bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct prelimbic cortex neuronal responses to emotional states of others drive emotion recognition in adult male mice
Authors: Jabarin Renad , Mohapatra Alok Nath , Ray Natali , Netser Shai , Wagner Shlomo
Published: March 2024

The ability to perceive the emotional states of others, termed emotion recognition, allows individuals to adapt their conduct to the social environment. The brain mechanisms underlying this capacity, known to be impaired in individuals with autism spectrum disorder (ASD), remain, however, elusive. Using the emotional state preference paradigm, we show that adult mice can discern emotional states of conspecifics in a sex-specific manner, behavior impaired in an ASD mouse model. Fiber photometry revealed inhibition of pyramidal neurons in the prelimbic medial prefrontal cortex (PrL) during investigation of aroused individuals, as opposed to transient excitation towards non-aroused conspecifics. Augmenting this differential neuronal response enhanced emotion recognition, while abolishing this response eliminated such behavior, as demonstrated via optogenetic stimulation. Chronic electrophysiological recordings at the single-cell level indicated social stimulus-specific responses in PrL neurons at the onset and conclusion of social investigation bouts, potentially regulating the initiation and termination of social interactions. The dysregulated activity of these neurons may thus contribute to deficits in social behavior observed in ASD.
Combining function and structure in a single macro-scale connectivity model of the human brain
Authors: Sairanen Viljami
Published: March 2024

Combining the macro-scale functional and structural connectivity matrices of the human brain could provide useful information on how various diseases and conditions affect the brain. However, it is not a simple task to combine such information as they are derived usually in very different ways with functional information typically gathered using fMRI, EEG, or MEG whereas structural information relies on robust diffusion-weighted MRI tractography methods. This work proposes a solution to this problem using an analogy to an electric circuit with the functional information being the voltage sources and the structural information resistance of the elements in the circuit. The voltage sources and resistances can be used to solve the current in the circuit using Modified Nodal Analysis, for example. In the proposed analogy, the solved electric current represents how the functional information flows in the structural brain network. This work demonstrates a connection-specific example of such analysis as well as whole-brain analysis using data from the Human Connectome Project. Another dataset of functional and structural data from healthy brains is used to demonstrate that the proposed method can be used to study the aging of the human brain. The main motivation for the proposed analysis method is that it could provide new information on various conditions and diseases such as Alzheimer’s that affect the human brain. In a sense, the proposed functio-structural current (FSC) analysis is a macro-scale version of the classical Hodkin-Huxley model.
A transient brain endothelial translatome response to endotoxin is associated with mild cognitive changes post-shock in young mice
Authors: Lu Shuhan , John Portela Iria Di , Martino Nina , Ramos Ramon Bossardi , Salinero Abigail E , Smith Rachel M , Zuloaga Kristen L , Adam Alejandro P
Published: March 2024

Sepsis-associated encephalopathy (SAE) is a common manifestation in septic patients that is associated with increased risk of long-term cognitive impairment. SAE is driven, at least in part, by brain endothelial dysfunction in response to systemic cytokine signaling. However, the mechanisms driving SAE and its consequences remain largely unknown. Here, we performed translating ribosome affinity purification and RNA-sequencing (TRAP-seq) from the brain endothelium to determine the transcriptional changes after an acute endotoxemic (LPS) challenge. LPS induced a strong acute transcriptional response in the brain endothelium that partially correlates with the whole brain transcriptional response and suggested an endothelial-specific hypoxia response. Consistent with a crucial role for IL-6, loss of the main regulator of this pathway, SOCS3, leads to a broadening of the population of genes responsive to LPS, suggesting that an overactivation of the IL-6/JAK/STAT3 pathway leads to an increased transcriptional response that could explain our prior findings of severe brain injury in these mice. To identify any potential sequelae of this acute response, we performed brain TRAP-seq following a battery of behavioral tests in mice after apparent recovery. We found that the transcriptional response returns to baseline within days post-challenge. Despite the transient nature of the response, we observed that mice that recovered from the endotoxemic shock showed mild, sex-dependent cognitive impairment, suggesting that the acute brain injury led to sustained, non-transcriptional effects. A better understanding of the transcriptional and non-transcriptional changes in response to shock is needed in order to prevent and/or revert the devastating consequences of septic shock.

Abstract Figure
Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice
Authors: Pomrenze Matthew B. , Vaillancourt Sam , Llorach Pierre , Rijsketic Daniel Ryskamp , Casey Austen B. , Gregory Nicholas , Salgado Juliana S. , Malenka Robert C. , Heifets Boris D.
Published: March 2024

Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both µOR (MOR) and PKCδ were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine.
Whole-brain neural substrates of behavioral variability in the larval zebrafish
Authors: Manley Jason , Vaziri Alipasha
Published: March 2024

Animals engaged in naturalistic behavior can exhibit a large degree of behavioral variability even under sensory invariant conditions. Such behavioral variability can include not only variations of the same behavior, but also variability across qualitatively different behaviors driven by divergent cognitive states, such as fight-or-flight decisions. However, the neural circuit mechanisms that generate such divergent behaviors across trials are not well understood. To investigate this question, here we studied the visual-evoked responses of larval zebrafish to moving objects of various sizes, which we found exhibited highly variable and divergent responses across repetitions of the same stimulus. Given that the neuronal circuits underlying such behaviors span sensory, motor, and other brain areas, we built a novel Fourier light field microscope which enables high-resolution, whole-brain imaging of larval zebrafish during behavior. This enabled us to screen for neural loci which exhibited activity patterns correlated with behavioral variability. We found that despite the highly variable activity of single neurons, visual stimuli were robustly encoded at the population level, and the visual-encoding dimensions of neural activity did not explain behavioral variability. This robustness despite apparent single neuron variability was due to the multi-dimensional geometry of the neuronal population dynamics: almost all neural dimensions that were variable across individual trials, i.e. the "noise" modes, were nearly orthogonal to those encoding for sensory information. Investigating this neuronal variability further, we identified two sparsely-distributed, brain-wide neuronal populations whose pre-motor activity predicted whether the larva would respond to a stimulus and, if so, which direction it would turn on a single-trial level. These populations predicted single-trial behavior seconds before stimulus onset, indicating they encoded time-varying internal modulating behavior, perhaps organizing behavior over longer timescales or enabling flexible behavior routines dependent on the animal's internal state. Our results provide the first whole-brain confirmation that sensory, motor, and internal variables are encoded in a highly mixed fashion throughout the brain and demonstrate that de-mixing each of these components at the neuronal population level is critical to understanding the mechanisms underlying the brain's remarkable flexibility and robustness.
Analysis of polyurethane/gelatin complex hydrogel system for protein imprinting
Authors: Porchkhidze Alegi , Endeladze Madona , Gogichaishvili Nana , Mikautadze Otar
Published: March 2024

Polyurethane served as the carrier in the synthesis of a hydrogel system, incorporating membrane protein as the template, N-Vinylformamide as the monomer, and 1,4-Butanediol diglycidyl ether as the crosslinker, along with gelatin, initiated by ultraviolet radiation. This resulted in the formation of the hydrogel PUNVF-Gelatin. The study investigated the influence of varying monomer concentration, crosslinker concentration, and gelatin concentration on both the adsorption capacity for membrane protein and the imprinting efficiency. Findings revealed that optimal conditions for achieving the maximum adsorption capacity occurred when the monomer mass fraction was 5%, the crosslinker mass fraction was 3%, and the gelatin mass fraction was 0.6%.
Salidroside and itsin vivometabolite tyrosol could act directly on dopamine D2 receptors: a study using RNAseq combined with Connectivity Map analysis
Authors: Zhang Ji-Zhou , Jiang Chang , Han Jing
Published: March 2024

Salidroside is an active ingredient in traditional Chinese medicine such as Rhodiola. Itsin vivometabolite, tyrosol, exist in olive oil and red wine. For a long time, clinical practice and research have shown that both of them have many pharmacological activities, but their targets have not reached unanimous conclusion. The present study proposed that dopamine D2 receptor (DRD2) may be the target of salidroside and tyrosol, by using RNA sequencing combined with Connectivity Map (CMAP) analysis. On this basis, molecular docking, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) were used to verify that both salidroside and tyrosol directly bind to DRD2. The results of this study can serve as a guide for further pharmacological research on salidroside and tyrosol.
Unethical amnesia brain: Memory and metacognitive distortion induced by dishonesty
Authors: Xu Xinyi Julia , Mobbs Dean , Wu Haiyan
Published: March 2024

Unethical actions and decisions may distort human memory in two aspects: memory accuracy and metacognition. However, the neural and computational mechanisms underlying the metacognition distortion caused by repeated dishonesty remain largely unknown. Here, we performed two fMRI studies, including one replication study, with an information-sending task in the scanner. The main moral decision task in the scanner involves consistency and reward as two main factors, combined with a pre-scan and post-scan memory test together with mouse tracking. With multiple dimensions of metrics to measure metacognition, we test whether the inter-subject metacognition change correlates with how participants trade off consistency and reward. We find that the compression of representational geometry of reward in the orbitofrontal cortex (OFC) is correlated with both immediate and delayed metacognition changes. Also, the functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and the left temporoparietal junction (lTPJ) under dishonest responses can predict both immediate and delayed metacognition changes in memory. These results suggest that decision-making, emotion, and memory-related brain regions together play a key role in metacognition change after immoral action, shedding light on the neural mechanism of the complex interplay between moral decisions, cognitive processes, and memory distortion.

‘I did that’, says my memory.

‘I could not have done that’, says my pride, and remains inexorable.

Eventually - the memory yields.

—Nietzsche[1]
Spatial Transcriptomics of Spinal Ependymoma in NF2-related Schwannomatosis
Authors: Burket Noah , Wang Jia , Gao Hongyu , Bell Robert , Zhang Chi , Liu Yunlong , Clapp Wade , Tailor Jignesh
Published: March 2024

Spinal ependymoma (SP-EPN) is a central nervous system (CNS) tumor that is associated with high morbidity. The only effective treatment for end-stage SP-EPN is surgery, but this is associated with high risk of injury to the sensorimotor spinal tracts and paralysis. There is a critical need to understand the cellular origins of this tumor so that disease models of tumor progression can be generated for drug development. Recent genomic studies with bulkRNA sequencing suggest the molecular signature of SP-EPN matches that of ependymal cells (EPCs). However, large-scale genomic studies can often misrepresent rare cancer stem cell populations within the tumor. In this study, we performed spatial transcriptomics (ST) on a SP-EPN resected from a patient with NF2-related neurofibromatosis to examine the spatial heterogeneity within the tumor. The SP-EPN sample exhibited cellular heterogeneity with diffuse expression of astrocytic and EPC markers, and smaller pockets with RGC or stem cell markers, as well as overlap between progenitor cell and mature cell markers. These findings suggest that there may be a developmental hierarchy within the EPC lineage in SP-EPN tumors, which may stem from aberrant radial glia cells.
Actionability of Synthetic Data in a Heterogeneous and Rare Healthcare Demographic; Adolescents and Young Adults (AYAs) with Cancer
Authors: Hogenboom J. Joshi , Gomes A. Aiara Lobo , Dekker A.L.A.J. Andre , Van Der Graaf W.T.A. Winette , Husson O. Olga , Wee L.Y.L. Leonard
Published: March 2024

Purpose

Research on rare diseases and atypical healthcare demographics is often slowed by high inter-subject heterogeneity and overall scarcity of data. Synthetic data (SD) has been proposed as means for data sharing, enlargement, and diversification, by artificially generating ‘real’ phenomena while obscuring the ‘real’ subject data. The utility of SD is actively scrutinised in healthcare research, but the role of sample size for actionability of SD is insufficiently explored. We aim to understand the interplay of actionability and sample size by generating SD sets of varying sizes from gradually diminishing amounts of real subjects’ data. We evaluate the actionability of SD in a highly heterogeneous and rare demographic: adolescents and young adults (AYAs) with cancer.

Methodology

A population-based cross-sectional cohort study of 3735 AYAs was sub-sampled at random to produce 13 training datasets of varying sample sizes. We studied four distinct generator architectures built on the open-source Synthetic Data Vault library. Each architecture was used to generate SD of varying sizes based on each aforementioned training subsets. SD actionability was assessed by comparing the resulting SD to its respective ‘real’ data against three metrics – veracity, utility, and privacy concealment.

Results

All examined generator architectures yielded actionable data when generating SD with sizes similar to the ‘real’ data. Large SD sample size increased veracity but generally increased privacy risks. Using fewer training subjects led to faster convergence in veracity, but partially exacerbated privacy concealment issues.

Conclusion

SD is a potentially promising option for data sharing and data augmentation, yet sample size plays a significant role in its actionability. SD generation should go hand-in-hand with consistent scrutiny and sample size should be carefully considered in this process.
High Prevalence of the Cardiovascular-Kidney-Metabolic Syndrome Among US Adults From 1999-2020 - An analysis of the NHANES survey
Authors: Tian Zhejia , Soltani Samira , Bauersachs Johann , Schmidt-Ott Kai , Melk Anette , Schmidt Bernhard MW
Published: March 2024

Background

The cardiovascular-kidney-metabolic (CKM) syndrome is a newly defined chronic health condition from American Heart Association. We assessed the prevalence of CKM syndrome stages 0-2, which have not yet progressed to cardiovascular disease (stage 3-4) with trends analysis over the past two decades.

Methods

We used cross-sectional data provided by National Health and Nutrition Examination Survey. including non-pregnant participants aged 18 or older between 1999 and 2020. Weighted prevalence was analyzed over the course of the past 20 years and by population subgroup (including age, sex, and race/ethnicity).

Results

A total of 32848 US adults were included in our study (weighted mean age, 47.3 years; women, 51.3%). 7.9% of US adults were at stage 0 without any CKM risk factors, with 64% of this subgroup being female. 18.3% of US adults were classified as stage 1 with issues related to excess or dysfunctional adiposity without other metabolic risk factors or chronic kidney disease (CKD). More than half of the US adults (56.5%) exhibited either metabolic risk factors, CKD, or both (stage 2). Between 1999 and 2020, the CKM features increased with decreasing prevalence of stage 0 (P for trends =0.0018), not only in females but also in males.

Conclusions

Our findings illustrate an exceptionally high and increasing prevalence of CKM syndrome among US adults. This emphasizes the importance of comprehensive preventive strategies targeting the life style of large parts of the population. Moreover, further risk assessment should be implemented into stage 2 cohort to define patients with exceptional cardiovascular risk.

Clinical Perspective

What is new?

CKM syndrome is a common chronic health condition in the general population. However, the prevalence of different CKM stages using real-world data has not been reported within the general population or its subgroups.

The prevalence of CKM syndrome was increasing over the past two decades. The majority of US adults were classified as stage 2.

A specific population remained undefined according to the current detailed definition of each CKM syndrome stage.

What are the clinical implications?

The high and increasing prevalence of CKM syndrome necessitates more precise preventive strategies, tailored to different target groups with consideration of age-, sex-, and gender-disparities.

Given that approximately half of the study population fell into stage 2 with a wide spectrum of risk factors, it is imperative to identify patients with exceptionally high risk through additional risk assessments. This approach would facilitate the implementation of intensified treatment measures aimed at preventing the progression to cardiovascular disease (CKM syndrome stages 3-4).
Yeast-based production platform for potent and stable heavy chain-only antibodies
Authors: Lonigro Chiara , Eeckhaut Hannah , Symakani Royan Alipour , Roose Kenny , Schepens Bert , Sedeyn Koen , De Smet Anne-Sophie , Zavala Marchan Jackeline Cecilia , Vanhaverbeke Pieter , Vanmarcke Sandrine , Claes Katrien , De Cae Sieglinde , Demol Hans , Devos Simon , Fijalkowska Daria , Nerinckx Wim , Rossey Iebe , Weyts Wannes , Abdelnabi Rana , Jochmans Dirk , Neyts Johan , Saelens Xavier , van Schie Loes , Callewaert Nico
Published: March 2024

Monoclonal antibodies are the leading drug of the biopharmaceutical market because of their high specificity and tolerability, but the current CHO-based manufacturing platform remains expensive and time-consuming leading to limited accessibility, especially in the case of diseases with high incidence and pandemics. Therefore, there is an urgent need for an alternative production system.

In this study, we present a rapid and cost-effective microbial platform for heavy chain-only antibodies (VHH-Fc) in the methylotrophic yeastKomagataella phaffii(akaPichia pastoris). We demonstrate the potential of this platform using a simplified single-gene VHH-Fc fusion construct instead of the conventional monoclonal antibody format, as this is more easily expressed inPichia pastoris. We demonstrate that thePichia-produced VHH-Fc fusion construct is stable and that aPichia-produced VHH-Fc directed against the SARS-CoV-2 spike has potent SARS-CoV-2 neutralizing activityin vitroandin vivo. We expect that this platform will pave the way towards faster and cheaper development and production of broadly neutralizing single-chain antibodies in yeast.
The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.
Authors: Ellis Charles , Ward Natasha L , Rice Matthew , Ball Neil J , Walle Pauline , Najdek Chloé , Kilinc Devrim , Lambert Jean-Charles , Chapuis Julien , Goult Benjamin Thomas
Published: March 2024

Misprocessing of Amyloid Precursor Protein (APP) is one of the major causes of Alzheimer's disease. APP is a transmembrane protein comprising a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talins are synaptic scaffold proteins that connect the cytoskeletal machinery to the plasma membrane via binding to one of two highly conserved NPxY motifs in the cytoplasmic tail of integrin transmembrane receptors. Here we report the crystal structure of an APP/talin1 complex identifying a new way to couple the cytoskeletal machinery to synaptic sites via APP. Proximity Ligation Assay (PLA) confirmed the close proximity of talin1 and APP in primary neurons, and we show that talin1 depletion has a dramatic effect on APP processing in cells. Structural modelling indicates that APP has the capacity to form an extracellular meshwork that mechanically couples the cytoskeletal meshworks of both the pre-, and post-synaptic compartments. In this context, we propose APP processing as a mechanical signalling pathway with similarities to Notch signalling, whereby the cleavage sites in APP represent mechanical sensors, with varying accessibility to cleavage by secretases. During synaptogenesis in healthy neurons, the APP/talin linkage would provide an exquisite mechanical coupling between synapses, with tightly controlled APP processing providing instructions to maintain this synchrony. Furthermore, APP directly coupling to the binary switches in talin indicates a role for APP in mechanical memory storage as postulated by the MeshCODE theory. The implication that APP is a regulator of mechanical signalling leads to a new hypothesis for Alzheimer's disease, where mis-regulation of APP dynamics results in loss of mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of the toxic plaque-forming Aβ42 peptide. Much needs to be done to experimentally validate this idea, but we present here a novel theory of Alzheimer's Disease with a role for APP in the mechanically coded binary information storage in the synapse, which identifies a potential novel therapeutic strategy for treating Alzheimer's Disease.
SARS-CoV-2 modulates NK cell responses via induction of HLA-E and triggers expansion of adaptive NK cells during acute infection
Authors: Hasan Mohammad Zahidul , Claus Maren , Kruger Nadine , Reusing Sarah , Gall Eline , Bade-Doding Christina , Braun Armin , Watzl Carsten , Uhrberg Markus , Walter Lutz
Published: March 2024

HLA-E expression plays a central role for modulation of NK cell function by interaction with inhibitory NKG2A and stimulatory NKG2C receptors on canonical and adaptive NK cells, respectively. Here, we demonstrate that infection of human primary lung tissue with SARS-CoV-2 leads to increased HLA-E expression and show that processing of the peptide YLQPRTFLL from the spike protein is primarily responsible for the strong, dose-dependent increase of HLA-E. Targeting the peptide site within the spike protein revealed that a single point mutation was sufficient to abrogate the increase in HLA-E expression. Spike-mediated induction of HLA-E differentially affected NK cell function: whereas degranulation, IFN-gamma production, and target cell cytotoxicity were enhanced in NKG2C+ adaptive NK cells, effector functions were inhibited in NKG2A+ canonical NK cells. Analysis of a cohort of COVID-19 patients in the acute phase of infection revealed that adaptive NK cells were induced irrespective of the HCMV status, challenging the paradigm that adaptive NK cells are only generated during HCMV infection. During the first week of hospitalization, patients exhibited a selective increase of early NKG2C+CD57- adaptive NK cells whereas mature NKG2C+CD57+ cells remained unchanged. Further analysis of recovered patients suggested that the adaptive NK cell response is primarily driven by a wave of early adaptive NK cells during acute infection that wanes once the infection is cleared. Together, this study suggests that NK cell responses to SARS-CoV-2 infection are majorly influenced by the balance between canonical and adaptive NK cells via the HLA-E/NKG2A/C axis.
Predicting Phylogenetic Bootstrap Values via Machine Learning
Authors: Wiegert Julius , Höhler Dimitri , Haag Julia , Stamatakis Alexandros
Published: March 2024

Estimating the statistical robustness of the inferred tree(s) constitutes an integral part of most phylogenetic analyses. Commonly, one computes and assigns a branch support value to each inner branch of the inferred phylogeny. The most widely used method for calculating branch support on trees inferred under Maximum Likelihood (ML) is the Standard, non-parametric Felsenstein Bootstrap Support (SBS). Due to the high computational cost of the SBS, a plethora of methods has been developed to approximate it, for instance, via the Rapid Bootstrap (RB) algorithm. There have also been attempts to devise faster, alternative support measures, such as the SH-aLRT (Shimodaira–Hasegawalike approximate Likelihood Ratio Test) or the UltraFast Bootstrap 2 (UFBoot2) method. Those faster alternatives exhibit some limitations, such as the need to assess model violations (UFBoot2) or meaningless low branch support intervals (SH-aLRT). Here, we present the Educated Bootstrap Guesser (EBG), a machine learning-based tool that predicts SBS branch support values for a given input phylogeny. EBG is on average 9.4 (σ= 5.5) times faster than UFBoot2. EBG-based SBS estimates exhibit a median absolute error of 5 when predicting SBS values between 0 and 100. Furthermore, EBG also provides uncertainty measures for all per-branch SBS predictions and thereby allows for a more rigorous and careful interpretation. EBG can predict SBS support values on a phylogeny comprising 1654 SARS-CoV2 genome sequences within 3 hours on a mid-class laptop. EBG is available under GNU GPL3.

Data and Code Availability

github.com/wiegertj/EBG

github.com/wiegertj/EBG-train

Contact

julius-wiegert@web.de
Modelling single-stress omics integration with HIVE enables the identification of responding signatures to multifactorial stress combinations in plants
Authors: Calia Giulia , Marguerit Sophia , Zotta Mota Ana Paula , Vidal Manon , Schuler Hannes , Miranda Brasileiro Ana Cristina , Guimaraes Patricia Messenberg , Bottini Silvia
Published: March 2024

All organisms are subjected to multiple stresses usually occurring at the same time, requiring the activation of the appropriate signalling pathways to respond to all or by prioritizing the response to one stress factor. Plants, as sessile organisms, are particularly impacted by the constantly changing environment that is often unfavourable or even hostile. Because of the experimental complexity of studying the response of one organism to multiple stressors simultaneously, usually experiments are conducted considering one individual stress factor at the time. An alternative consists in performingin silicointegration of those data on single stress response. Currently used methods to integrate unpaired experiments consist of performing meta-analysis or finding differentially expressed genes for each condition separately and then selecting the commonly regulated ones. Although these approaches allowed to find valuable results, they mainly identify specific signatures in response to one stress and very few signature responding to multiple stresses and lack those modulated differently in each condition.

For this purpose, we developed HIVE (Horizontal Integration analysis using Variational AutoEncoders) to integrate multiple single-stress transcriptomics datasets composed of unpaired experiments. Briefly, we coupled a variational autoencoder, that alleviates batch effects, with a random forest regression and the SHAP explainer to select relevant genes modulated specifically in response to one or multiple stresses.

We illustrate the functionality of HIVE to study the transcriptional changes of several different plants namelyArabidopsis thaliana, rice, maize, wheat, grapevine and peanut by collecting publicly available experiments on single stress, either biotic and/or abiotic, and jointly analyse them. HIVE performed better than the differential expression analysis, meta-analysis and the state-of-the-art tool for horizontal integration allowing to identify novel promising candidates responsible for triggering effective defence responses to multiple stresses.
Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistantAcinetobacterspp
Authors: Wong Olivia , Mezcord Vyanka , Lopez Christina , Traglia German Matias , Pasteran Fernando , Tuttobene Marisel R. , Corso Alejandra , Tolmasky Marcelo E. , Bonomo Robert A. , Ramirez María Soledad
Published: March 2024

The emergence of Gram-negative bacteria resistant to multiple antibiotics, particularly carbapenem-resistant (CR)Acinetobacterstrains, poses a significant threat globally. Despite efforts to develop new antimicrobial therapies, limited progress has been made, with only two drugs—cefiderocol and sulbactam-durlobactam—showing promise for CR-Acinetobacterinfections. Cefiderocol, a siderophore cephalosporin, demonstrates promising efficacy in the treatment of Gram-negative infections. However, resistance to cefiderocol has been reported inA. baumannii. Combination therapies, such as cefiderocol with avibactam or sulbactam, show reduced MICs against cefiderocol-non-susceptible strains with in vivo efficacy, although the outcomes can be complex and species-specific. In the present work, the molecular characterization of spontaneous cefiderocol-resistant variants, a CRAB strain displaying antagonism with sulbactam and anA. lwoffiistrain showing antagonism with avibactam, were studied. The results reveal intriguing insights into the underlying mechanisms, including mutations affecting efflux pumps, transcriptional regulators, and iron homeostasis genes. Moreover, gene expression analysis reveals significant alterations in outer membrane proteins, iron homeostasis, and β-lactamases, suggesting adaptive responses to selective pressure. Understanding these mechanisms is crucial for optimizing treatment strategies and preventing adverse clinical outcomes. This study highlights the importance of preemptively assessing drug synergies to navigate the challenges posed by antimicrobial resistance in CR-Acinetobacterinfections.
Cisinhibition of co-expressed DIPs and Dprs shapes neural development
Authors: Morano Nicholas C. , Lopez Davys H. , Meltzer Hagar , Sergeeva Alina P. , Katsamba Phinikoula S. , Rostam Kevin D. , Gupta Himanshu Pawankumar , Becker Jordan E. , Bornstein Bavat , Cosmanescu Filip , Schuldiner Oren , Honig Barry , Mann Richard S. , Shapiro Lawrence
Published: March 2024

InDrosophila, two interacting adhesion protein families, Dprs and DIPs, coordinate the assembly of neural networks. While intercellular DIP/Dpr interactions have been well characterized, DIPs and Dprs are often co-expressed within the same cells, raising the question as to whether they also interact incis. We show, in cultured cells andin vivo,that DIP-α and DIP-δ can interact inciswith their ligands, Dpr6/10 and Dpr12, respectively. When co-expressed inciswith their cognate partners, these Dprs regulate the extent oftransbinding, presumably through competitivecisinteractions. We demonstrate the neurodevelopmental effects ofcisinhibition in fly motor neurons and in the mushroom body. We further show that a long disordered region of DIP-α at the C-terminus is required forcisbut nottransinteractions, likely because it alleviates geometric constraints oncisbinding. Thus, the balance betweencisandtransinteractions plays a role in controlling neural development.
Salmonella exploits the reactive oxygen species generated by the plant immune system to enhance colonization
Authors: Aldin M Srai , Tzipilevich E
Published: March 2024

Understanding bacterial interaction with the plant immune system is essential for building a sustainable food system. Discouraging pathogens enhancing beneficial bacteria and preventing food spoilage and contamination by human enteric pathogens. Immune system activation triggers a burst of toxic reactive oxygen species (ROS). We discovered that the food-poisoning bacteriumSalmonellaexploits the plant ROS to enhance biofilm formation and colonization. Scavenging the ROS with antioxidants or inhibiting their production reduces colonization. Further, combining the antioxidant vitamin C and immune system activation with salicylic acid synergistically inhibitedSalmonellacolonization of the plant model Arabidopsis and edible plants. This safe-to-use combination is an eco-friendly method to prevent plant contamination bySalmonella, Listeriaand enteropathogenicE. coli. Finally, we have found that exploiting the plant immunity for enhancing colonization is not exclusive toSalmonellaand diverse beneficialpseudomonasspecies isolated from plants can also exploit the plant immune system, suggesting that it is a general plant colonization strategy.
Deep5hmC: Predicting genome-wide 5-Hydroxymethylcytosine landscape via a multimodal deep learning model
Authors: Ma Xin , Thela Sai Ritesh , Zhao Fengdi , Yao Bing , Wen Zhexing , Jin Peng , Zhao Jinying , Chen Li
Published: March 2024

5-hydroxymethylcytosine (5hmC), a critical epigenetic mark with a significant role in regulating tissue-specific gene expression, is essential for understanding the dynamic functions of the human genome. Using tissue-specific 5hmC sequencing data, we introduce Deep5hmC, a multimodal deep learning framework that integrates both the DNA sequence and the histone modification information to predict genome-wide 5hmC modification. The multimodal design of Deep5hmC demonstrates remarkable improvement in predicting both qualitative and quantitative 5hmC modification compared to unimodal versions of Deep5hmC and state-of-the-art machine learning methods. This improvement is demonstrated through benchmarking on a comprehensive set of 5hmC sequencing data collected at four time points during forebrain organoid development and across 17 human tissues. Notably, Deep5hmC showcases its practical utility by accurately predicting gene expression and identifying differentially hydroxymethylated regions in a case-control study of Alzheimer’s disease.
Nucleolar accumulation of APE1 through condensates is mediated by rRNA forming G-quadruplex structures
Authors: Dall’Agnese Giuseppe , Hannett Nancy M. , Overholt Kalon J. , Platt Jesse M. , Henninger Jonathan E. , Marcos-Vidal Asier , Antoniali Giulia , Tell Gianluca
Published: March 2024

APE1 (apurinic/apyrimidinic endodeoxyribonuclease 1) is the main endonuclease of the base excision repair (BER) pathway acting on abasic (AP)-sites in damaged DNA. APE1 is an abundant nuclear protein with a higher concentration than other BER pathway enzymes, and therefore, improper expression and localization of this factor could lead to the accumulation of toxic DNA intermediates. Altered APE1 sub-cellular localization, expression levels, or hyper-acetylation are associated with cancer development suggesting the importance of a fine-tuning mechanism for APE1 nuclear-associated processes. Recent work highlighted multi-functional roles of APE1, including rRNA quality control. However, how rRNA influences the sub-cellular localization and activity of APE1 remains poorly understood, but previously underappreciated APE1-RNA interactions may influence the ability of this protein to form biomolecular condensates and tune APE1 partitioning into nucleoli. Since nucleolar accumulation of ectopic proteins could be the result of overexpression strategies, it is imperative to have cellular models to study APE1 trafficking under physiological conditions. Here we created the first cell line to express fluorescently tagged APE1 at its endogenous locus, enabling live-cell imaging. Live-cell imaging demonstrates that APE1 nucleolar accumulation requires active rRNA transcription. When modeled in vitro, APE1 condensate formation depends on RNA G-quadruplex (rG4) structures in rRNA and is modulated by critical lysine residues of APE1. This study sheds light on the mechanisms underlying APE1 trafficking to the nucleolus and formation of RNA-dependent APE1 nucleolar condensates that may modulate a switch between the activity of this factor in rRNA processing and DNA damage repair.

Significance Statement

We created and characterized the first endogenous, fluorescently tagged cell line to study APE1 subcellular trafficking under physiological and stress conditions. Using this cell line, we show that APE1 nucleolar enrichment occurs under physiological conditions and, performingin vitrodroplet assays, we associate APE1 condensates with active transcription of RNA G-quadruplexes, abundantly present in healthy nucleoli. This work deepens our understanding of APE1’s role in healthy cells in the absence of DNA damage and provide a novel mechanism for how this protein responds to stress. Our results suggest that phase separation is an important part of how DNA damage repair proteins switch between their normal physiological functions and their ability to correct DNA lesions.
Increased Risk of Cirrhosis in Patients with Inflammatory Bowel Disease: A Danish registry-based cohort study (1998-2018)
Authors: Deepak Parakkal , McHenry Scott , Sandri Anastasia Karachalia , De Freitas Maiara Brusco , Zamani Mohammad , Yarur Andres J. , Jess Tine
Published: March 2024

Background and Aims

Prior studies suggest an increased risk of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD). We aimed to investigate the risk of cirrhosis in a nationwide cohort of IBD patients compared to a matched non-IBD population.

Methods

Patients diagnosed with IBD without prior cirrhosis during 1998-2018 were identified in the Danish health registries and were matched 1:10 to persons without IBD. Cox regression was used to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs).

Results

Within the study population of 495,220 persons, a total of 2,741 cirrhosis cases were identified during follow-up, with a higher proportion of cases among patients with IBD (0.9%) compared to non-IBD persons (0.5%). Patients with IBD had a significantly higher risk of cirrhosis compared to non-IBD persons (adjusted HR (aHR) (95% CI): 1.84 (1.64-2.04)). The leading etiology of cirrhosis in IBD was NAFLD (51.6%), followed by alcohol (39.0%). The risk of cirrhosis among IBD patients (compared to non-IBD persons) was more pronounced among those diagnosed with IBD ≤ 40 years of age (aHR (95% CI): 3.08 (2.45-3.87); vs. > 40 years of age, 1.63 (1.45-1.84); p-value <0.001) and CD patients (aHR (95% CI): 2.20 (1.80-2.67); vs. 1.72 (1.52-1.95) among UC; p-value 0.04).

Conclusion

IBD was associated with an increased risk of incident cirrhosis, especially in patients aged ≤ 40 years at IBD diagnosis and in patients with CD. These findings point towards a need for focused screening for cirrhosis among IBD patients, especially in certain groups.
Amino acid profiling of COVID-19 patients blood serum
Authors: Russkikh Ya.V. , Sushentseva N.N. , Popov O.S. , Apalko S.V. , Shimansky V.S. , Asinovskaya A.Yu. , Mosenko S.V. , Sarana A.M. , Scherbak S.G.
Published: March 2024

Main objectives of this study were to analyse metabolomic profile features of patients with COVID-19 using mass spectrometry techniques while taking into account the clinical and laboratory history, and to study the relationship between the severity of COVID-19 symptoms and the concentration of primary metabolites, primarily amino acids. We used frozen blood serum samples of 935 COVID-19 patients from the City Hospital No. 40 biobank collection. Metabolomic profile was studied by HPLS-MS/MS method. R programming language was used for statistical data processing. The difference of metabolic profile of patients with COVID-19 depending on the severity of the disease was revealed based on the performed analysis - for 52 out of 84 detected compounds there were differences with reliability p<0,01. Statistically significant differences in concentration were recorded for organic acids, amino acids and their derivatives. Using samples from the biobank collection, a metabolomic study of the biomaterial of patients hospitalised with the diagnosis of COVID-19 was carried out. According to the results obtained, kynurenine, phenylalanine and acetylcarnitine were associated with the severity of COVID-19 infection.
Welsh hospital admissions due to dog bites and strikes (2014-2022)
Authors: Owczarczak-Garstecka Sara C , Oxley James A , Tulloch John SP
Published: March 2024

Objective

To describe the incidence and victim demographics of Welsh hospital admissions due to dog bites and strikes from 2014 to 2022.

Study design

Descriptive analysis of Welsh hospital admissions data.

Methods

Residents of Wales admitted to a Welsh National Health Service (NHS) hospital for a dog bite or strike, were identified using ICD-10 codes. The annual incidence of dog bite admissions between 2014 and 2022 was calculated and stratified by child–adult status, sex, and Local Health Boards. Trends over time were analysed using Chi-square test for trends.

Results

Hospital admissions due to dog bites and strikes have significantly increased from 16.3 per 100,000 to 23.7 per 100,000 population in 2022. This was driven by an increase in non-geriatric adults, and an increase in three Local Health Boards. The Swansea Bay area has the highest incidence in Wales (56.1 admissions per 100,000).

Conclusions

Wales has a higher incidence of dog bites than England or the Republic of Ireland. Work in the communities where incidence is exceptionally high is needed to understand the reasons behind having the highest incidence of dog bites in the British Isles and to establish the most efficacious methods for bite prevention.
Comprehensive Evaluation of Artificial Intelligence Models for Diagnosis of Multiple Sclerosis Using Information from Retinal Layers Multicenter OCT Images
Authors: Khodabandeh Zahra , Rabbani Hossein , Bidabadi Neda Shirani , Bonyani Mehdi , Kafieh Rahele
Published: March 2024

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system. Optical coherence tomography (OCT) is a retinal imaging technology with great promise as a possible MS biomarker. Unlike other ophthalmologic diseases, the variations in shape of raw cross-sectional OCTs in MS are subtle and not differentiable from healthy controls (HCs). More detailed information like thickness of particular layers of retinal tissues or surface of individual retinal boundaries are more appropriate discriminators for this purpose. Artificial Intelligence (AI) has demonstrated a robust performance in feature extraction and classification of retinal OCTs in different ophthalmologic diseases using OCTs. We explore a comprehensive range of AI models including (1) feature extraction with autoencoder (AE) and shallow networks for classification, (2) classification with deep networks designed from scratch, and (3) fine-tuning of pretrained networks (as a generic model of the visual world) for this specific application. We also investigate different input data including thickness and surfaces of different retinal layers to find the most representative data for discrimination of MS. Moreover, channel-wise combination and mosaicing of multiple inputs are examined to find the better merging model. To address interpretability requirement of AI models in clinical applications, the visualized contribution of each input data to the classification performance is shown using occlusion sensitivity and Grad-CAM approaches. The data used in this study includes 38 HC and 78 MS eyes from two independent public and local datasets. The effectiveness and generalizability of the classification methods are demonstrated by testing the network on these independent datasets. The most discriminative topology for classification, utilizing the proposed deep network designed from scratch, is determined when the inputs consist of a channel-wise combination of the thicknesses of the three layers of the retina, namely the retinal fiber layer (RNFL), ganglion cell and inner plexiform layer (GCIP), and inner nuclear layer (INL). This structure resulted in balanced-accuracy of 97.3, specificity of 97.3, recall 97.4%, and g-mean of 97.3% in discrimination of MS and HC OCTs.
XBB.1.5 mRNA COVID-19 Vaccination and Inpatient or Emergency Department Visits Among Adults Infected with SARS-CoV-2 JN.1 and XBB-Lineage Variants
Authors: Levy Matthew E. , Chilunda Vanessa , Heaton Phillip R. , McKeen Deran , Goldman Jason D. , Davis Richard E. , Schandl Cynthia A. , Glen William B. , McEwen Lisa M. , Cirulli Elizabeth T. , Wyman Dana , Rossi Andrew Dei , Dai Hang , Isaksson Magnus , Washington Nicole L. , Basler Tracy , Tsan Kevin , Nguyen Jason , Ramirez Jimmy , Sandoval Efren , Lee William , Lu James , Luo Shishi
Published: March 2024

Within a multi-state viral genomic surveillance program, we conducted a case-control analysis comparing prior receipt of XBB.1.5-adapted mRNA vaccination between SARS-CoV-2-infected adults with inpatient/ED visits (proxy for severe illness) vs outpatient visits. Among 6,551 patients from September 2023-January 2024, 6.1% with inpatient/ED visits vs 12.0% with outpatient visits had received XBB.1.5 vaccination (aOR=0.41; 95%CI:0.32-0.53). This protective association was weaker among JN.1 (aOR=0.62; 95%CI:0.40-0.96) vs XBB-lineage (aOR=0.28; 95%CI:0.18-0.43) variant infections (interaction, p=0.003). XBB.1.5 vaccination was also protective specifically compared to BA.4/BA.5-adapted mRNA vaccination (aOR=0.60; 95%CI:0.45-0.79). XBB.1.5 vaccines protect against severe illness, but protection may be weaker against JN.1 vs XBB-lineage variants.