bluuebunny/crossref_metadata_2025_split huggingface dataset:
PHARAOH: A collaborative crowdsourcing platform for PHenotyping And Regional Analysis Of Histology
Authors: Faust Kevin , Chen Min Li , Zadeh Parsa Babaei , Oreopoulos Dimitrios , Leon Alberto J. , Kamski-Hennekam Evelyn Rose , Mikhail Marly , Duan Xianpi , Duan Xianzhao , Liu Mugeng , Ahangari Narges , Cotau Raul , Castillo Vincent Francis , Nikzad Nikfar , Sugden Richard J. , Murphy Patrick , Done Susan , Aljohani Safiyh S. , Echelard Philippe , Jakate Kiran , Alwelaie Yazeed , Alyousef Mohammed J. , Alsafwani Noor Said , Alrumeh Assem Saleh , Saleeb Rola , Richer Maxime , Marins Lidiane Vieira , Yousef George M. , Diamandis Phedias 
Published: March 2024

ABSTRACTDeep learning has proven to be capable of automating key aspects of histopathologic analysis, but its continual reliance on large expert-annotated training datasets hinders widespread adoption. Here, we present an online collaborative portal that streamlines tissue image annotation to promote the development and sharing of custom computer vision models for PHenotyping And Regional Analysis Of Histology (PHARAOH;https://www.pathologyreports.ai/). PHARAOH uses a weakly supervised active learning framework whereby patch-level image features are leveraged to organize large swaths of tissue into morphologically-uniform clusters for batched human annotation. By providing cluster-level labels on only a handful of cases, we show how custom PHARAOH models can be developed and used to guide the quantification of cellular features that correlate with molecular, pathologic and patient outcome data. Both custom model design and feature extraction pipelines are amenable to crowdsourcing making PHARAOH a fully scalable systems-level solution for the systematic expansion and cataloging of computational pathology applications.
In Vitro Efficacy of Next Generation Dihydrotriazines and Biguanides Against Babesiosis and Malaria Parasites
Authors: Vydyam Pratap , Chand Meenal , Gihaz Shalev , Renard Isaline , Heffernan Gavin D. , Jacobus Laura R. , Jacobus David P. , Saionz Kurt W. , Shah Raju , Shieh Hong-Ming , Terpinski Jacek , Zhao Wenyi , Cornillot Emmanuel , Mamoun Choukri Ben 
Published: March 2024

AbstractBabesiaandPlasmodiumpathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutics strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus are vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates such as the aminopyrimidine, pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here we utilized an in vitro culture condition suitable for continuous propagation ofB. duncani, B. divergens, B. MO1andP. falciparumin human erythrocytes to screen a library of 51 dihydrotriazines and 28 biguanides for their efficacy in vitro and to compare their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including theP. falciparumpyrimethamine-resistant strain HB3 with IC50values below 10 nM and demonstrated excellent therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.
Molecular stratification of human fetal vaginal epithelium by spatial transcriptome analysis
Authors: Ye Ziying , Jiang Peipei , Zhu Qi , Pei Zhongrui , Hu Yali , Zhao Guangfeng 
Published: March 2024

AbstractThe human vaginal epithelium is a crucial component in numerous reproductive processes and serves as a vital protective barrier against pathogenic invasion. Despite its significance, a comprehensive exploration of its molecular profiles, including molecule expression and distribution across its multiple layers, remains elusive. In our study, we undertook a spatial transcriptomic analysis within the vaginal wall of human fetuses to fill this knowledge gap. We successfully categorized vaginal epithelium into four distinct zones based on their transcriptomic profiles and anatomical features. This approach unveiled unique transcriptomic signatures within these regions, allowing us to identify differentially expressed genes and uncover novel markers for distinct regions of the vaginal epithelium. Additionally, our findings have highlighted the varied expression of KRT genes across different zone of the vaginal epithelium, with a gradual shift in expression patterns observed from the basal layer to the surface/superficial layer. This suggests a potential differentiation trajectory of human vaginal epithelium, shedding light on the dynamic nature of this tissue. Furthermore, abundant biological processes were found to be enriched in the basal zone by the KEGG pathway analysis, indicating an active state of the basal zone cells. Subsequently, the expression of latent stem cell markers in the basal zone were identified. In summary, our research provides crucial understanding of human vaginal epithelial cells and the complex mechanisms of the vaginal mucosa, with potential applications in vaginal reconstruction and drug delivery, making this atlas a valuable tool for future research in women’s health and reproductive medicine.
Sensory integration of food availability and population density during the diapause exit decision involves insulin-like signaling inCaenorhabditis elegans
Authors: Zhang Mark G , Seyedolmohadesin Maedeh , Hawk Soraya , Park Heenam , Finnen Nerissa , Schroeder Frank , Venkatachalam Vivek , Sternberg Paul W 
Published: March 2024

AbstractDecisions made over long time scales, such as life cycle decisions, require coordinated interplay between sensory perception and sustained gene expression. TheCaenorhabditis elegansdauer (or diapause) exit developmental decision requires sensory integration of population density and food availability to induce an all-or-nothing organismal-wide response, but the mechanism by which this occurs remains unknown. Here, we demonstrate how the ASJ chemosensory neurons, known to be critical for dauer exit, perform sensory integration at both the levels of gene expression and calcium activity. In response to favorable conditions, dauers rapidly produce and secrete the dauer exit-promoting insulin-like peptide INS-6. Expression ofins-6in the ASJ neurons integrate population density and food level and can reflect decision commitment since dauers committed to exiting have higherins-6expression levels than those of non-committed dauers. Calcium imaging in dauers reveals that the ASJ neurons are activated by food, and this activity is suppressed by pheromone, indicating that sensory integration also occurs at the level of calcium transients. We find thatins-6expression in the ASJ neurons depends on neuronal activity in the ASJs, cGMP signaling, a CaM-kinase pathway, and the pheromone components ascr#8 and ascr#2. We propose a model in which decision commitment to exit the dauer state involves an autoregulatory feedback loop in the ASJ neurons that promotes high INS-6 production and secretion. These results collectively demonstrate how insulin-like peptide signaling helps animals compute long-term decisions by bridging sensory perception to decision execution.Summary/Significance StatementAnimals must respond appropriately to multiple sensory stimuli to make informed decisions. It remains unclear how the nervous system is able to integrate different sensory cues and propagate that information towards making decisions over longer timescales. We use the nematodeCaenorhabditis elegansto investigate how sensory integration occurs during the decision to exit diapause, a stress-resistant developmentally arrested state triggered by multiple sensory inputs including food availability and population density. We show how expression of an insulin-like peptide critical to dauer exit reflects the sensory integration process and decision commitment, and we dissect the regulation of this insulin-like peptide’s expression. Our study explicitly analyzes the relationship between neuronal activity and neuropeptide expression during a complex decision with diverse sensory inputs.
Blood immune profiles reveal a CXCR3/CCR5 axis of dysregulation in early sepsis
Authors: Kealy David , Wilson Julie , Jaconelli Tom , Hogg Karen , Coop Rebecca , Forshaw Greg , Todd Neil , Yates David , Signoret Nathalie 
Published: March 2024

AbstractSepsis is defined as a systemic inflammatory host response syndrome after serious microbial infection, which requires prompt treatment to lower the risk of complications and death. However, early sepsis recognition can be a challenge at presentation when patients show symptoms difficult to distinguish from other acute conditions.We designed a pilot study to explore whether blood immune signatures could reveal early specific indicator profiles for patients meeting sepsis criteria upon admission at the hospital Emergency Department. We analysed blood samples from study-recruited sepsis-suspected patients (N=20) and of age-spanning healthy volunteers (N=12), using flow cytometry-based assays. 25 circulating inflammatory cytokines and chemokines (CCs) were measured from blood plasma, while freshly isolated unfixed blood leukocytes were immunophenotyped to ascertain major cell subsets representation and expression of activation markers, including chemokine receptors. We found that beside IL-6 and sCD14, blood levels of CXCL9 and CXCL10 (two ligands of CXCR3) show good separation between healthy controls and sepsis-suspected patients. The abundance of CD4+T cells was significantly reduced while the expression of chemokine receptors was altered on monocytes, B and all T cells from patients. In particular, we report substantial losses of CCR5-expressing monocytes and CXCR3/CCR5 double positive T cells. Full dataset analysis and post-hoc subgrouping of patients according to their diagnosis on discharge (confirmed or unconfirmed sepsis), identified CXCR3/CCR5 double expression on T cells as a separating characteristic within the study. Overall, our observational study suggests a new CCR5 and CXCL9-10/CXCR3 axis of dysregulation in early sepsis.
MULTIPLE ENDEMIC EQUILIBRIA IN AN ENVIRONMENTALLY-TRANSMITTED DISEASE WITH THREE DISEASE STAGES
Authors: Islas José Manuel , Corona-Moreno Ruth , Velasco-Hernández Jorge X. 
Published: March 2024

ABSTRACTWe construct, analyze and interpret a mathematical model for an environmental transmitted disease characterized for the existence of three disease stages, acute, severe and asymptomatic where severe and asymptomatic cases may present relapse between them. Transmission dynamics driven by the contact rates (as normally occur in directly-transmitted or vector-transmitted diseases) only occurs when a parameterR*>1. In this case, the forward transcritical bifurcation that exists forR*<1, becomes a backward bifurcation, producing multiple steady-states, a hysteresis effect and dependence on initial conditions. A threshold parameter for an epidemic outbreak, independent ofR*is only the ratio of the external contamination inflow shedding rate to the environmental clearance rate.R*describes the strength of the transmission to infectious classes other than theI-(acute) type infections. The epidemic outbreak conditions and the structure ofR*appearing in this model are both resposible for the existence of endemic states.
Risk factors for anaemia among pregnant women: A cross-sectional study in Upper East Region, Ghana
Authors: Asobuno Clotilda , Adjei-Gyamfi Silas , Aabebe Felix Gumaayiri , Hammond John , Taikeophithoun Chansathit , Amuna Norbert Ndaah , Aoki Tsunoneri , Aiga Hirotsugu 
Published: March 2024

AbstractBackgroundAnaemia in pregnancy (AIP) is a public health concern due to its devastating effects on women and their unborn babies, resulting in increased maternal and neonatal deaths in developing countries. Despite several Ghanaian health policies to combat AIP, AIP is still on the rise. It becomes imperative to identify geographic-specific factors for developing appropriate interventions for the management of AIP. However, Kassena Nankana West District (KNWD) in the Upper East Region of Ghana lacks a study on anaemia risk factors, therefore, this study estimated the prevalence and risk factors for anaemia among pregnant women in the district.MethodsA household-based cross-sectional study was conducted on 376 pregnant women in their third trimester from February to March 2023. Anthropometric, obstetric, sociodemographic, and health facility resource characteristics were collected using structured questionnaires and antenatal records. Mixed-effect logistic regression was used to identify independent factors of anaemia at 95% confidence interval.ResultsPrevalence of AIP was 53.9%. Mild, moderate, and severe anaemia prevalence was 16.9%, 35.3%, and 1.7% respectively. Malaria infection during pregnancy (aOR=1.563; 95%CI:1.087 – 2.475) and accessing health facilities without trained laboratory personnel (aOR=5.271; 95%CI:1.641 – 16.93) were associated with increased odds of AIP. Belonging to the major ethnic group (aOR=0.431; 95%CI:0.280 – 0.675), accessing health facilities without laboratory services (aOR=0.151; 95%CI:0.047 – 0.487), and accessing health facilities without sulphadoxine-pyrimethamine drugs (aOR=0.234; 95%CI:0.061 – 0.897) in KNWD were also associated with decreased odds of AIP.ConclusionAIP prevalence remains high in the KNWD. Maternal and health facility-related factors were responsible for anaemia in the district. These factors are preventable. Therefore, health facility strengthening and enhanced strategies for malaria prevention are recommended for anaemia control in the district.
Psychological distress after COVID-19 recovery and subsequent prolonged post-acute sequelae of COVID-19: A longitudinal study with 1-year follow-up in Japan
Authors: Hazumi Megumi , Kataoka Mayumi , Narita Zui , Usuda Kentaro , Okazaki Emi , Nishi Daisuke 
Published: March 2024

AbstractBackgroundThis study investigated the longitudinal association between psychological distress in the post-acute phase and the subsequent prolonged post-acute sequelae of COVID-19 (PASC) among individuals with PASC.MethodsAn online longitudinal survey with 1-year interval was conducted from July to September 2021 (T1) and July to September 2022 (T2). Individuals who were 20-years-old or older, had a positive Polymerase Chain Reaction test, were one month post-infection, and did not select “Nothing” to a question regarding PASC presence were included. The primary outcome was the presence of PASC at T2. The presence of general, respiratory, muscular, neurological, gastrointestinal, dermatological, and cardiac symptoms at T2 was also used as an outcome among patients with relevant symptoms at time 1 (T1). Exposure was measured using the Kessler distress scale (K6) at T1, and those whose K6 was 13 or higher were identified as having psychological distress. Marginal structure models with robust standard errors were used to examine the association between psychological distress at T1 and any PASC symptoms at T2, and the associations between psychological distress and each symptom at T2 among participants with relevant symptoms at T1.ResultsA total of 1674 patients were analyzed; 17%had psychological distress. ; In total, 818 (48.9%), 523 (31.2%), and 672 (40.1%) patients reported general, respiratory, and neurological symptoms at T1, respectively. Individuals with psychological distress had higher odds of any symptoms at T2 (Odds Ratio [OR] =1.81, 95% Confidence Interval [CI]= 1.08 – 3.03) and general and respiratory symptoms at T2 among participants with relevant symptoms at T1 (OR = 1.95, 95% CI = 1.02 – 3.76; OR = 2.44, 95% CI = 1.03 – 5.80).ConclusionPsychological distress in the post-acute phase may lead to prolonged PASC symptoms, mainly general and respiratory symptoms, at the 1-year follow-up in individuals with PASC.Key MessagesPsychological distress before infection and during the acute phase predicts prolonged Post-Acute Sequelae of COVID-19 (PASC); however, in individuals with PASC, it is unclear whether psychological distress during the post-acute phase predicts prolonged PASC. This longitudinal survey indicated that psychological distress in the post-acute phase led to prolonged any levels of PASC, especially general and respiratory symptoms, at the 1-year follow-up. Therefore, mental health care for individuals with PASC may help to improve or mitigate prolonged PASC.
Engineering of highly active and diverse nuclease enzymes by combining machine learning and ultra-high-throughput screening
Authors: Thomas Neil , Belanger David , Xu Chenling , Lee Hanson , Hirano Kathleen , Iwai Kosuke , Polic Vanja , Nyberg Kendra D , Hoff Kevin G , Frenz Lucas , Emrich Charlie A , Kim Jun W , Chavarha Mariya , Ramanan Abi , Agresti Jeremy J , Colwell Lucy J 
Published: March 2024

AbstractOptimizing enzymes to function in novel chemical environments is a central goal of synthetic biology, but optimization is often hindered by a rugged, expansive protein search space and costly experiments. In this work, we present TeleProt, an ML framework that blends evolutionary and experimental data to design diverse protein variant libraries, and employ it to improve the catalytic activity of a nuclease enzyme that degrades biofilms that accumulate on chronic wounds. After multiple rounds of high-throughput experiments using both TeleProt and standard directed evolution (DE) approaches in parallel, we find that our approach found a significantly better top-performing enzyme variant than DE, had a better hit rate at finding diverse, high-activity variants, and was even able to design a high-performance initial library using no prior experimental data. We have released a dataset of 55K nuclease variants, one of the most extensive genotype-phenotype enzyme activity landscapes to date, to drive further progress in ML-guided design.
Hepatitis B Virus genomes associate with cellular sites of DNA damage by inducing replication stress
Authors: Marcoe Gavin J. , Larsen Clairine I. S. , Majumder Kinjal 
Published: March 2024

AbstractHepatitis B Virus (HBV) is a leading cause of liver cancer, with almost 300 million infected individuals worldwide. Although HBV-infected patients benefit from drug regimens that help to control chronic infection, they are rarely clinically cured of HBV. The HBV genome persists in the nucleus of infected hepatocytes in the form of a covalently closed circular DNA (cccDNA) molecule, a reservoir of HBV DNA molecules that serve as the template for reactivation of long-term chronic HBV. However, despite playing a central role in the viral life cycle, little is understood about where cccDNA molecules localize, why they are so stable, and how they impact the host nuclear compartment. Perhaps because of this, there are few treatments that target cccDNA, which is critical for eradication of clinical HBV. Here, we show that HBV infection induces a cellular DNA Damage Response (DDR) that is comparable with cells undergoing replication stress, and this cellular replication stress is initiatedafterthe formation of cellular cccDNA molecules. Using a novel high-throughput chromosome conformation capture technology that monitors the localization of HBV cccDNA molecules, we show that cccDNA molecules persist in the vicinity of many cellular fragile sites. Induction of cellular DNA damage leads to relocalization of the viral HBx oncoprotein to DDR sites in an ATM, ATR and DNA-PK dependent manner. Our findings contribute to the understanding of how HBV cccDNA navigates the host nuclear environment, identifying functional targets for development of therapies against HBV infection and resulting liver cancer.ImportanceHepatitis B Virus (HBV) is the leading infectious cause of liver cancer globally. The virus persists in the nucleus long term by forming reservoirs in human liver cells. We have discovered that the HBV DNA localizes to sites on the host genome associated with DNA damage, and in doing so, HBV interferes with the host’s ability to efficiently amplify itself. This results in the induction of cellular DNA breaks, which we propose contributes to eventual cancer progression. Our findings provide new insights into how HBV infection may lead to liver cancer.
A high-throughput zebrafish screen identifies novel candidate treatments for Kaposiform Lymphangiomatosis (KLA)
Authors: Bassi Ivan , Jabali Amani , Farag Naama , Egozi Shany , Moshe Noga , Leichner Gil S. , Geva Polina , Levin Lotan , Barzilai Aviv , Avivi Camila , Long Jonathan , Otterstrom Jason J. , Paran Yael , Barr Haim , Yaniv Karina , Greenberger Shoshana 
Published: March 2024

AbstractKaposiform Lymphangiomatosis (KLA) is a rare, aggressive, and incurable disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by driving conditional expression of the human NRAS mutation in venous and lymphatic ECs. We find that mutant embryos recapitulated clinical features of KLA, including pericardial edema and a dilated thoracic duct, and that the phenotypes were reverted by Trametinib, a MEK inhibitor used for KLA treatment. We further leverage this model in combination with an AI-based high-throughput drug screening platform to search for small compounds selectively reverting the mutant phenotypes and identify Cabozantinib, an FDA-approved tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as leading hits. Finally, we test these drugs in cultured cells derived from KLA patient and demonstrate their ability to normalize LEC sprouting and block NRAS downstream pathways, underscoring the potential of GSK690693 and Cabozantinib as potential KLA treatments. Overall, our novel zebrafish model provides a valuable tool for research into the etiology of KLA and for identifying new therapeutic avenues.