bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of long-term benzodiazepine hypnotic use and prediabetes in US population: A cross-sectional analysis of national health and nutrition examination survey data
Authors: Wu Weizhen , Zhang Junning , Qiao Yizhuo , Ren Lijiang , Chen Zhe , Fu Yan , Yang Zhixu
Published: November 2023

Benzodiazepine hypnotics’ effects on glucose metabolism are seldom reported, and the association between long-term (≥4 weeks) benzodiazepine usage and prediabetes has not been studied. This study was aimed to investigate the association between benzodiazepine hypnotic usage for ≥ 3 months and the prevalence of prediabetes. We analyzed cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) during 2005 to 2008, selecting adult participants without diabetes who used benzodiazepine hypnotics for at least 3 months or did not take any hypnotics. Individuals taking other hypnotics, antipsychotics, glucocorticoids, or hypoglycemic drugs were excluded. We defined prediabetes as an hemoglobin A1C (HbA1C) 5.7–6.4%, as suggested by the American Diabetes Association. Prescribed drug information was self-reported and checked by official interviewers, and HbA1C data in NHANES was recognized by the National Glycohemoglobin Standardization Program. We calculated the propensity score according to the covariates and adjusted it using multivariate logistic regression. Lower thresholds of HbA1C ≥ 5.5% or ≥ 5.3% were also analyzed. Among 4694 eligible participants, 38 received benzodiazepine hypnotics; using these hypnotics for ≥ 3 months was not significantly associated with the prevalence of prediabetes, as well as HbA1C ≥ 5.5% or ≥ 5.3%. Adjusted for propensity score, the respective odds ratios for prediabetes, HbA1C ≥ 5.5%, and HbA1C ≥ 5.3% were 1.09 (95% confidence interval [CI] 0.19–6.32), 0.83 (95% CI 0.22–3.13), and 1.22 (95% CI 0.3–4.93). No significant association was found between benzodiazepine hypnotic usage ≥ 3 months and the prevalence of prediabetes.
Can the Autogenous Nanofat Injection Improve the Symptoms of Patients With Temporomandibular Joint Internal Derangement? A Prospective Observational Clinical Study
Authors: Ali Huda Akram , Hadi Hassanien Ahmed
Published: November 2023

Since nanofat is considered one of the richest sources of adipose-derived stem cells with an increased need for new biological approaches for managing temporomandibular joint internal derangement (TMJ-ID) symptoms that impair a patient’s lifestyle, this study evaluated the effectiveness of autogenous nanofat intra-articular injection in managing ID symptoms regarding pain, mouth opening, and joint sound. Furthermore, to assess the consequences and complications of this procedure, 20 patients with 38 TMJs with varying stages of Wilkes classification were included in the study. All involved patients were previously diagnosed with ID depending on a clinical and radiographical basis and had no previous response to conservative management for at least 4 to 6 months. Evaluation of the ID in the preoperative phase, as well as 2 weeks, 1 month, 3 months, and 6 months postoperatively. An evaluation was done depending on pain assessment using a visual analog scale (VAS), measuring maximum mouth opening (MMO) and joint noise if it was present or absent preoperatively and postoperatively. The results show improvement in the symptoms in all follow-up appointments since the VAS of pain decreased significantly with increased MMO and the absence of clicking in most cases during follow-up appointments. We conclude from this study that nanofat intra-articular injection was influential in managing ID symptoms and was safe without significant side effects.
Technique for Cephalometric Analysis of the Craniofacial Skeleton Following Facial Feminization Surgery
Authors: Williams Mica C.G. , Almeida Mariana , Alper David P. , Allam Omar , Shah Jinesh , Craver Andrew , Judge Abigail , Rivera Jean Carlo , Persing John A. , Alperovich Michael
Published: November 2023

Facial feminization surgery (FFS) is characterized by a series of relatively diverse procedures aimed at aligning skeletal and soft tissue facial appearance with one’s experienced feminine gender. Although there are several well-described outcomes from surgical techniques, there is no standardized methodology to provide reliable analyses of postoperative FFS outcomes. This paper describes the first reliable and reproducible technique to accurately and consistently measure post-FFS changes to guide surgical planning to optimize patient outcomes.
Agentic processes in cultural evolution: relevance to Anthropocene sustainability
Authors: Richerson Peter J. , Boyd Robert T. , Efferson Charles
Published: November 2023

Humans have evolved culturally and perhaps genetically to be unsustainable. We exhibit a deep and consistent pattern of short-term resource exploitation behaviours and institutions. We distinguish agentic and naturally selective forces in cultural evolution. Agentic forces are quite important compared to the blind forces (random variation and natural selection) in cultural evolution and gene-culture coevolution. We need to use the agentic policy-making processes to evade the impact of blind natural selection. We argue that agentic forces became important during our Pleistocene history and into the Anthropocene present. Human creativity in the form of deliberate innovations and the deliberate selective diffusion of technical and social advances drove this process forward for a long time before planetary limits became a serious issue. We review models with multiple positive feedbacks that roughly fit this observed pattern. Policy changes in the case of large-scale existential threats like climate change are made by political and diplomatic agents grasping and moving levers of institutional power in order to avoid the operation of blind natural selection and agentic forces driven by narrow or short-term goals.

This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
Maternal Mortality and Last Mile Challenges: Improved Perspective for Leapfrogging
Authors: Ahmed Shabbir , Tanbi Fatema Akter , Rahman Hossain Zillur
Published: November 2023

Background

Reducing maternal mortality to zero is one of the 3 targeted agendas of the International Conference of Population and Development (ICPD). Though global improvements in align with SDGs commitment have witnessed comparative development but in the case of reaching zero agenda there are still much more improvements to make.

Objectives

Understanding the bottom-level reality with field experiences while also paying attention to the policy voices to understand the last mile stumbling blocks.

Methods

Reality check along with expert opinions working at the field level and beneficiary consultations were the primary components for this study. Three specific modalities (i) field-level consultations with the stakeholders, (ii) facility inspection and (iii) roundtable discussion were the specific tools used for this study.

Results

Findings show that in Bangladesh, substantial inequities exist both in the use of facility-based maternal healthcare with scarce and the absence of competent birth attendants for home births. Moreover, socio-cultural norms and the socioeconomic status of the families contribute to maternal deaths. The poor family setting, the hospital referral system, and the familial understanding of the overall maternal healthcare are largely responsible for maternal deaths.

Conclusion

All these issues related to maternal deaths need proper attention to leap forward to overcome the last mile challenges. Determined focus on defining and identifying the last mile population, breaking the pedagogical limitations and institutional barriers with an additional focus on the last mile research to reach the underserved population is imperative to reach the last mile.

Problem

Improving maternal health is one of three ICPD 3 zeroes priority, and a nested target in the third goal of the Sustainable Development Goals (SDGs). Alarmingly, maternal mortality is the third highest cause of death among women aged 15 to 49 in Bangladesh contributing to stalling the progress ahead in achieving SDGs.

What is Already Known

The business as usual and contextual factors including poverty, distance to health facilities, lack of information, inadequate services, cultural practices, education coupled with governance and macro-structural factors, private sector infrastructure investment and health finance are greatly responsible for maternal mortality to overcome last mile challenge.

What this Paper Adds

This study identifies barriers that limit the availability and access to quality maternal health services at all levels of the health system focusing the grass root maternal services. Underlines the prevailing inadequate and absence of services delivery and suggests necessary steps to address the last mile challenges towards ending preventable maternal deaths,
GGA1 interacts with the endosomal Na+/H+ Exchanger NHE6 governing localization to the endosome compartment
Authors: Ma Li , Kasula Ravi Kiran , Ouyang Qing , Schmidt Michael , Morrow Eric M.
Published: November 2023

Mutations in the endosomal Na+/H+ exchanger (NHE6) cause Christianson syndrome (CS), an X-linked neurological disorder. Previous studies have shown that NHE6 functions in regulation of endosome acidification and maturation in neurons. Using yeast two-hybrid screening with the NHE6 carboxyl-terminus as bait, we identify Golgi-associated, Gamma adaptin ear containing, ARF binding protein 1 (GGA1) as an interacting partner for NHE6. We corroborated the NHE6-GGA1 interaction using co-immunoprecipitation (co-IP): using over-expressed constructs in mammalian cells; and co-IP of endogenously-expressed GGA1 and NHE6 from neuroblastoma cells, as well as from mouse brain. We demonstrate that GGA1 interacts with organellar NHEs (NHE6, NHE7 and NHE9) but not with cell-surface localized NHEs (NHE1 and NHE5). By constructing hybrid NHE1/NHE6 exchangers, we demonstrate that the cytoplasmic tail of NHE6 is necessary and sufficient for interactions with GGA1. We demonstrate the co-localization of NHE6 and GGA1 in cultured, primary hippocampal neurons, using super-resolution microscopy. We test the hypothesis that the interaction of NHE6 and GGA1 functions in the localization of NHE6 to the endosome compartment. Using subcellular fractionation experiments, we show that NHE6 is mis-localized in GGA1 knockout cells wherein we find less NHE6 in endosomes but more NHE6 transport to lysosomes, and more Golgi retention of NHE6 with increased exocytosis to the surface plasma membrane. Consistent with NHE6 mis-localization, and Golgi retention, we find the intra-luminal pH in Golgi to be alkalinized. Our study demonstrates a new interaction between NHE6 and GGA1 which functions in the localization of this intra-cellular NHE to the endosome compartment.
Stacking models of brain dynamics improves prediction of subject traits in fMRI
Authors: Griffin B , Ahrends C , Alfaro-Almagro F , Woolrich M , Smith S , Vidaurre D
Published: November 2023

Beyond structural and time-averaged functional connectivity brain measures, the way brain activity dynamically unfolds can add important information when investigating individual cognitive traits. One approach to leveraging this information is to extract features from models of brain network dynamics to predict individual traits. However, there are two potential sources of variation in the models’ estimation which will in turn affect the predictions: first, in certain cases, the estimation variability due to different initialisations or choice of inference method; and second, the variability induced by the choice of the model hyperparameters that determine the complexity of the model. Rather than merely being statistical noise, this variability may be useful in providing complementary information that can be leveraged to improve prediction accuracy. We propose stacking, a prediction-driven approach for model selection, to leverage this variability. Specifically, we combine predictions from multiple models of brain dynamics to generate predictions that are accurate and robust across multiple cognitive traits. We demonstrate the approach using the Hidden Markov Model, a probabilistic generative model of brain network dynamics. We show that stacking can significantly improve the prediction of subject-specific phenotypes, which is crucial for the clinical translation of findings.
Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent anti-PD-L1- and anti-NKG2A-based adjuvant immunotherapy
Authors: Patin Emmanuel C , Nenclares Pablo , Hak Charleen Chan Wah , Dillon Magnus T , Patrikeev Anton , McLaughlin Martin , Grove Lorna , Foo Shane , Soliman Heba , Barata Joao P , Marsden Joanna , Baldock Holly , Roulstone Victoria , Kyula Joan , Burley Amy , Hubbard Lisa C , Pedersen Malin , Smith Simon A , Clancy-Thompson Eleanor , Melcher Alan A , Ono Masahiro , Rullan Antonio , Harrington Kevin J
Published: November 2023

Despite some success in other cancer types, the results of combining radiotherapy/chemoradiotherapy and immune checkpoint blockade have been disappointing in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). For such a potentially radiocurable disease, there remains an imperative to explore novel combination approaches. Here, we show that combining ATR inhibition with radiotherapy (ATRi/RT) increases the frequency of highly activated NKG2A/PD-1 double-positive T cells in patients and in animal models of HNSCC. Addition of dual anti-NKG2A and anti-PD-1/-PD-L1 blockade to ATRi/RT in the adjuvant, post-radiotherapy setting induces a robust antitumour immune response in HNSCC preclinical models. Efficacy of the combination regimen relies on CD40/CD40L costimulatory-mediated infiltration of activated/proliferative/memory CD8 and CD4 conventional T cells with persistent or new T cell receptor (TCR) signalling, respectively, as defined by tracking of T cell dynamics. In this favourable therapeutic context, TCR sequencing shows increased richness of the TCR repertoire and the emergence of numerous and large TCR clusters that share antigen specificity in response to full combination therapy. Collectively, our data point towards promising combination approaches for future clinical testing in HNSCC.
Easy, fast and reproducible Stochastic Cellular Automata with chouca
Authors: Génin Alexandre , Dupont Guillaume , Valencia Daniel , Zucconi Mauro , Ávila-Thieme M. Isidora , Navarrete Sergio A. , Wieters Evie A.
Published: November 2023

Stochastic cellular automata (SCA) are models that describe spatial dynamics using a grid of cells that switch between discrete states over time. They are widely used to understand how small-scale processes scale up to affect ecological dynamics at larger spatial scales, and have been applied to a wide diversity of theoretical and applied problems in all systems, such as arid ecosystems, coral reefs, forests, bacteria, or urban growth.

Despite their wide applications, SCA implementations are often ad-hoc, lacking performance, guarantees of correctness and poorly reproducible.De novoimplementation of SCA for each specific system and application also represents a major barrier for many practitioners. To provide a unifying, well-tested technical basis to this class of models and facilitate their implementation, we built chouca, an R package that translates definitions of SCA models into compiled code, and runs simulations in an efficient way.

chouca supports SCA based on rectangular grids where transition probabilities are defined for each cell, with performance typically two to three orders of magnitude above typical implementations in interpreted languages (e.g. R, Python), all while maintaining an intuitive interface in the R environment. Exact and mean-field simulations can be run, and both numerical and graphical results can be easily exported.

Besides providing better reproducibility and accessibility, a fast engine for SCA unlocks novel, computationally intensive statistical approaches, such as simulation-based inference of ecological interactions from field data, which represents by itself an important avenue for research. By providing an easy and efficient entry point to SCAs, chouca lowers the bar to the use of this class of models for ecologists, managers and general practitioners, providing a leveled-off reproducible platform while opening novel methodological approaches.
Experimental evolution for the recovery of growth loss due to genome reduction
Authors: Hitomi Kenya , Ishii Yoichiro , Ying Bei-Wen
Published: November 2023

As the genome encodes the information crucial for cell growth, a sizeable genomic deficiency often causes a significant decrease in growth fitness. Whether and how the decreased growth fitness caused by genome reduction could be compensated by evolution was investigated here. Experimental evolution with anEscherichia colistrain carrying a reduced genome was conducted in multiple lineages for approximately 1,000 generations. The growth rate, which was largely declined due to genome reduction, was considerably recovered, associated with the improved carrying capacity. Genome mutations accumulated during evolution were significantly varied across the evolutionary lineages and were randomly localized on the reduced genome. Transcriptome reorganization showed a common evolutionary direction and conserved the chromosomal periodicity, regardless of highly diversified gene categories, regulons, and pathways enriched in the differentially expressed genes. Genome mutations and transcriptome reorganization caused by evolution, which were found to be dissimilar to those caused by genome reduction, must have followed divergent mechanisms in individual evolutionary lineages. Gene network reconstruction successfully identified three gene modules functionally differentiated, which were responsible for the evolutionary changes of the reduced genome in growth fitness, genome mutation, and gene expression, respectively. The diversity in evolutionary approaches improved the growth fitness associated with the homeostatic transcriptome architecture as if the evolutionary compensation for genome reduction was like all roads leading to Rome.
miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice
Authors: Narayanan Ramanathan , Levone Brunno Rocha , Winterer Jochen , Nanda Prakruti , Ranft Alexander Mueller , Fiore Roberto , Germain Pierre-Luc , Mihailovich Marija , Testa Giuseppe , Schratt Gerhard
Published: November 2023

Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to increased excitatory synaptic transmission and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, was sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members were reciprocally dysregulated in isogenic human iPSC-derived neurons harboring a deletion present in Williams-Beuren-Syndrome patients, which are characterized by hypersocial behavior. Together, our results unveil a novel microRNA-actomyosin pathway involved in the control of sociability.
In situobservation and range extension of the first monoplacophoranNeopilina galatheae
Authors: Chen Chong , Jamieson John W.
Published: November 2023

Monoplacophoran molluscs have been dubbed ‘living fossils’ due to their absence in the fossil record for about 375 million years, untilNeopilina galatheaeLemche, 1957 was trawled off Costa Rica in 1952. Since then, over 35 species of living monoplacophorans have been discovered. Nevertheless,in situobservations of these rare deep-sea animals remain scant. Here, we observed and collected an intact specimen ofN. galatheaeusing a remotely operated vehicle from 2460 m deep on the Eastern Galápagos Spreading Center. The animal was found attached to the glassy surface of solidified basalt lava flow, and no feeding trails were found near the animal. Such hard substrate is in contrast with previous records that were trawled on sand and mud, suggestingNeopilinacan be found on a wide range of substrates. This is the first time this species was collected since 1959, and represents a southeast range extension of about 1000 km for the species.
Chromosome-level assembly of the gray fox (Urocyon cinereoargenteus) confirms the basal loss ofPRDM9in Canidae
Authors: Armstrong Ellie E. , Bissell Ky L. , Fatima H. Sophia , Heikkinen Maya A. , Jessup Anika , Junaid Maryam O. , Lee Dong H. , Lieb Emily C. , Liem Josef T. , Martin Estelle M. , Moreno Mauricio , Otgonbayar Khuslen , Romans Betsy W. , Royar Kim , Adler Mary Beth , Needle David B. , Harkess Alex , Kelley Joanna L. , Mooney Jazlyn A. , Mychajliw Alexis M.
Published: November 2023

Reference genome assemblies have been created from multiple lineages within the Canidae family, however, despite its phylogenetic relevance as a basal genus within the clade, there is currently no reference genome for the gray fox (Urocyon cinereoargenteus). Here, we present a chromosome-level assembly for the gray fox (U. cinereoargenteus), which represents the most contiguous, non-domestic canid reference genome available to date, with 90% of the genome contained in just 34 scaffolds and a contig N50 and scaffold N50 of 59.4 and 72.9 Megabases (Mb), respectively. Repeat analyses identified an increased number of simple repeats relative to other canids. Based on mitochondrial DNA, our Vermont sample clusters with other gray fox samples from the northeastern US and contains slightly lower levels of heterozygosity than gray foxes on the west coast of California. This new assembly lays the groundwork for future studies to describe past and present population dynamics, including the delineation of evolutionarily significant units of management relevance. Importantly, the phylogenetic position ofUrocyonallows us to verify the loss ofPRDM9functionality in the basal canid lineage, confirming that pseudogenization occurred at least 10 million years ago.
Microbiota-dependent early life programming of gastrointestinal motility
Authors: Frith Mary E. , Kashyap Purna C. , Linden David R. , Theriault Betty , Chang Eugene B.
Published: November 2023

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNAseq of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later – or not at all – showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early life microbiome in later life dysmotility.
Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells
Authors: Iascone Daniel Maxim , Zhang Xue , Bafford Patricia , Mesaros Clementina , Sela Yogev , Hofbauer Samuel , Zhang Shirley L. , Cook Kieona , Pivarshev Pavel , Stanger Ben Z. , Anderson Stewart , Dang Chi V. , Sehgal Amita
Published: November 2023

Crosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in anin vitromouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.
Cholinergic Modulation of Neurovascular Coupling and Neuroimaging Signals
Authors: Brezzo Gaia , Berwick Jason , Martin Chris J
Published: November 2023

The use of non-invasive functional neuroimaging methods to discriminate levels or patterns of brain activity between different groups, across different time points, or in response to drug treatment, depends on an understanding of neurovascular coupling relationships and how they themselves are affected by the factors of interest. For instance, Alzheimer’s disease (AD) features cerebral blood flow (CBF) and neurovascular unit changes as well as being characterised by a cholinergic dysfunction which impacts upon CBF regulation. The present study investigated the acute neurovascular effects of cholinergic agonist and antagonist treatment in a rat model utilising a multimodal measurement approach. Drugs were administered to rats during concurrent imaging of cortical CBF and recording of local field potential responses to somatosensory stimulation. Analysis of concurrent neuronal and vascular measures revealed a pronounced loss of neurovascular coupling following treatment with the cholinergic antagonist scopolamine. Separate analysis of CBF and neuronal responses reveal an interaction effect of stimulus input and drug treatment for both cholinergic agonist and antagonist treatment, as well as an augmentation of both neuronal and haemodynamic response magnitudes after treatment with the clinically prescribed cholinergic agonist donepezil. These findings have implications for the use and interpretation of functional neuroimaging data acquired in individuals with disease-related or pharmacological manipulations of cholinergic function.
Tick bite-induced Alpha-Gal Syndrome and Immunologic Responses in an Alpha-Gal Deficient Murine Model
Authors: Sharma Surendra Raj , Choudhary Shailesh K. , Vorobiov Julia , Commins Scott P. , Karim Shahid
Published: November 2023

Introduction

Alpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-α-1,3-galactose (α-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to α-gal antigens and elevate the levels of α-gal specific IgE. However, the precise mechanism by which tick bites influence the host’s immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism.

Methods

Lone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined.

Results

Our results showed a significant increase in the titer of total IgE, IgG1, and α-gal IgG1 antibodies in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge inAm. americanum-sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed thatAm. americanumbites direct mouse immunity toward Th2 and facilitate host sensitization to the α-gal antigen, whileAm. maculatumdid not.

Conclusion

This study supports the hypothesis that specific tick species may increase the risk of developing α-gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development.
An Artificial Intelligence-Assisted Digital Microfluidic System for Multistate Droplet Control
Authors: Guo Kun-Lun , Song Ze-Rui , Zhou Jia-Le , Shen Bin , Yan Bing-Yong , Gu Zhen , Wang Hui-Feng
Published: November 2023

Abstract

Digital microfluidics (DMF) is a versatile technique for parallel and field-programmable control of individual droplets. Given the high freedom in droplet manipulation, it is essential to establish self-adaptive and intelligent control methods for DMF systems with informed of the transient state of droplets and their interactions. However, most related studies focus on the localization and shape recognition of droplets. Here, we develop an AI-assisted DMF framework named “μDropAI” for multistate droplet control based on droplet morphology. Semantic segmentation model is integrated into our custom-designed DMF system to recognize the droplet states and their interactions for feedback control with a state machine. The proposed model has a strong generalization ability and can recognize droplets of different colors and shapes with an error rate of less than 0.63%. It enables control of droplets without user intervene. The proposed system will inspire the development of semantic-driven DMF systems which can interface with artificial general intelligence (AGl) models for fully automatic control.
A new take on missing value imputation for bottom-up label-free LC-MS/MS proteomics
Authors: Etourneau Lucas , Fancello Laura , Wieczorek Samuel , Varoquaux Nelle , Burger Thomas
Published: November 2023

Label-free bottom-up proteomics using mass spectrometry and liquid chromatography has long established as one of the most popular high-throughput analysis workflow for proteome characterization. However, it produces data hindered by complex and heterogeneous missing values, which imputation has long remained problematic. To cope with this, we introduce Pirat, an algorithm that harnesses this challenge following an unprecedented approach. Notably, it models the instrument limit by estimating a global censoring mechanism from the data available. Moreover, it leverages the correlations between enzymatic cleavage products (i.e., peptides or precursor ions), while offering a natural way to integrate complementary transcriptomic information, when available. Our benchmarking on several datasets covering a variety of experimental designs (number of samples, acquisition mode, missingness patterns, etc.) and using a variety of metrics (differential analysis ground truth or imputation errors) shows that Pirat outperforms all pre-existing imputation methods. These results pinpoint the potential of Pirat as an advanced tool for imputation in proteomic data analysis, and more generally underscore the worthiness of improving imputation by explicitly modeling the correlation structures either grounded to the analytical pipeline or to the molecular biology central dogma governing multiple omic approaches.
Reconciling land sharing and sparing: a conceptual model for land use
Authors: Junod Marco Fioratti , Borchers Nicolas , Reid Brian J. , Sims Ian , Miller Anthony J.
Published: November 2023

Since the introduction of the terms in the early 2000s, the land sharing versus land sparing dichotomy has sparked considerable discussion stemming from the relationship between food production and ecological function. The theory underpinning these approaches straddles disciplinary and ideological boundaries and is frequently outlined within a general economy versus ecology background. Both strategies have come up with competing models on the relationship linking agricultural production and ecological function.

The present work introduces a conceptual synthesis to unify alternative models under a single coherent framework. A generalized model linking agricultural production with ecological function that can harmonize these conflicting views is presented. In addition, a conceptual shift of paradigm is suggested to approach the issue, moving from yield targets to preservation thresholds.

This article provides the theoretical means to identify the environmental and policy conditions under which land sharing strategies, based on low inputs and low impact per unit of cultivated land, can compete with land sparing approaches for the combined goals of biodiversity preservation and food safety.
Are most human specific proteins encoded by long non-coding RNA ?
Authors: Sanejouand Yves-Henri
Published: November 2023

By looking for a lack of homologues in a reference database of 27 well-annotated proteomes of primates and 52 well-annotated proteomes of other mammals, 170 putative human-specific proteins were identified. Among them, only 2 are known at the protein level and 23 at the transcript level, according to Uniprot. Though 21 of these 25 proteins are found encoded by an open reading frame of a long non-coding RNA, 60% of them are predicted to be at least 90% globular, with a single structural domain. However, there is a near complete lack of structural knowledge about these proteins, with no tridimensional structure presently available in the Protein Databank and a fair prediction for a single of them in the AlphaFold Protein Structure Database. Moreover, the knowledge about the function of these possibly key proteins remains scarce.
Ultrasonic reporters of calcium for deep tissue imaging of cellular signals
Authors: Jin Zhiyang , Lakshmanan Anupama , Zhang Ruby , Tran Teresa A. , Rabut Claire , Dutka Przemysław , Duan Mengtong , Hurt Robert C. , Malounda Dina , Yao Yuxing , Shapiro Mikhail G.
Published: November 2023

Calcium imaging has enabled major biological discoveries. However, the scattering of light by tissue limits the use of standard fluorescent calcium indicators in living animals. To address this limitation, we introduce the first genetically encoded ultrasonic reporter of calcium (URoC). Based on a unique class of air-filled protein nanostructures called gas vesicles, we engineered URoC to produce elevated nonlinear ultrasound signal upon binding to calcium ions. With URoC expressed in mammalian cells, we demonstrate noninvasive ultrasound imaging of calcium signalingin vivoduring drug-induced receptor activation. URoC brings the depth and resolution advantages of ultrasound to thein vivoimaging of dynamic cellular function and paves the way for acoustic biosensing of a broader variety of biological signals.
Anti-cancer compound screening identifies Aurora Kinase A inhibition as a means to favor CRISPR/Cas9 gene correction over knock-out
Authors: Wilbie Danny , Eising Selma , Amo-Addae Vicky , Walther Johanna , Bosman Esmeralda , de Jong Olivier G , Molenaar Jan J , Mastrobattista Enrico
Published: November 2023

CRISPR gene therapy holds the potential to cure a variety of genetic diseases by targeting causative mutations and introducing double stranded DNA breaks, subsequently allowing the host DNA repair mechanisms to introduce mutations. One option to introduce precise gene corrections is via the homology-directed repair (HDR) pathway. HDR can introduce a range of desired mutations dictated by a DNA template which holds a corrected DNA sequence which is written into the targeted gene. The problem in utilizing this pathway is that CRISPR-induced double stranded DNA breaks are repaired more often through the non-homologous end joining (NHEJ) pathway, which does not use a designed template and introduces random DNA damage in the form of insertions and deletions at the cut site. Since HDR activation depends on many interconnected processes in the cell, we aimed to screen a small library of drug compounds in clinical use or clinical development for cancer, to steer the DNA repair process towards preferential HDR activation.

We included compounds in our screen based on three relevant mechanisms in CRISPR gene editing: the cell cycle, DNA repair processing and chromosomal packing. We included forty compounds, based on these criteria, screened their toxicity and dosed them in sub-toxic concentrations in cells during genome editing. Of these forty compounds we identified nine potential hits to have an effect on preferential activation of the HDR pathway over NHEJ. Alisertib, rucaparib and belinostat revealed a significant and major effect on gene editing pathway selection in further validation.

Alisertib, an Aurora kinase A inhibitor, showed a particularly strong effect towards improving HDR over NHEJ. We subsequently investigated this effect at the genetic level and in a murine hepatoma cell line, which corroborated the initial findings. Alisertib led to an over 4-fold increase in preferential gene correction over gene knock-out, at a dose of 0.3 micromolar. However, the observations that Aurora kinase A inhibitors show considerable cytotoxicity (<50% cell viability) and can induce morphological changes at this concentration pose a limitation for the direct use of these inhibitors as HDR enhancers. However these findings do implicate that the pathways mediated by Aurora kinase A strongly influence HDR outcomes, which warrants further investigation into the downstream pathways driving this effect.
GFETM: Genome Foundation-based Embedded Topic Model for scATAC-seq Modeling
Authors: Fan Yimin , Osakwe Adrien , Han Shi , Li Yu , Ding Jun , Li Yue
Published: November 2023

Single-cell Assay for Transposase-Accessible Chromatin with sequencing (scATAC-seq) has emerged as a powerful technique for investigating open chromatin landscapes at single-cell resolution. However, analyzing scATAC-seq data remain challenging due to its sparsity and noise. Genome Foundation Models (GFMs), pre-trained on massive DNA sequences, have proven effective at genome analysis. Given that open chromatin regions (OCRs) harbour salient sequence features, we hypothesize that leveraging GFMs’ sequence embeddings can improve the accuracy and generalizability of scATAC-seq modeling. Here, we introduce the Genome Foundation Embedded Topic Model (GFETM), an interpretable deep learning framework that combines GFMs with the Embedded Topic Model (ETM) for scATAC-seq data analysis. By integrating the DNA sequence embeddings extracted by a GFM from OCRs, GFETM demonstrates superior accuracy and generalizability and captures cell-state specific TF activity both with zero-shot inference and attention mechanism analysis. Finally, the topic mixtures inferred by GFETM reveal biologically meaningful epigenomic signatures of kidney diabetes.
Inference of the demographic histories and selective effects of human gut commensal microbiota over the course of human history
Authors: Mah Jonathan C. , Lohmueller Kirk E. , Garud Nandita
Published: November 2023

Despite the importance of gut commensal microbiota to human health, there is little knowledge about their evolutionary histories, including their population demographic histories and their distributions of fitness effects (DFE) of new mutations. Here, we infer the demographic histories and DFEs of 27 of the most highly prevalent and abundant commensal gut microbial species in North Americans over timescales exceeding human generations using a collection of lineages inferred from a panel of healthy hosts. We find overall reductions in genetic variation among commensal gut microbes sampled from a Western population relative to an African rural population. Additionally, some species in North American microbiomes display contractions in population size and others expansions, potentially occurring at several key historical moments in human history. DFEs across species vary from highly to mildly deleterious, with accessory genes experiencing more drift compared to core genes. Within genera, DFEs tend to be more congruent, reflective of underlying phylogenetic relationships. Taken together, these findings suggest that human commensal gut microbes have distinct evolutionary histories, possibly reflecting the unique roles of individual members of the microbiome.
Comparative mutant analyses reveal a novel mechanism of ARF regulation in land plants
Authors: Prigge Michael J. , Morffy Nicholas , de Neve Amber , Szutu Whitnie , Abraham-Juárez María Jazmín , Johnson Kjel , Do Nicole , Lavy Meirav , Hake Sarah , Strader Lucia , Estelle Mark , Richardson Annis E.
Published: November 2023

A major challenge in plant biology is to understand how the plant hormone auxin regulates diverse transcriptional responses throughout development, in different environments, and in different species. The answer may lie in the specific complement of auxin signaling components in each cell. The balance between activators (class-A AUXIN RESPONSE FACTORS) and repressors (class-B ARFs) is particularly important. It is unclear how this balance is achieved. Through comparative analysis of novel, dominant mutants in maize and the mossPhyscomitrium patens, we have discovered a ∼500-million-year-old mechanism of class-B ARF protein level regulation, important in determining cell fate decisions across land plants. Thus, our results add a key piece to the puzzle of how auxin regulates plant development.
Examining models of modern human origins through the analysis of 43 fully sequenced human Y chromosomes
Authors: Huang Shi
Published: November 2023

Molecular studies have yielded two primary models for understanding the uniparental DNA phylogenetic trees of modern humans: the Recent Out of Africa (ROA) and the Recent Out of East Asia (ROE) models. These models differ in their underlying assumptions, particularly in relation to early stem haplotypes, even though they share many haplotype relationships. Leveraging the wealth of new genetic variants within the male-specific region unveiled through the comprehensive sequencing of 43 diverse human Y chromosomes, we here investigated the presence of shared variants among different haplotypes to determine which model better aligns with the genetic data. We were able to corroborate the existence of stem haplotypes specific to the ROE model, but not those exclusive to the ROA model. We found that A0b and A1a shared the most variants with each other, aligning with the A00A1a clade of the ROE model. Also, stem haplotypes specific to the ROE model showed the expected relationships, with A00A1a closest to B, AB closest to E, E closest to B, A, and C, ABDE closest to C. Our findings also revealed extensive variant sharing independent of common ancestry, consistent with the maximum genetic diversity theory underlying the ROE model but challenging the neutral theory behind the ROA model. These new genetic data lend robust support to the ROE model as the more accurate representation of modern human origins.
A modular platform to display multiple hemagglutinin subtypes on a single immunogen
Authors: Lamson Dana Thornlow , Mohamed Faez Amokrane Nait , Vu Mya , Maurer Daniel P. , Ronsard Larance , Lingwood Daniel , Schmidt Aaron G.
Published: November 2023

Next-generation influenza vaccines aim to elicit cross-reactive humoral responses to multiple influenza subtypes. Such increased breadth would not only improve seasonal vaccines but may afford ‘universal’ protection against influenza subtypes including those with pandemic potential. Here, we describe a “beads-on-a-string” (BOAS) immunogen, that tandemly links up to eight distinct hemagglutinin (HA) head domains from circulating and non-circulating influenzas. These BOAS are immunogenic in the murine model and elicit comparable serum responses to each individual component. Notably, we also find that BOAS elicit cross-reactive, and neutralizing responses to influenza subtypes not included in the immunizing immunogen. Furthermore, BOAS conjugation to protein-based ferritin nanoparticles does not significantly augment serum responses suggesting that our BOAS platform is sufficient for eliciting cross-reactive responses without off-target effects induced by the nanoparticle scaffold. This mix-and-match immunogen design strategy is a robust platform for eliciting responses to multiple influenza subtypes via a single immunogen, and a potential platform for other viral glycoproteins.
Targeting CD74-positive macrophages improves neoadjuvant therapy in cervical cancer as revealed by single-cell transcriptomics analysis
Authors: Wang Zixiang , Wang Bingyu , Feng Yuan , Ye Jinwen , Mao Zhonghao , Zhang Teng , Xu Meining , Zhang Wenjing , Jiao Xinlin , Zhang Youzhong , Cui Baoxia
Published: November 2023

Uterine cervical cancer (UCC) has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic strategy for cervical cancer. However, the efficacy of PD-1 (programmed cell death protein 1) blockade combined with neoadjuvant chemotherapy (NACT) and the ensuing alterations within the tumor microenvironment need further investigation. We conducted single-cell RNA sequencing using 46,950 cells from nine sequential human cervical cancer tissues representing different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and unveiled crucial factors involved in the combination therapy. Cell communication analysis revealed the inferred interaction strength decreased between T cell-cancer cells, while the communication between macrophage-cancer cells intensified after NACT therapy. We verified that macrophages are necessary for PD-1 blockade combination to exert antitumor effects in vitro. Detailed analysis unraveled the CD74-positive macrophages frequently interacted with the immunoreactive Epi 3 subgroup during neoadjuvant combination therapy. CD74 upregulation limited phagocytosis and stimulated M2 polarization. The CD74 blockade enhanced macrophage phagocytosis, resulting in decreased viability of cervical cancer cells in vitro and in vivo. This study unveils the dynamic microenvironment of UCC influenced by NACT and PD-1 blockade combination therapy, and targeting CD74 was a potential strategy to augment the therapy efficacy.