published: August 2024

With the explosive growth of whole-genome datasets, the accurate detection of orthologous synteny has become crucial for the reconstruction of evolutionary history. However, the currently available methods for the identification of orthologous synteny have great limitations: the methods are difficult to scale with varying polyploidy histories, and the accurate removal of out-paralogy is challenging. In this study, we developed a scalable and robust approach, theOrthology Index(OI), to identify orthologous synteny. Our evaluation of a large-scale dataset with diverse polyploidization events demonstrated that the technique is highly reliable. This discovery highlightsOIas a potentially unified criterion for the identification of orthologous synteny, and this is further validated using simulation-based benchmarks. In addition, we explore its broad applications in reconstructing the evolutionary histories of plant genomes, including inference of polyploidy, identification of reticulation, and phylogenomics. In conclusion,OIoffers a robust, interpretable, and scalable approach for identifying orthologous synteny, significantly enhancing our analytical prowess in plant evolutionary genomics.
Structural basis of phosphate export by human XPR1
Authors: He Qixian , Zhang Ran , Tury Sandrine , Courgnaud Valerie , Liu Fenglian , Battini Jean-luc , Li Baobin , Chen Qingfeng
Published: August 2024

Phosphorus is an essential element for all living organisms. While inorganic phosphate (Pi) cellular import is well documented, export is poorly characterized despite the recent discovery of the inositol pyrophosphate (PP-IP)-dependent Pi exporter XPR1. In this study, we determined the cryo-EM structures of XPR1. XPR1 forms a loose dimer, with each protomer containing 10 transmembrane helices (TMs) that can be divided into a peripheral domain (TM1, 3 and 4) and a core domain (TM2 and TM5-10) structurally related to ion-translocating rhodopsins. Bound Pi is observed in a tunnel formed by the α helical bundle inside the core domain at a narrowest point that separates the tunnel into an intracellular vestibule (IV) and an extracellular vestibule (EV). This narrowest point contains a cluster of Pi-coordinating basic residues, and their substitution by mutagenesis strongly impaired phosphate export. PP-IPs stimulate XPR1 activity by binding to its SPX domain. Loss of this interaction induces a conformational change of the wide open EV (conducting state) into a collapsed EV (closed state), mainly caused by structural movements of TM9 and the bulky sidechain of Trp573 right above the Pi binding site, which are essential for the Pi export activity of XPR1. Our structural and functional characterization paves the way for further in-depth studies of XPR1.
Sensitive and modular amplicon sequencing ofPlasmodium falciparumdiversity and resistance for research and public health
Authors: Aranda-Díaz Andrés , Vickers Eric Neubauer , Murie Kathryn , Palmer Brian , Hathaway Nicholas , Gerlovina Inna , Boene Simone , Garcia-Ulloa Manuel , Cisteró Pau , Katairo Thomas , Semakuba Francis Ddumba , Nsengimaana Bienvenu , Gwarinda Hazel , García-Fernández Carla , Louie William , Esayas Endashaw , Silva Clemente Da , Datta Debayan , Kiyaga Shahiid , Wiringilimaana Innocent , Fekele Sindew Mekasha , Bennett Adam , Smith Jennifer L. , Gadisa Endalamaw , Parr Jonathan B. , Conrad Melissa , Raman Jaishree , Tukwasibwe Stephen , Ssewanyana Isaac , Rovira-Vallbona Eduard , Tato Cristina M. , Briggs Jessica , Mayor Alfredo , Greenhouse Bryan
Published: August 2024

Background

Targeted amplicon sequencing is a powerful and efficient tool for interrogating thePlasmodium falciparumgenome, generating actionable data from infections to complement traditional malaria epidemiology. For maximum impact, genomic tools should be multi-purpose, robust, sensitive, and reproducible.

Methods

We developed, characterized, and implemented MAD4HatTeR, an amplicon sequencing panel based on Multiplex Amplicons for Drug, Diagnostic, Diversity, and Differentiation Haplotypes using Targeted Resequencing, along with a bioinformatic pipeline for data analysis. Additionally, we introduce an analytical approach to detect gene duplications and deletions from amplicon sequencing data. Laboratory control and field samples were used to demonstrate the panel’s high sensitivity and robustness.

Results

MAD4HatTeR targets 165 highly diverse loci, focusing on multiallelic microhaplotypes, key markers for drug and diagnostic resistance (including duplications and deletions), andcspand potential vaccine targets. The panel can also detect non-falciparum Plasmodiumspecies. MAD4HatTeR successfully generated data from low-parasite-density dried blood spot and mosquito midgut samples, and detected minor alleles at within-sample allele frequencies as low as 1% with high specificity in high-parasite-density dried blood spot samples. Gene deletions and duplications were reliably detected in mono- and polyclonal controls. Data generated by MAD4HatTeR were highly reproducible across multiple laboratories.

Conclusions

The successful implementation of MAD4HatTeR in five laboratories, including three in malaria-endemic African countries, showcases its feasibility and reproducibility in diverse settings. MAD4HatTeR is thus a powerful tool for research and a robust resource for malaria public health surveillance and control.
Deconvolution of cancer methylation patterns determines that altered methylation in cancer is dominated by a non-disease associated proliferation signal
Authors: Lalchungnunga H , Atasoy H , Schwalbe EC , Bacon CM , Strathdee G
Published: August 2024

All cancers are associated with massive reorganisation of cellular epigenetic patterns, including extensive changes in the genomic patterns of DNA methylation. However, the huge scale of these changes has made it very challenging to identify key DNA methylation changes responsible for driving cancer development. Here, we present a novel approach to address this problem called methylation mapping. Through comparison of multiple types of B-lymphocyte derived malignancies and normal cell populations, this approach can define the origins of methylation changes as proliferation-driven, differentiation-driven and disease-driven (including both cancer-specific changes and cancer absent changes). Each of these categories of methylation change were found to occur at genomic regions that vary in sequence context, chromatin structure and associated transcription factors, implying underlying mechanistic differences behind the acquisition of methylation at each category. This analysis determined that only a very small fraction (about 3%) of DNA methylation changes in B-cell cancers are disease related, with the overwhelming majority (97%) being driven by normal biological processes, predominantly cell proliferation. Furthermore, the low level of true disease-specific changes can potentially simplify identification of functionally relevant DNA methylation changes, allowing identification of previously unappreciated candidate drivers of cancer development, as illustrated here by the identification and functional confirmation ofSLC22A15as a novel tumour suppressor candidate in acute lymphoblastic leukaemia. Overall, this approach should lead to a clearer understanding of the role of altered DNA methylation in cancer development, facilitate the identification of DNA methylation targeted genes with genuine functional roles in cancer development and thus identify novel therapeutic targets.
Neuropeptides from a praying mantis: What the loss of pyrokinins and tryptopyrokinins suggests about the endocrine functions of these peptides
Authors: Veenstra Jan Adrianus
Published: August 2024

Background. Neuropeptides play important roles in insects, but in many cases their functions remain obscure. Comparative neuropeptidome analyses may provide clues to what these functions might be. Praying mantises are predators and close relatives of cockroaches that are scavengers. Cockroach neuropeptidomes are well established, but little is known about mantis neuropeptides. The recently published genome assembly of the praying mantis Tenodera sinensis makes it possble to change that. Methods. The genome assembly from T. sinensis was analyzed for the presence of genes coding neuropeptides. For comparison publicly available short read archives from this and other mantis species were also examined for the presence and expression of neuropeptides. Results. As a rule the neuropeptidomes of the Mantodea and Blattodea are almost identical; praying mantises and cockroaches use very similar neuropeptides. However, there is one surprising exception. Praying mantises lack the receptors for pyrokinins, including those for the tryptopyrokinins. No typical pyrokinin genes were found, but some species do have a tryptopyrokinin gene, in others this has also been lost and in one species it is a speudogene. For most praying mantises there is no information where tryptopyrokinin is expressed, but in Deroplatys truncata it is in the thorax and thus not in the suboesophageal ganglion as in other insects. In the genomic short read archives of two species, out 52, sequences were found for a tryptopyrokinin specific receptor. The phylogenetic position of those two species implies that the receptor gene was independently lost on multiple occasions. The loss of the tryptopyrokinin gene also happened more than once. Discussion. The multiple independent losses of the pyrokinin receptors in mantises suggests that these receptors are irrelevant in praying mantises. This is very surprising, since expression of tryptopyrokinin is very strongly conserved in two neuroendocrine cells in the suboeosphageal ganglion. In those species for which this is known, the expression of its receptor is in the salivary gland. As a neuroendocrine. tryptopyrokinin is unlikely to acutely regulate salivation, which in other insects is regulated by well characterized neurons. If the action of tryptopyrokinin were to prime the salivary gland for subsequent salivation, it would make perfect sense for a praying mantis to loose this capacity, as they can not anticipate when they will catch their next prey. Priming the salivary gland hours before it is actually needed would be energetically costly. The other pyrokinins are known to facilitate feeding and may in a similar fashion prime muscles needed for moving to the food source and digesting it. This hypothesis provides a good explanation as to why praying mantises do not need pyrokinins and also what the function of these ubiquitous arthropod neuropeptides may be.
Castor is a temporal transcription factor that specifies early born central complex neuron identity
Authors: Dillon Noah R , Doe Chris Q
Published: August 2024

The generation of neuronal diversity is important for brain function, but how diversity is generated is incompletely understood. We used the development of the Drosophila central complex (CX) to address this question. The CX develops from eight bilateral Type 2 neuroblasts (T2NBs), which generate hundreds of different neuronal types. T2NBs express broad opposing temporal gradients of RNA-binding proteins. It remains unknown whether these protein gradients are sufficient to directly generate all known neuronal diversity, or whether there are temporal transcription factors (TTFs) with narrow expression windows that each specify a small subset of CX neuron identities. Multiple candidate TTFs have been identified, but their function remains uncharacterized. Here, we show that: (i) the adult E-PG neurons are born from early larval T2NBs; (ii) the candidate TTF Castor is expressed transiently in early larval T2NBs when E-PG and P-EN neurons are born; and (iii) that Castor is required to specify early born E-PG and P-EN neuron identities. We conclude that Castor is a TTF in larval T2NB lineages that specifies multiple, early born CX neuron identities.
The Common Marmoset as a Translational Model for Longitudinal Studies of Cognitive Aging and Individual Vulnerability to Decline
Authors: Vanderlip Casey R. , Asch Payton A. , Glavis-Bloom Courtney
Published: August 2024

In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.
Nageotte nodules in human DRG reveal neurodegeneration in painful diabetic neuropathy
Authors: Shiers Stephanie , Mazhar Khadijah , Wangzhou Andy , Haberberger Rainer V , Lesnak Joseph B , Sankaranarayanan Ishwarya , Tavares-Ferreira Diana , Cervantes Anna , Funk Geoffrey , Horton Peter , Vines Erin , Dussor Gregory , Price Theodore J
Published: August 2024

Diabetic neuropathy is frequently accompanied by pain and loss of sensation attributed to axonal dieback. We recovered dorsal root ganglia (DRGs) from 90 organ donors, 19 of whom had medical indices for diabetic painful neuropathy (DPN). Nageotte nodules, dead sensory neurons engulfed by non-neuronal cells, were abundant in DPN DRGs and accounted for 25% of all neurons. Peripherin-and Nav1.7-positive dystrophic axons invaded Nageotte nodules, forming small neuroma-like structures. Using histology and spatial sequencing, we demonstrate that Nageotte nodules are mainly composed of satellite glia and non-myelinating Schwann cells that express SPP1 and are intertwined with sprouting sensory axons originating from neighboring neurons. Our findings solve a 100-year mystery of the nature of Nageotte nodules linking these pathological structures to pain and sensory loss in DPN.
Bidirectional locomotion induces unilateral limb adaptations
Authors: Hardesty Russell L. , Motjabavi Helia , Gemoets Darren E. , Wolpaw Jonathan R.
Published: August 2024

Humans can acquire and maintain motor skills throughout their lives through motor learning. Motor learning and skill acquisition are essential for rehabilitation following neurological disease or injury. Adaptation, the initial stage of motor learning, involves short-term changes in motor performance in response to a new demand in the person’s environment. Repeated adaptation can improve skill performance and result in long-term skill retention. Locomotor adaptation is extensively studied using split-belt treadmill paradigms. In this study we explored whether bidirectional walking (BDW) on a split-belt treadmill can induce short-term gait adaptations. Twelve healthy volunteers participated in our single session, starting with 2 minutes of normal walking (NW), followed by four 5-minute blocks of BDW with a 1-minute passive rest in between blocks, and ending with another 2-minute of NW. We recorded body kinematics and ground reaction forces throughout the experiment. Participants quickly adapted to BDW with both legs showing decreased step lengths. However, only the backward-walking leg exhibited aftereffects upon returning to NW, indicating short-term adaptation. Notable kinematic changes were observed, particularly in hip extension and pelvis tilt, though these varied among participants. Our findings suggest that BDW induces unilateral adaptations despite bilateral changes in gait, offering new insights into locomotor control and spinal CPG organization.

Key Points

Locomotor adaptation extensively studied using split-belt treadmill paradigms with asymmetric belt speeds.

This study examined whether bidirectional walking, i.e. walking with each leg stepping in opposite directions, would induce short-term adaptations in spatiotemporal characteristics of gait.

Volunteers performed bidirectional walking with bilateral changes in step length.

Despite equal but opposite belt speeds, volunteers exhibited a unilateral aftereffect of decreased step length in the leg which performed backwards stepping during bidirectional walking.