bluuebunny/crossref_metadata_2025 huggingface dataset:
Moesin controls cell-cell fusion and osteoclast function
Authors: Dufrancais Ophélie , Verdys Perrine , Plozza Marianna , Métais Arnaud , Juzans Marie , Sanchez Thibaut , Bergert Martin , Halper Julia , Panebianco Christopher J , Mascarau Rémi , Gence Rémi , Arnaud Gaëlle , Neji Myriam Ben , Maridonneau-Parini Isabelle , Cabec Véronique Le , Boerckel Joel D , Pavlos Nathan J , Diz-Muñoz Alba , Lagarrigue Frédéric , Blin-Wakkach Claudine , Carréno Sébastien , Poincloux Renaud , Burkhardt Janis K , Raynaud-Messina Brigitte , Vérollet Christel
Published: May 2024

Cell-cell fusion is an evolutionarily conserved process that is essential for many functions, including fertilisation and the formation of placenta, muscle and osteoclasts, multinucleated cells that are unique in their ability to resorb bone. The mechanisms of osteoclast multinucleation involve dynamic interactions between the actin cytoskeleton and the plasma membrane that are still poorly characterized. Here, we found that moesin, a cytoskeletal linker protein member of the Ezrin/Radixin/Moesin (ERM) protein family, is activated during osteoclast maturation and plays an instrumental role in both osteoclast fusion and function. In mouse and human osteoclast precursors, moesin inhibition favors their ability to fuse into multinucleated osteoclasts. Accordingly, we demonstrated that moesin depletion decreases membrane-to-cortex attachment and enhances the formation of tunneling nanotubes (TNTs), F-actin-based intercellular bridges that we reveal here to trigger cell-cell fusion. Moesin also controls HIV-1- and inflammation-induced cell fusion. In addition, moesin regulates the formation of the sealing zone, the adhesive structure determining osteoclast bone resorption area, and thus controls bone degradation, via a β3-integrin/RhoA/SLK pathway. Supporting our results, moesin-deficient mice present a reduced density of trabecular bones and increased osteoclast abundance and activity. These findings provide a better understanding of the regulation of cell-cell fusion and osteoclast biology, opening new opportunities to specifically target osteoclast activity in bone disease therapy.
Recurrent extreme climatic events are driving gorgonian populations to local extinction: low adaptive potential to marine heatwaves
Authors: Ramirez-Calero Sandra , Gómez-Gras D , Barreiro A , Bensoussan N , Figuerola-Ferrando L , Jou M , López-Sanz A , López-Sendino P , Medrano A , Montero-Serra I , Pagès-Escolà M , Linares C , Ledoux JB , Garrabou J
Published: May 2024

Extreme climatic events (ECEs), such as marine heatwaves (MHWs), are a major threat to biodiversity. Understanding the variability in ecological responses to recurrent ECEs within species and underlying drivers arise as a key issue owing to their implications for conservation and restoration. Yet, our knowledge on such ecological responses is limited since it has been mostly gathered following “single-event approaches” focused on one particular event. These approaches provide snapshots of ecological responses but fall short of capturing heterogeneity patterns that may occur among recurrent ECEs, questioning current predictions regarding biodiversity trends. Here, we adopt a “multi-event” perspective to characterize the effects of recurrent ECEs and the ecological responses inParamuricea clavata, a Mediterranean temperate coral threatened by MHWs. Through a common-garden experiment repeated three consecutive years with the same individuals from three populations, we assessed the respective roles of environmental (year effect), genetic (population effect) and phenotypic (population-by-environmentinteractions effect) components in the ecological response to recurrent heat stress. The environmental component (year) was the main driver underlying the responses ofP. clavatacolonies across experiments. To build on this result, we showed that: i) the ecological responses were not related to population (genetic isolation) and individual (multilocus heterozygosity) genetic make-up, ii) while all the individuals were characterized by a high environmental sensitivity (genotype-by-environmentinteractions) likely driven byin-situsummer thermal regime. We confront our experimental results toin situmonitoring of the same individuals conducted in 2022 following two MHWs (2018, 2022). This confirms that the targeted populations harbor limited adaptive and plastic capacities to on-going recurrent ECEs and thatP. clavatamight face unavoidable population collapses in shallow Mediterranean waters. Overall, we suggest that biodiversity forecasts based on “single event” experiments may be overly optimistic and underscore the need to consider the recurrence of ECEs in assessing threats to biodiversity.
Cooperative coding of continuous variables in networks with sparsity constraint
Authors: Züge Paul , Memmesheimer Raoul-Martin
Published: May 2024

A hallmark of biological and artificial neural networks is that neurons tile the range of continuous sensory inputs and intrinsic variables with overlapping responses. It is characteristic for the underlying recurrent connectivity in the cortex that neurons with similar tuning predominantly excite each other. The reason for such an architecture is not clear. Using an analytically tractable model, we show that it can naturally arise from a cooperative coding scheme. In this scheme neurons with similar responses specifically support each other by sharing their computations to obtain the desired population code. This sharing allows each neuron to effectively respond to a broad variety of inputs, while only receiving few feedforward and recurrent connections. Few strong, specific recurrent connections then replace many feedforward and less specific recurrent connections, such that the resulting connectivity optimizes the number of required synapses. This suggests that the number of required synapses may be a crucial constraining factor in biological neural networks. Synaptic savings increase with the dimensionality of the encoded variables. We find a trade-off between saving synapses and response speed. The response speed improves by orders of magnitude when utilizing the window of opportunity between excitatory and delayed inhibitory currents that arises if, as found in experiments, spike frequency adaptation is present or strong recurrent excitation is balanced by strong, shortly-lagged inhibition.
A toolbox for genetic targeting of the claustrum
Authors: Tuberosa Joël , Boillat Madlaina , Dal Col Julien , Marconi Leonardo , Codourey Julien , Mannino Loris , Georgiou Elena , Menoud Marc , Carleton Alan , Rodriguez Ivan
Published: May 2024

The claustrum (CLA), a subcortical nucleus in mammals, essentially composed of excitatory projection neurons and known for its extensive connections with the neocortex, has recently been associated with a variety of functions ranging from consciousness to impulse control. However, research on the CLA has been challenging due to difficulties in specifically and comprehensively targeting its neuronal populations. In various cases, this limitation has led to inconsistent findings and a lack of reliable data. In the present work, we describe the expression profile of theSmim32gene, which is almost exclusively transcribed in excitatory neurons of the CLA and the endopiriform nucleus, as well as in inhibitory neurons of the thalamic reticular nucleus. Leveraging this unique expression pattern, we developed a series of Cre- and Flippase-expressing knockin and BAC transgenic mouse lines with different expression profiles. With these novel tools in hand, we propose new standards for the interrogation of CLA function.
Cluster efficient pangenome graph construction with nf-core/pangenome
Authors: Heumos Simon , Heuer Michael F. , Hanssen Friederike , Heumos Lukas , Guarracino Andrea , Heringer Peter , Ehmele Philipp , Prins Pjotr , Garrison Erik , Nahnsen Sven
Published: May 2024

Motivation

Pangenome graphs offer a comprehensive way of capturing genomic variability across multiple genomes. However, current construction methods often introduce biases, excluding complex sequences or relying on references. The PanGenome Graph Builder (PGGB) addresses these issues. To date, though, there is no state-of-the-art pipeline allowing for easy deployment, efficient and dynamic use of available resources, and scalable usage at the same time.

Results

To overcome these limitations, we presentnf-core/pangenome, a reference-unbiased approach implemented in Nextflow following nf-core’s best practices. Leveraging biocontainers ensures portability and seamless deployment in HPC environments. Unlike PGGB, nf-core/pangenome distributes alignments across cluster nodes, enabling scalability. Demonstrating its efficiency, we constructed pangenome graphs for 1000 human chromosome 19 haplotypes and 2146E. colisequences, achieving a two to threefold speedup compared to PGGB without increasing greenhouse gas emissions.

Availability

nf-core/pangenome is released under the MIT open-source license, available on GitHub and Zenodo, with documentation accessible athttps://nf-co.re/pangenome/1.1.2/docs/usage.

Contact

simon.heumos@qbic.uni-tuebingen.de,sven.nahnsen@qbic.uni-tuebingen.de
Energy-Based Systematic Modeling of Adaptive Immune Repertoire Behavior: Study on Cell Proliferation & Somatic Hypermutation process
Authors: Chen Yexing , Ni Haiwen , Ma Jin , Li Yongjie , Huang Chen , Yang Sixian , Xie Xiangfei , Lv Haitao , Li Min , Cao Peng
Published: May 2024

Monitoring and describing the adaptive immune repertoire(IR) for disease detection and diagnosis is essential in healthcare research. Many phenomenon have been observed to generalize the static property of IR, but the mathematical description of the formation and dynamic changes of IR still lacks research. Here, we present a mathematical and physical model to interpret the cell proliferation and somatic hypermutation(SHM) process in IR, difficulties to generate different clones in IR are computed, and IR distance is calculated as the minimum effort required to transform one IR distribution to another. IR distribution and distance can be detected from samples containing 104cells. The validity of our method is confirmed by the unsupervised clustering of data from mice spleen and clinical PBMC samples including various immune stages and diseases. Our work dynamically characterize and quantify IR process, enabling a macroscopic immunoevaluation by sensitive immune fluctuation detection from minute samples.
SARS-CoV-2 Infection of Salivary Glands Compromises Oral Antifungal Innate Immunity and Predisposes to Oral Candidiasis
Authors: Alfaifi Areej A , Wang Tristan W , Perez Paola , Sultan Ahmed A , Meiller Timothy F , Rock Peter , Kleiner David , Chertow Daniel S , Hewitt Stephen , Gasmi Billel , Stein Sydney , Ramelli Sabrina , Martin Daniel , Warner Blake , Jabra-Rizk Mary Ann
Published: May 2024

SARS-CoV-2 targets salivary glands potentially impacting oral health. We show that presence of replicating viruses in the acinar cells of salivary glands compromises production and secretion of histatin-5, a key host-produced antifungal peptide. The salivary levels of histatin-5 were significantly reduced in SARS-CoV-2 infected subjects, concomitant with enhanced prevalence of the fungal opportunistic pathogen Candida albicans. These findings provide direct evidence associating SARS-CoV-2 infection with predisposition to oral candidiasis.
OoCount: A Machine-Learning Based Approach to Mouse Ovarian Follicle Counting and Classification
Authors: Folts Lillian , Martinez Anthony S. , Bunce Corey , Capel Blanche , McKey Jennifer
Published: May 2024

The number and distribution of ovarian follicles in each growth stage provides a reliable readout of ovarian health and function. Leveraging techniques for three-dimensional (3D) imaging of ovariesin totohas the potential to uncover total, accurate ovarian follicle counts. However, because of the size and holistic nature of these images, counting oocytes is time consuming and difficult. The advent of deep-learning algorithms has allowed for the rapid development of ultra-fast, automated methods to analyze microscopy images. In recent years, these pipelines have become more user-friendly and accessible to non-specialists. We used these tools to create OoCount, a high-throughput, open-source method for automatic oocyte segmentation and classification from fluorescent 3D microscopy images of whole mouse ovaries using a deep-learning convolutional neural network (CNN) based approach. We developed a fast tissue-clearing and spinning disk confocal-based imaging protocol to obtain 3D images of whole mount perinatal and adult mouse ovaries. Fluorescently labeled oocytes from 3D images of ovaries were manually annotated in Napari to develop a machine learning training dataset. This dataset was used to retrain StarDist using a CNN within DL4MicEverywhere to automatically label all oocytes in the ovary. In a second phase, we utilize Accelerated Pixel and Object Classification, a Napari plugin, to classify labeled oocytes and sort them into growth stages. Here, we provide an end-to-end protocol for producing high-quality 3D images of the perinatal and adult mouse ovary, obtaining follicle counts and staging. We also demonstrate how to customize OoCount to fit images produced in any lab. Using OoCount, we can obtain accurate counts of oocytes in each growth stage in the perinatal and adult ovary, improving our ability to study ovarian function and fertility.

Graphical Abstract

Summary sentence

This protocol introduces OoCount, a high-throughput, open-source method for automatic oocyte segmentation and classification from fluorescent 3D microscopy images of whole mouse ovaries using a machine learning-based approach.
Distinct evolutionary patterns of tumor immune escape and elimination determined by ECM architectures
Authors: Fan Yijia , George Jason T.
Published: May 2024

Cancer progression remains a significant clinical challenge. Phenotypic adaptation by tumor cells results in disease hetero-geneity, which drives treatment resistance and immune escape. T cell immunotherapy, while effective at treating some cancer subtypes, can also fail due to limits on tumor immunogenicity or T cell recognition. For example, one potential contributor to immune escape involves the density and alignment of the extracellular matrix (ECM) surrounding tumors, also known as Tumor-Associated Collagen Signature (TACS). However, the specific mechanisms by which aligned fibers contribute to decreased patient survival rates have not yet been decoupled. Here, we developed our EVO-ACT (EVOlutionary Agent-based Cancer T cell interaction) model to study how TACS affects tumor evolution and dynamic tumor-T cell interactions. We identified a variety of TACS-specific dynamical features that influence T cell infiltration, cancer immunoediting, and ultimate immune escape. Our model demonstrates how TACS and phenotypic adaptation together explain overall survival trends in breast cancer.
Multiregional Representations of Intertemporal Decision Making in Human Single Neurons
Authors: Gill Jay L. , Omidbeigi Mahmoud , Ryu Jihye , Suthana Nanthia , Kao Jonathan C. , Bari Ausaf
Published: May 2024

Characterization of the neural basis of delay discounting provides insight into the origin of impulsive decision-making, which underlies several psychiatric diseases including substance use disorder. Here, we identify human single unit representations of decisions, and their level of difficulty, in the orbitofrontal cortex, hippocampus and amygdala that are related to preferences for immediate vs. delayed rewards. Results provide an initial account of multiregional intracranial computations related to impulsive behaviors in humans.
Inhibition of EGFR/ErbB does not protect againstC. difficiletoxin B
Authors: Siddiqi Uswah , Lunnemann Hannah M. , Childress Kevin O. , Shupe John A. , Rutherford Stacey A. , Farrow Melissa A. , Washington M. Kay , Coffey Robert J. , Lacy D. Borden , Markham Nicholas O.
Published: May 2024

Clostridioides difficileis a common cause of diarrhea and mortality, especially in immunosuppressed and hospitalized patients.C. difficileis a toxin-mediated disease, but the host cell receptors forC. difficiletoxin B (TcdB) have only recently been revealed. Emerging data suggest TcdB interacts with receptor tyrosine kinases during infection. In particular, TcdB can elicit Epidermal Growth Factor Receptor (EGFR) transactivation in human colonic epithelial cells. The mechanisms for this function are not well understood, and the involvement of other receptors in the EGFR family of Erythroblastic Leukemia Viral Oncogene Homolog (ErbB) receptors remains unclear. Furthermore, in an siRNA-knockdown screen for protective genes involved with TcdB toxin pathogenesis, we show ErbB2 and ErbB3 loss resulted in increased cell viability. We hypothesize TcdB induces the transactivation of EGFR and/or ErbB receptors as a component of its cell-killing mechanism. Here, we show in vivo intrarectal instillation of TcdB in mice leads to phosphorylation of ErbB2 and ErbB3. However, immunohistochemical staining for phosphorylated ErbB2 and ErbB3 indicated no discernible difference between control and TcdB-treated mice for epithelial phospho-ErbB2 and phospho-ErbB3. Human colon cancer cell lines (HT29, Caco-2) exposed to TcdB were not protected by pre-treatment with lapatinib, an EGFR/ErbB2 inhibitor. Similarly, lapatinib pre-treatment failed to protect normal human colonoids from TcdB-induced cell death. Neutralizing antibodies against mouse EGFR failed to protect mice from TcdB intrarectal instillation as measured by edema, inflammatory infiltration, and epithelial injury. Our findings suggest TcdB-induced colonocyte cell death does not require EGFR/ErbB receptor tyrosine kinase activation.
Exploration-exploitation trade-off is regulated by metabolic state and taste value inDrosophila
Authors: Whitehead Samuel C. , Sahai Saumya Y. , Stonemetz Jamie , Yapici Nilay
Published: May 2024

Similar to other animals, the fly,Drosophila melanogaster,changes its foraging strategy from exploration to exploitation upon encountering a nutrient-rich food source. However, the impact of metabolic state or taste/nutrient value on exploration vs. exploitation decisions in flies is poorly understood. Here, we developed a one-source foraging assay that uses automated video tracking coupled with high-resolution measurements of food ingestion to investigate the behavioral variables flies use when foraging for food with different taste/caloric values and when in different metabolic states. We found that flies alter their foraging and ingestive behaviors based on their hunger state and the concentration of the sucrose solution. Interestingly, sugar-blind flies did not transition from exploration to exploitation upon finding a high-concentration sucrose solution, suggesting that taste sensory input, as opposed to post-ingestive nutrient feedback, plays a crucial role in determining the foraging decisions of flies. Using a Generalized Linear Model (GLM), we showed that hunger state and sugar volume ingested, but not the nutrient or taste value of the food, influence flies’ radial distance to the food source, a strong indicator of exploitation. Our behavioral paradigm and theoretical framework offer a promising avenue for investigating the neural mechanisms underlying state and value-based foraging decisions in flies, setting the stage for systematically identifying the neuronal circuits that drive these behaviors.
Metabolome-wide association of carotid intima media thickness identifies FDX1 as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations
Authors: Sadhu Nilanjana , Dalan Rinkoo , Jain Pritesh R , Lee Chang Jie Mick , Pakkiri Leroy Sivappiragasam , Tay Kai Yi , Mina Theresia H , Low Dorrain , Min Yilin , Ackers-Johnson Matthew , Thi Thi Tun , Kota Vishnu Goutham , Shi Yu , Liu Yan , Yu Henry , Tay Darwin , Ng Hong Kiat , Wang Xiaoyan , Wong Kari E , Lam Max , Guan Xue Li , Bertin Nicolas , Wong Eleanor , Best James , Sarangarajan Rangaprasad , Elliott Paul , Riboli Elio , Lee Jimmy , Lee Eng Sing , Ngeow Joanne , Tan Patrick , Cheung Christine , Drum Chester Lee , Foo Roger SY , Michelotti Gregory A , Yu Haojie , Sheridan Patricia A , Loh Marie , Chambers John C
Published: May 2024

The burden of cardiovascular disease (CVD) is rising in the Asia-Pacific region, in contrast to falling CVD mortality rates in Europe and North America. To provide new insights into the pathways influencing cardiovascular risk in Asian populations, we quantified 883 metabolites by untargeted mass spectroscopy in 8,124 Singaporean adults, and investigated their relationships to carotid intima media thickness (cIMT), a marker of atherosclerosis. We found that plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, associated inversely with cIMT (Beta[SE]=-0.013[0.002]). Genetic instruments support a causal relationship of 3BH5C metabolic pathways on cardiovascular risk, with a 5-6 fold higher effect size in Asians (ORGSMR[95% CI]=0.89[0.87-0.92], ORIVW[95% CI]=0.86[0.80-0.92]) compared to Europeans (ORIVW[95% CI] = 0.98[0.96-0.99]). Colocalization analyses indicate the presence of a shared causal variant between 3BH5C plasma levels and expression of ferredoxin-1 (FDX1), a protein essential for sterol and bile acid synthesis. We validatedFDX1as a key regulator of 3BH5C synthesis in hepatocytes, and macrophages, and cholesterol efflux in aortic smooth muscle cells, through knockout and overexpression models. In summary, this study makes an important contribution to our understanding of the metabolic basis for atherosclerosis in Asian populations, and identifiesFDX1as a potential therapeutic target for prevention of CVD.
Concurrent changes in sleep and cognitive function during retirement transition: the Finnish Retirement and Aging Study
Authors: Teräs Tea , Myllyntausta Saana , Pentti Jaana , Pasanen Jesse , Rovio Suvi , Stenholm Sari
Published: May 2024

Background

The transition to retirement has been shown to be accompanied by increased sleep duration and improved sleep quality. In addition, some studies suggest accelerated decline in cognitive function in post-retirement years. However, less is known about their interconnectedness. The aim of this study was to examine the concurrent changes in sleep and cognitive function during retirement transition.

Methods

The study population consisted of 250 public sector workers (mean age before retirement 63.1 years, standard deviation 1.4) from the Finnish Retirement and Aging study. The participants used a wrist-worn ActiGraph accelerometer, responded to the Jenkins Sleep Problem Scale and underwent cognitive testing annually before and after retirement. Computerized Cambridge Neuropsychological Test Automated Battery (CANTAB®) was used to evaluate learning and memory, working memory, sustained attention and information processing, executive function and cognitive flexibility and reaction time.

Results

Cognitive function improved in all cognitive domains, except for reaction time, during 1- year retirement transition period. The improvement was temporary in learning and memory, working memory and executive function and cognitive flexibility, which plateaued in post- retirement years. The participants were categorized into constantly short (49%), increasing (20%), decreasing (6%), and constantly mid-range (25%) sleep duration; and constantly without (36%), increasing (10%), decreasing (16%), and constantly with (38%) sleep difficulties. There were no associations between changes in sleep duration or sleep difficulties and cognitive function during retirement transition.

Conclusions

Cognitive function improves temporarily during transition to retirement, but the improvement is independent of changes in sleep characteristics.
Neurobiology-based Cognitive Biotypes Using Multi-scale Intrinsic Connectivity Networks in Psychotic Disorders
Authors: Andrés-Camazón Pablo , Martínez Diaz-Caneja Covadonga , Ballem Ram , Chen Jiayu , Calhoun Vince D. , Iraji Armin
Published: May 2024

Objective

Understanding the neurobiology of cognitive dysfunction in psychotic disorders remains elusive, as does developing effective interventions. Limited knowledge about the biological heterogeneity of cognitive dysfunction hinders progress. This study aimed to identify subgroups of patients with psychosis with distinct patterns of functional brain alterations related to cognition (cognitive biotypes).

Methods

B-SNIP consortium data (2,270 participants including participants with psychotic disorders, relatives, and controls) was analyzed. Researchers used reference-informed independent component analysis and the NeuroMark 100k multi-scale intrinsic connectivity networks (ICN) template to obtain subject-specific ICNs and whole-brain functional network connectivity (FNC). FNC features associated with cognitive performance were identified through multivariate joint analysis. K-means clustering identified subgroups of patients based on these features in a discovery set. Subgroups were further evaluated in a replication set and in relatives.

Results

Two biotypes with different functional brain alteration patterns were identified. Biotype 1 exhibited brain-wide alterations, involving hypoconnectivity in cerebellar-subcortical and somatomotor-visual networks and worse cognitive performance. Biotype 2 exhibited hyperconnectivity in somatomotor-subcortical networks and hypoconnectivity in somatomotor-high cognitive processing networks, and better preserved cognitive performance. Demographic, clinical, cognitive, and FNC characteristics of biotypes were consistent in discovery and replication sets, and in relatives. 70.12% of relatives belonged to the same biotype as their affected family members.

Conclusions

These findings suggest two distinctive psychosis-related cognitive biotypes with differing functional brain patterns shared with their relatives. Patient stratification based on these biotypes instead of traditional diagnosis may help to optimize future research and clinical trials addressing cognitive dysfunction in psychotic disorders.
SAFETY AND IMMUNOGENICITY OF A PHH-1V BOOSTER DOSE AFTER DIFFERENT PRIME VACCINATION SCHEMES AGAINST COVID-19: PHASE III CLINICAL TRIAL FINAL RESULTS UP TO ONE YEAR
Authors: Natalini Martínez Silvina , Ramos Rafael , Navarro-Perez Jorge , Lopez Maria Jesus , Vazquez Maria del Mar , Molto Jose , Munoz Patricia , Echave Jose M , Arribas Jose R , Alvarez Melchor , Arana-Arri Eunate , Calls Jordi , Otero-Romero Susana , Scaglione Francesco , Bernad Laia , Pérez-Caballero Raúl , Prado Julia G , Esteban Ignasi , Aurrecoechea Elena , Pomarol Roc , Plana Montserrat , Soriano Alex
Published: May 2024

In this phase III, open label, single arm, multicenter clinical study, we report safety, tolerability and immunogenicity of PHH-1V as a booster dose in subjects primary vaccinated against COVID-19 with the BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S vaccines, with or without previous COVID-19 infection. A total of 2661 subjects were included in this study and vaccinated with the PHH-1V vaccine. Most treatment-emergent adverse events (TEAE) were solicited local and systemic reactions with grade 1 (58.70%) or grade 2 (27.58%) intensity, being the most frequently reported injection site pain (82.83%), fatigue (31.72%) and headache (31.23%). Additionally, immunogenicity was assessed at Baseline and Days 14, 91, 182 and 365 in a subset of 235 subjects primary vaccinated. On Day 14, geometric mean triter (GMT) in neutralizing antibody against SARS-CoV-2 Wuhan and Beta, Delta and Omicron BA.1 variants increased in all primary vaccination with a geometric mean fold raise (GMFR) of 6.90 (95% CI 4.96-9.58), 12.27 (95% CI 8.52-17.67), 7.24 (95% CI 5.06-10.37) and 17.51 (95% CI 12.28-24.97), respectively. Despite GMT decay after day 14, it remains in all cases significatively higher from baseline up to 1 year after PHH-1V booster administration and GMFR against Beta and Omicron BA.1 variants over 3 at 1 year after booster compared to baseline. PHH-1V booster vaccination elicited also a significant RBD/Spike-specific IFN-γ+T-cell responses on Day 14. Overall, PHH-1V vaccine was immunogenic and well-tolerated regardless of the previous primary vaccination scheme received with no reported cases of severe COVID-19 infection throughout the entire study.
Evaluating the Effectiveness of the Mozambique-Canada Maternal Health (MCMH) Project Abstraction Tool in the Identification of Maternal Near-Miss (MNM) Events
Authors: Muosieyiri Maud Z , Andre Fernanda , Forsyth Jessie , Adoni Ana Paula Ferrão da Silva , Muhajarine Nazeem
Published: May 2024

Maternal Near-Miss (MNM) is described as a woman who survives a severe obstetric event. The World Health Organization (WHO) developed an abstraction tool in 2009 for identifying MNMs, but it has come under criticism for not being suitable for use in low-resource settings. The maternal near-miss tool developed by the Mozambique-Canada Maternal Health Project, including additional clinical criteria, is an adaptation of the WHO version to suit the resource availability in Mozambique. This study examined whether these additional criteria enhanced maternal near-miss identification; if so, whether this was observed in particular groups of women.

A cross-sectional study was conducted in two hospitals, the Provincial Hospital of Inhambane province, a tertiary referral care center, and a rural hospital, Vilankulo Rural Hospital, with a large rural catchment area (approximately 46,543 inhabitants), in the Inhambane province in Mozambique. Consecutive admissions in the maternity wards in these two hospitals between August 2021 and February 2022 were eligible and data from 2057 women were included. Chi-square test of independence, kappa statistics, and multiple logistic regression analyses were performed to address the study aims.

The newer tool with additional clinical criteria identified more maternal near-misses (Expanded Disease criterion = 28.2%; Comorbidities criterion = 21.1%) than the original WHO tool (16.20%). Hypertension and Anemia, two criteria in the newer tool, showed strong associations with the original WHO disease criterion (p < 0.001). Hypertension demonstrated a moderate agreement with the WHO disease criterion (κ = 0.58, 95% CI: 0.53-0.63) while anemia showed a fair agreement (κ = 0.21, 95% CI: 0.16-0.26). However, HIV/AIDS, the most prevalent comorbidity, was not significantly associated with the original WHO disease criterion. Furthermore, socio-demographic indicators like distance from home to hospital, age of woman, and type of health facility (provincial or rural district) were significant predictors of identifying maternal near-misses.

In conclusion, incorporating additional criteria enhances – it casts a larger net – the original WHO disease criterion’s capacity to identify maternal near-misses. Distance from home to the hospital and age emerge as strong predictors for recognizing MNMs in Inhambane province.
Birds affected by a 2021 avian mortality event are strongly associated with supplemental feeding and ground foraging behaviors
Authors: Ayala Andrea J. , Baillargeon Tessa , Gordon Lawrence M. , Greening Sabrina S. , Mwakibete Lusajo , Sevigny Joseph L. , Burrell Caitlin E. , Casey Christine , Driscoll Cindy P. , Klein Patrice , Lewis Nicole L. , Murphy Lisa A. , Poppenga Robert , Thomas W. Kelly , Yabsley Michael J. , Gagne Roderick B. , Nemeth Nicole M. , Tato Cristina M. , Needle David B. , Ogbunugafor C. Brandon
Published: May 2024

In 2021, news outlets and state natural resources agencies reported a large number of avian deaths across several states in the eastern and midwestern USA. This event fomented a rapid and robust response from animal health experts from across the country. Given the clustered pattern of disease and death, an infectious etiology was rigorously investigated. No single causative pathogen was identified, leaving the cause and thus epidemiology of the mortality event unex-plained. In this study, we attempted to hone in on potential causes or contributors to this event by constructing a dataset on affected birds’ life history, phylogeny, and ecology. After a preliminary analysis of these features, we developed a statistical pipeline to test two hypotheses regarding features of birds associated with the mortality event: (1) that a significant proportion of affected birds in the total sample are members of the Cornell Feederwatch list (i.e., birds that consume supplemental feed, and their predators), and that (2) ground-feeding species would be significantly represented in the sample. While logistic regression models support the plausibility of the two hypotheses, they are statistically indistinguishable. We discuss the implications of these findings, propose future work, and highlight the importance of ecological and behavioral expertise in understanding epidemiological phenomena.
Plasma-derived Extracellular Vesicles (EVs) as Biomarkers of Sepsis in Burn Patients via Label-free Raman Spectroscopy
Authors: O’Toole Hannah J. , Lowe Neona , Arun Vishalakshi , Kolesov Anna V. , Palmieri Tina L. , Tran Nam K. , Carney Randy P.
Published: May 2024

Sepsis following burn trauma is a global complication with high mortality, with ∼60% of burn patient deaths resulting from infectious complications. Sepsis diagnosis is complicated by confounding clinical manifestations of the burn injury, and current biomarkers markers lack the sensitivity and specificity required for prompt treatment. Circulating extracellular vesicles (EVs) from patient liquid biopsy as biomarkers of sepsis due to their release by pathogens from bacterial biofilms and roles in subsequent immune response. This study applies Raman spectroscopy to patient plasma derived EVs for rapid, sensitive, and specific detection of sepsis in burn patients, achieving 97.5% sensitivity and 90.0% specificity. Furthermore, spectral differences between septic and non-septic burn patient EVs could be traced to specific glycoconjugates of bacterial strains associated with sepsis morbidity. This work illustrates the potential application of EVs as biomarkers in clinical burn trauma care, and establishes Raman analysis as a fast, label-free method to specifically identify features of bacterial EVs relevant to infection amongst the host background.
Dishevelled localization and function are differentially regulated by structurally distinct sterols
Authors: Sengupta Sonali , Yaeger Jazmine D.W. , Schultz Maycie M. , Francis Kevin R.
Published: May 2024

The Dishevelled (DVL) family of proteins form supramolecular protein and lipid complexes at the cytoplasmic interface of the plasma membrane to regulate tissue patterning, proliferation, cell polarity, and oncogenic processes through DVL-dependent signaling, such as Wnt/β-catenin. While DVL binding to cholesterol is required for its membrane association, the specific structural requirements and cellular impacts of DVL-sterol association are unclear. We report that intracellular sterols which accumulate within normal and pathological conditions cause aberrant DVL activity.In silicoand molecular analyses suggested orientation of the β- and α-sterol face within the DVL-PDZ domain regulates DVL-sterol binding. Intracellular accumulation of naturally occurring sterols impaired DVL2 plasma membrane association, inducing DVL2 nuclear localization via Foxk2. Changes to intracellular sterols also selectively impaired DVL2 protein-protein interactions This work identifies sterol specificity as a regulator of DVL signaling, suggests intracellular sterols cause distinct impacts on DVL activity, and supports a role for intracellular sterol homeostasis in cell signaling.
Clonal determinants of organotropism and survival in metastatic uveal melanoma
Authors: Jones Bailey S.C.L. , Demkowicz Patrick C. , Matesva Mitchelle , Lim Renelle Pointdujour , Sinard John H. , Bacchiocchi Antonietta , Halaban Ruth , Bosenberg Marcus , Sznol Mario , Kluger Harriet M. , Bakhoum Mathieu F.
Published: May 2024

Uveal melanoma (UM), the most common intraocular primary cancer in adults, demonstrates a unique proclivity for liver metastasis. To understand the molecular underpinnings of this organotropism, we analyzed the genomic features of liver and extrahepatic UM metastases, identifying distinct molecular signatures that mirror the clonal diversity in primary UM tumors. Liver metastases were enriched inBAP1mutations and exhibited a higher prevalence of monosomy 3 compared to extrahepatic metastases. Analysis of the tumor-liver microenvironment crosstalk at the single-cell level underscored a significant role for hepatic stellate cells in facilitating UM growth and establishment in the liver. Notably, within the primary tumor, clones that demonstrated a high affinity for the liver, compared to those with low liver affinity, exhibited a distinct transcriptional profile characterized by the upregulation of pathways that activate hepatic stellate cells, specifically involving TGF-β signaling, cytokine signaling, extracellular matrix remodeling, and angiogenesis. Liver-tropic clones displayed not only an increased affinity for liver colonization but were also associated with worse survival outcomes, underscoring the adverse prognostic significance of hepatic metastases in UM. Our findings demonstrate that trajectories of metastatic dissemination and patient survival in UM are established early in the primary tumor’s evolution, opening pathways for the development of targeted therapeutic interventions to improve patient outcomes.
Exogenous lipid vesicles induce endocytosis-mediated cellular aggregation in a close unicellular relative of animals
Authors: Kidner Ria Q. , Goldstone Eleanor B. , Rodefeld Henry J. , Brokaw Lorin P. , Gonzalez Aria M. , Ros-Rocher Núria , Gerdt Joseph P.
Published: May 2024

Capsaspora owczarzakiis a protozoan that may both reveal aspects of animal evolution and also curtail the spread of schistosomiasis, a neglected tropical disease.Capsasporaexhibits a chemically regulated aggregative behavior that resembles cellular aggregation in some animals. This behavior may have played a key role in the evolution of animal multicellularity. Additionally, this aggregative behavior may be important forCapsaspora’s ability to colonize the intermediate host of parasitic schistosomes and potentially prevent the spread of schistosomiasis. Both applications demand elucidation of the molecular mechanism ofCapsasporaaggregation. Toward this goal, we first determined the necessary chemical properties of lipid cues that activate aggregation. We found that a wide range of abundant zwitterionic lipids induced aggregation, revealing that the aggregative behavior could be activated by diverse lipid-rich conditions. Furthermore, we demonstrated that aggregation inCapsasporarequires clathrin-mediated endocytosis, highlighting the potential significance of endocytosis-linked cellular signaling in recent animal ancestors. Finally, we found that aggregation was initiated by post-translational activation of cell-cell adhesion—not transcriptional regulation of cellular adhesion machinery. Our findings illuminate the chemical, molecular and cellular mechanisms that regulateCapsasporaaggregative behavior—with implications for the evolution of animal multicellularity and the transmission of parasites.
Early and widespread engagement of the cerebellum during hippocampal epileptiform activity Format: Brief Communication
Authors: Streng M.L. , Kottke B.W. , Wasserman E.M. , Zecker L. , Luong L. , Ebner T.J. , Krook-Magnuson E.
Published: May 2024

Despite research illustrating the cerebellum may be a critical circuit element in the epilepsies, remarkably little is known about cerebellar engagement during seizures. We therefore implemented a novel method for repeated imaging of the cerebellum in awake, chronically epileptic animals. We found widespread changes in cerebellar calcium signals during behavioral seizuresandduring hippocampal seizures that remained electrographic only, arguing against cerebellar modulation simply reflecting motor components. Moreover, even brief interictal spikes produced widespread alterations in cerebellar activity. Changes were noted in the anterior and posterior cerebellum, along the midline, and both ipsilaterally and contralaterally to the seizure focus. Remarkably, changes in the cerebellum also occurredpriorto any noticeable change in the hippocampal electrographic recordings, suggesting a special relationship between the cerebellum and hippocampal epileptiform activity. Together these results underscore the importance of the cerebellum in epilepsy, warranting a more consistent consideration of the cerebellum when evaluating epilepsy patients.
Decreased CREB phosphorylation impairs embryonic retinal neurogenesis in theOa1-/-mouse model of Ocular albinism
Authors: Guha Sonia , Nguyen Andrew M. , Young Alejandra , Mondell Ethan , Farber Debora B.
Published: May 2024

Mutations in the human Ocular albinism type-1 geneOA1are associated with abnormal retinal pigment epithelium (RPE) melanogenesis and poor binocular vision resulting from misrouting of ipsilateral retinal ganglion cell (iRGC) axons to the brain. We studied the latter using wild-type (WT) andOa1-/-mouse eyes. At embryonic stages, the WT RPE-specific Oa1 protein signals through cAMP/Epac1-Erk2-CREB. Following CREB phosphorylation, a pCREB gradient extends from the RPE to the differentiating retinal amacrine and RGCs. In contrast to WT, theOa1-/-RPE and ventral ciliary-margin-zone, a niche for iRGCs, express less pCREB while their retinas have a disrupted pCREB gradient, indicating Oa1’s involvement in pCREB maintenance.Oa1-/-retinas also show hyperproliferation, enlarged nuclei, reduced differentiation, and fewer newborn amacrine and RGCs than WT retinas. Our results demonstrate that Oa1’s absence leads to reduced binocular vision through a hyperproliferation-associated block in differentiation that impairs neurogenesis. This may affect iRGC axon’s routing to the brain.
Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib
Authors: Sklenicka Jan , Tran Tung , Ramirez Maria S. , Donow Haley M. , Magaña Angel J. , LaVoi Travis , Mamun Yasir , Chapagain Prem , Santos Radleigh , Pinilla Clemencia , Giulianotti Marc A. , Tolmasky Marcelo E.
Published: May 2024

Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by aminoglycoside 6′-N-acetyltransferase type I enzyme, of which type Ib [AAC(6′)-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive compounds to be developed as drugs. Mixture-based combinatorial libraries and positional scanning strategy led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1 - R5), inhibits AAC(6′)-Ib-mediated inactivation of amikacin. Structure-activity relationship (SAR) studies showed that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds,2700.001and2700.003, reduced inhibition levels, demonstrating the essential nature not only of the presence of anS-phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions have varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity.

Highlights

Amikacin resistance in Gram-negatives is mostly caused by the AAC(6′)-Ib enzyme

AAC(6′)-Ib has been identified in most Gram-negative pathogens

Inhibitors of AAC(6′)-Ib could be used to treat resistant infections

Combinatorial libraries and positional scanning identified an inhibitor

The lead compound can be optimized by structure activity relationship studies
ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity
Authors: Nguyen Binh An , Afrin Shumaila , Yakubovska Anna , Singh Virender , Alicea Jaime Vaquer , Kunach Peter , Singh Preeti , Pekala Maja , Ahmed Yasmin , Fernandez-Ramirez Maria del Carmen , Hernandez Luis O. Cabrera , Pedretti Rose , Bassett Parker , Wang Lanie , Lemoff Andrew , Villalon Layla , Kluve-Beckerman Barbara , Saelices Lorena
Published: May 2024

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.
Enhanced Recognition of a Herbal Compound Epiberberine by a DNA Quadruplex-Duplex Structure
Authors: Zhan Xuan , Deng Liping , Lian Yun , Shu Zhiyu , Xu Yunong , Mai Xinyi , Krishna Manchugondanahalli S. , Xiong Chi , Lu Rongguang , Wang Anni , Bai Shiyao , Xu Yingyi , Ni Jie , Vandana J. Jeya , Wang Zi , Li Yuqing , Sun Dongmei , Huang Shaohui , Liu Jingyan , Cheng Gui-Juan , Wu Song , Chiang Ying-Chih , Stjepanovic Goran , Jiang Cheng , Shao Yong , Chen Gang
Published: May 2024

The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases, including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5′ side of a human telomeric G-quadruplex (HTG) sequence Q4, resulting in a nanomolar binding affinity (KDapproximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures in physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer the Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5′ end. Q4-ds-A is a superb EPI binder with aKDof 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI fromRhizoma coptidis(Huang Lian) extracts.