bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of a cortical neurogenesis transcriptional program during NEUROD1-induced astrocyte-to-neuron conversion
Authors: Li Wen , Su Dan , Li Xining , Lu Kang , Huang Qingpei , Zheng Jiajun , Luo Xiaopeng , Chen Gong , Fan Xiaoying
Published: September 2023

NEUROD1-induced astrocyte-to-neuron (AtN) conversion has garnered significant attention as a potential therapeutic intervention to neurological disorders. To gain insight into the molecular regulations underlying this neuronal reprogramming process, we applied single-cell multiomics analyses onin vitroND1-induced AtN conversion to systematically investigate how ND1 changed the fate of astrocytes at transcriptomic and epigenetic levels. Our findings reveal that the initial immature astrocytes go through an intermediate state where both astrocytic and neuronal genes are activated at early stage of AtN conversion. ND1 directly reshapes the chromatin accessibility landscape of astrocytes to that of neurons, promoting expression of endogenousNeurod1 and otherneurogenic genes such asHes6, Insm1etc. Interestingly, cell proliferation status is highly correlated with conversion rate, and inhibition of cell division significantly reduces the conversion ratio. Moreover, in comparison with another AtN reprogramming transcription factor, ASCL1, external ND1 can activate endogenousNeurod1and directly promote neuronal gene transcription; whereas external ASCL1 hardly activates endogenousAscl1,leading to slower and inefficient conversion. Together, our studies demonstrate thatin vitroAtN conversion mimics neurogenic transcriptional program in embryonic neurogenesis.
Ascites in malignant ovarian cancer confer ovarian cancer cells chemoresistance to platinum. Combination treatment with crizotinib and 2-hydroxyestradiol restores platinum sensitivity
Authors: Carmi Yifat Koren , Agbarya Abed , Khamaisi Hazem , Farah Raymond , Shechtman Yelena , Korobochka Roman , Gopas Jacob , Mahajna Jamal
Published: September 2023

Ovarian cancer (OC), the second most common form of gynecologic malignancy, has a poor prognosis and is often discovered in the late stages. Platinum-based chemotherapy is the first line of therapy. Nevertheless, treatment OC has proven challenging due to toxicity and the development of acquired resistance to therapy. Tumor microenvironment (TME) has been associated with platinum chemoresistance.

Malignant ascites has been used as OC tumor microenvironment and its ability to induce platinum chemoresistance has been investigated.

Our results suggest that exposure to OC ascites induces platinum chemoresistance in 11 of 13 cases (85%) on OC cells. In contrast, 75% of cirrhotic ascites (3 of 4) failed to confer platinum chemoresistance to OC cells. Cytokine array analysis revealed that IL -6 and to a lesser extent HGF were enriched in OC ascites, whereas IL -22 was enriched in cirrhotic ascites. Pharmaceutical inhibitors targeting the IL -6/ JAK pathway were mildly effective in overcoming platinum chemoresistance induced by malignant ascites. In contrast, crizotinib, an HGF/c-MET inhibitor, and 2-hydroxyestradiol (2HE2) were effective in restoring platinum chemosensitivity to OC.

Our results demonstrate the importance of OC ascites in supporting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity of OC cells.
Responses of root-associated fungal communities of mature beech and spruce during five years of experimental drought
Authors: Weikl Fabian C. , Grams Thorsten E. E. , Pritsch Karin
Published: September 2023

Drought affects the fine-root systems of European beech (Fagus sylvaticaL.) and Norway spruce (Picea abies[L.] KARST) in different ways, but little is known about how this impacts their fine-root-associated fungal communities.

In a five-year throughfall exclusion experiment (KROOF) in a mature stand, we investigated whether recurrent drought periods progressively alter fine-root associated fungal communities, fine-root vitality, and ectomycorrhizal functionality in relation to the tree root zone (pure beech, pure spruce, or their mixture) and abiotic soil parameters.

We found that the influence of recurrent droughts on root fungal communities peaked in the third year of the experiment and affected fungal functional groups in different ways. The root zone was the predominant factor in structuring all functional groups of root-associated fungi, while we did not find a prominent effect of root mixture. The importance of other factors (year of sampling, soil depth) varied among fungal functional groups.

Our results indicate a robust biotrophic root-fungal system relying mainly on surviving root tips, complemented by a fluctuating saprotrophic fungal assembly.
In silico optimization of DNA codons in genes encoded by various strains of Ebola Virus
Authors: Mathuria Anshu , Ahmed Mehak , Mani Indra
Published: September 2023

Ebola hemorrhagic fever (HF) is a severe and often lethal disease that occurs in primates, including humans. It was first identified in 1976 during two outbreaks of fatal haemorrhagic fever in Central Africa. Due to its high fatality rate and lack of a widespread cure, Ebola HF poses a considerable challenge in treatment, making Ebola virus disease (EVD) one of the deadliest zoonotic diseases. The viral genome is ∼19kb long, linear, non-segmented, and negative single-stranded (-SS) RNA. The genome of the Ebola virus (EBOV) comprises seven genes, namely NP, GP, L, and VP (VP30, VP24, VP40, VP35), which encode nucleoprotein, glycoprotein, RNA polymerase, and viral proteins. By optimizing the DNA sequence through codon adaptation, we observed significant enhancements in the codon adaptation index (CAI) and the GC content compared to the wild-type strain. These findings demonstrate that optimized genes hold the potential for improved expression in the host organism without the production of truncated proteins. Further, these optimized genes can facilitate proper protein folding and function. In conclusion, these results have implications for vaccine production, as higher codon optimization enhances the expression of the genes, making them appropriate amounts for vaccine development.
Conditioned Protein Structure Prediction
Authors: Xie Tengyu , Song Zilin , Huang Jing
Published: September 2023

Deep learning based protein structure prediction has facilitated major breakthroughs in biological sciences. However, current methods struggle with alternative conformation prediction and offer limited integration of expert knowledge on protein dynamics. We introduce AFEXplorer, a generic approach that tailors AlphaFold predictions to user-defined constraints in coarse coordinate spaces by optimizing embedding features. Its effectiveness in generating functional protein conformations in accordance with predefined conditions were demonstrated through comprehensive examples. AFEXplorer serves as a versatile platform for conditioned protein structure prediction, bridging the gap between automated models and domain-specific insights.
Spatial-Live: A lightweight and versatile tool for single cell spatial-omics data visualization
Authors: Ye Zhenqing , Lai Zhao , Zheng Siyuan , Chen Yidong
Published: September 2023

Single cell spatial-omics data visualization plays a pivotal role in unraveling the intricate spatial organization and heterogeneity of cellular systems. Although various software tools and packages have been developed for this purpose, challenges persist in terms of user-friendly accessibility, data integration, and interactivity. In this study, we introduce Spatial-Live, alightweight andversatile viewer tool designed for flexible single-cell spatial-omics data visualization. Spatial-Live overcomes the fundamental limitations of two-dimensional (2D) orthographic modes by employing a layer-stacking strategy, enabling efficient rendering of diverse data types with interactive features, and enhancing visualization with richer information in a unified three-dimensional (3D) space.
Dicer-mediated RNA silencing is the key regulatory mechanism in the biocontrol fungusClonostachys rosea-wheat interactions
Authors: Piombo Edoardo , Vetukuri Ramesh Raju , Jensen Dan Funck , Karlsson Magnus , Dubey Mukesh
Published: September 2023

The intricate molecular interplay between beneficial fungi and plants is vital to plant growth promotion and induced defense response. This study explored the role of DCL-mediated RNA silencing in the interaction between the biocontrol fungusClonostachys roseaand wheat roots. We investigated the impact of DCL (Dicer-like) gene deletions inC. roseaon its root colonization ability. Our results revealed that the deletion ofdcl2significantly enhancedC. roseabiomass on wheat roots, indicating a pivotal role of DCL2 in root colonization. Transcriptome sequencing ofC. roseaand wheat during their interactions unveiled extensive gene expression changes. In wheat, genes related to stress responses were upregulated duringC. roseainteractions, while genes associated with plant cell wall modification and metabolic processes were downregulated, suggesting complex regulatory responses and a trade-off between defense mechanisms and growth promotion. Deletion ofC. rosea dcl1anddcl2altered the transcriptomic responses of wheat roots during interactions. Wheat genes associated with stress responses were downregulated during interactions with DCL deletion strains. In contrast, genes involved in metabolic processes and growth were upregulated, emphasizing the cross-kingdom regulatory role ofC. roseasmall RNAs (sRNAs). We identified 18 wheat miRNAs responsive toC. roseainteractions. Furthermore, we identified 24 endogenous and six cross-kingdom potential gene targets for seven and five differentially expressed miRNAs, supported by their inverse gene expression pattern. InC. rosea, we found a large transcriptional reprogramming of genes during interaction with wheat roots. The upregulated genes were associated with carbohydrate and polysaccharide catabolic processes, membrane transporters and effectors. Conversely, downregulated genes were mainly associated with transition metal ion transport and homeostasis processes. The deletion ofdcl1anddcl2had significant effects on gene expression. A higher number of genes upregulated in WT during the interaction were restored in DCL deletion mutants, suggesting DCL-mediated gene expression regulation. Furthermore, we identified 21 differentially expressed micro-RNA-like RNAs (milRNAs) inC. rosea; nine were DCL-dependent. They had putative gene targets inC. rosea, including transcription factors, effectors, transporters, and enzymes involved in specialized metabolite production. Cross-kingdom RNA silencing was also observed, with seven DCL-dependentC. roseamilRNAs potentially targeting 29 genes in wheat. These findings provide valuable insights into the molecular mechanisms underlying the beneficial interaction between fungi and plant roots. In addition, the study shed light on the role of sRNA-mediated gene regulation in theC. rosea-wheat interaction, with potential implications for sustainable agriculture and biocontrol strategies.
Eye-specific detection and a multi-eye integration model of biological motion perception
Authors: De Agrò Massimo , Rößler Daniela C. , Shamble Paul S.
Published: September 2023

The term biological motion refers to the peculiar kinematics of living organisms. Their interconnected joints move at a fixed distance from each other, a pattern that is common among all locomotive, rigid animals. Across the animal kingdom, many species have developed specialized circuitry to visually recognize biologically moving stimuli and discriminate them from other patterns. Recently, this skill has also been observed in the distributed visual system of jumping spiders. These eight-eyed animals use three of their eye pairs to perceive motion. Then, the gaze of the remaining pair is shifted towards the detected object for further inspection. When presented with a biologically moving stimulus and a random one, jumping spiders turn to face the latter, demonstrating discrimination. In the current paper, we systematically tested the ability of jumping spiders to discriminate biological from random displays using every single eye-pair, by blocking the others with paint. The animals were able to discriminate the stimuli only when the anterior-lateral eyes were unblocked, performing at chance level with the other pairs. Crucially, the spiders preferred the biological stimulus, not the random one. To explain this preference reversal we hypothesized a model, describing how the anterior-lateral eyes’ specialization in detecting biological motion feeds into a multi-eye integration system, generating more complex behavior from the combination of the simple, single-eye responses. We propose that this in-built modularity may be a solution to the limited resources of these invertebrates’ brains, constituting a novel approach to visual processing.
Context and Attention Shape Electrophysiological Correlates of Speech-to-Language Transformation
Authors: Anderson Andrew J. , Davis Christopher , Lalor Edmund C.
Published: September 2023

To transform speech into words, the human brain must accommodate variability across utterances in intonation, speech rate, volume, accents and so on. A promising approach to explaining this process has been to model electroencephalogram (EEG) recordings of brain responses to speech. Contemporary models typically invoke speech categories (e.g. phonemes) as an intermediary representational stage between sounds and words. However, such categorical models are typically hand-crafted and therefore incomplete because they cannot speak to the neural computations that putatively underpin categorization. By providing end-to-end accounts of speech-to-language transformation, new deep-learning systems could enable more complete brain models. We here model EEG recordings of audiobook comprehension with the deep-learning system Whisper. We find that (1) Whisper provides an accurate, self-contained EEG model of speech-to-language transformation; (2) EEG modeling is more accurate when including prior speech context, which pure categorical models do not support; (3) EEG signatures of speech-to-language transformation depend on listener-attention.
A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations
Authors: Cabrera-Álvarez Jesús , Stefanovski Leon , Martin Leon , Susi Gianluca , Maestú Fernando , Ritter Petra
Published: September 2023

While the accumulation of amyloid-beta (Aβ) and hyperphosphorylated-tau (hp-tau) as two classical histopathological biomarkers are crucial in Alzheimer’s disease (AD), their detailed interaction with the electrophysiological changes at the meso- and macroscale are not yet fully understood. We developed a mechanistic mequltiscale model of AD progression, linking proteinopathy to its effects on neural activity and vice-versa. We integrated a heterodimer model of prion-like protein propagation, and a network of Jansen-Rit electrical oscillators whose model parameters varied due to neurotoxicity. Changes in inhibition guided the electrophysiological alterations found in AD, and bothAβand hp-tau-related inhibition changes were able to produce similar effects independently. Additionally, we found a causal disconnection between cellular hyperactivity and interregional hypersynchrony. Finally, we demonstrated that earlyAβand hp-tau depositions’ location determine the spatiotemporal profile of the proteinopathy. The presented model combines the molecular effects of bothAβand hp-tau together with a mechanistic protein propagation model and network effects within a unique closed-loop model. This holds the potential to enlighten the interplay between AD mechanisms on various scales, aiming to develop and test novel hypotheses on the contribution of different AD-related variables to the disease evolution.

Significance Statement

This research presents a groundbreaking closed-loop model of AD mechanisms, bridging the gap between protein distribution and neural activity. Contrary to prior assumptions, the study reveals that interregional hyper-synchrony and cellular hyperactivity are not directly linked. Notably, the model identifies neural inhibition as a potential causal factor in neurophysiological AD alterations and posits early depositions ofAβas a determinant of the spatiotemporal profile of proteinopathy. The significance of this mechanistic disease framework lies in its potential to produce insights into AD evolution and to guide novel treatment strategies. It underscores the importance of further experiments and modelling efforts to refine our understanding of AD, offering hope for more effective treatments and personalized care in the fight against dementia.
Increased deformations are dispensable for cell mechanoresponse in engineered bone analogs mimicking aging bone marrow
Authors: Regner Alexander M , DeLeon Maximilien , Gibbons Kalin D. , Howard Sean , Nesbitt Derek Q. , Lujan Trevor J. , Fitzpatrick Clare K. , Farach-Carson Mary C , Wu Danielle , Uzer Gunes
Published: September 2023

Aged individuals and astronauts experience bone loss despite rigorous physical activity. Bone mechanoresponse is in-part regulated by mesenchymal stem cells (MSCs) that respond to mechanical stimuli. Direct delivery of low intensity vibration (LIV) recovers MSC proliferation in senescence and simulated microgravity models, indicating that age-related reductions in mechanical signal delivery within bone marrow may contribute to declining bone mechanoresponse. To answer this question, we developed a 3D bone marrow analog that controls trabecular geometry, marrow mechanics and external stimuli. Validated finite element (FE) models were developed to quantify strain environment within hydrogels during LIV. Bone marrow analogs with gyroid-based trabeculae of bone volume fractions (BV/TV) corresponding to adult (25%) and aged (13%) mice were printed using polylactic acid (PLA). MSCs encapsulated in migration-permissive hydrogels within printed trabeculae showed robust cell populations on both PLA surface and hydrogel within a week. Following 14 days of LIV treatment (1g, 100 Hz, 1 hour/day), type-I collagen and F-actin were quantified for the cells in the hydrogel fraction. While LIV increased all measured outcomes, FE models predicted higher von Mises strains for the 13% BV/TV groups (0.2%) when compared to the 25% BV/TV group (0.1%). Despite increased strains, collagen-I and F-actin measures remained lower in the 13% BV/TV groups when compared to 25% BV/TV counterparts, indicating that cell response to LIV does not depend on hydrogel strains and that bone volume fraction (i.e. available bone surface) directly affects cell behavior in the hydrogel phase independent of the external stimuli. Overall, bone marrow analogs offer a robust and repeatable platform to study bone mechanobiology.
A 3D Printed Ventilated Perfused Lung Model Platform to Dissect the Lung’s Response to Viral Infection in the Presence of Respiration
Authors: Derman I. Deniz , Alioglu Mecit Altan , Banerjee Dishary , Holton Sarah E. , Klunk Danielle Nicole , Nagamine Momoka , Rizvi Syed Hasan Askari , Mikacenic Carmen , Celik Nazmiye , Castaneda Diana Cadena , Prajakta Warang , Chen Phylip , Schotsaert Michael , Peeples Mark E. , Palucka Karolina , Koff Jonathan , Ozbolat Ibrahim T.
Published: September 2023

In this study, we developed a three-dimensionally (3D) printed lung model that faithfully recapitulates the intricate lung environment. This 3D model incorporated alveolar and vascular components that allow for a comprehensive exploration of lung physiology and responses to infectionin vitro. In particular, we investigated the intricate role of ventilation on formation of the alveolar epithelial layer and its response to viral infections. In this regard, we subjected our 3D printed, perfused lung model to a continuous respiratory cycle at the air-liquid interface (ALI) for up to 10 days followed by infection with two viruses: influenza virus (Pr8) and respiratory syncytial virus (RSV), at two different concentrations for 24 or 48 h. The results revealed that ventilation induced increased tight-junction formation with better epithelial barrier function over time, facilitated higher expression of alveolar epithelial specific genes, enabled higher level of infection with an increased progression of viral spread and replication over time, and modulated the production of pro-inflammatory cytokines and chemokines. Our findings represent a critical step forward in advancing our understanding of lung-specific viral responses and respiratory infections in response to ventilation, which sheds light on vital aspects of pulmonary physiology and pathobiology.
SDC4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging spine
Authors: Sao Kimheak , Risbud Makarand V.
Published: September 2023

Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of SDC4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that SDC4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in SDC4 KO mice. These changes in vertebral bone were due to elevated osteoclastic activity in KO mice. The histological assessment also showed subtle phenotypic changes in the intervertebral discs. Imaging-Fourier transform-infrared (FTIR) analyses showed a reduced relative ratio of mature collagen crosslink in young adult NP and AF compartments of KO compared to wildtype (WT) mice. Additionally, relative chondroitin sulfated glycosaminoglycan (GAG) levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, and endoplasmic reticulum to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the intervertebral disc.
Insect biomass of protected habitats under the impact of arable farming in Germany
Authors: Mühlethaler Roland , Köthe Sebastian , Hörren Thomas , Sorg Martin , Eichler Lisa , Lehmann Gerlind U. C.
Published: September 2023

Five years after the well-known study on insect biomass decline in nature protected habitats in Germany over three decades, the project DINA (Diversity of Insects in Nature protected Areas) has investigated the status of insects in 21 selected nature reserves across Germany in the years 2020 and 2021. We used the same methods and protocols for trapping and measuring the biomass of flying insects as in the mentioned study. Across two seasons, we accumulated a comprehensive data set of 1621 data points of two-week emptying intervals. The measured overall insect biomass remained at low levels and corresponds to the published latest figures from the years 2007–2016. There were no significant regional differences, but biomass was negatively correlated with agricultural production area within 2 km of nature reserves. Differences between the two consecutive years were very likely due to well-known natural fluctuations of insect populations, changes in agricultural cultivation and local weather events. The results show that protected habitats are essential for insects, but not sufficient in their function, and that further steps need to be taken for a better protection and sustainment of insects, which fulfil key functions in many ecosystems.
A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli
Authors: García Miguel Turrero , Tran Diana N. , Peterson Ralph E. , Stegmann Sarah K. , Hanson Sarah M. , Reid Christopher M. , Xie Yajun , Vu Steve , Harwell Corey C.
Published: September 2023

When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lackingNkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.
PDZ Domains from the Junctional Proteins Afadin and ZO-1 Act as Mechanosensors
Authors: Vachharajani Vipul T. , DeJong Matthew P. , Dutta Soumya , Chapman Jonathan , Ghosh Eashani , Singharoy Abhishek , Dunn Alexander R.
Published: September 2023

Intercellular adhesion complexes must withstand mechanical forces to maintain tissue cohesion while also retaining the capacity for dynamic remodeling during tissue morphogenesis and repair. Many cell-cell adhesion complexes contain at least one PSD95/Dlg/ZO-1 (PDZ) domain situated between the adhesion molecule and the actin cytoskeleton. However, PDZ-mediated interactions are characteristically nonspecific, weak, and transient, with multiple binding partners per PDZ domain, micromolar dissociation constants, and bond lifetimes of seconds or less. Here, we demonstrate that the bonds between the PDZ domain of the cytoskeletal adaptor protein afadin and the intracellular domains of the adhesion molecules nectin-1 and JAM-A form molecular catch bonds that reinforce in response to mechanical load. In contrast, the bond between the PDZ3-SH3-GUK (PSG) domain of the cytoskeletal adaptor ZO-1 and the JAM-A intracellular domain becomes dramatically weaker in response to ∼2 pN of load, the amount generated by single molecules of the cytoskeletal motor protein myosin II. Thus, physiologically relevant forces can exert dramatic and opposite effects on the stability of two of the major linkages between cell-cell adhesion proteins and the F-actin cytoskeleton. Our data demonstrate that that PDZ domains can serve as force-responsive mechanical anchors at cell-cell adhesion complexes. More broadly, our findings suggest that mechanical force may serve as a previously unsuspected regulator of the hundreds of PDZ-ligand interactions present in animal cells.
The impact of multiband and in-plane acceleration on white matter microstructure analysis
Authors: Zhang Zhengwu , Venkataraman Arun , Cole Martin , Ye Tianrui , Qiu Deqiang , Lin Feng V. , Risk Benjamin B.
Published: September 2023

Accelerated imaging has been broadly adopted in diffusion MRI studies, yet little is known about its impacts. Acceleration can achieve higher spatial and q-space resolution in shorter time, reduce motion artifacts, and reduce patient burden. However, it leads to noise amplification, and its impacts in clinical cohorts are poorly understood. This study examined the impact of multiband (also called simultaneous multislice, or SMS) and in-plane acceleration (IPA, also called phase acceleration) in diffusion imaging in forty older adults differing in cognitive status. We evaluated a total of 400 scans from five acquisitions: no acceleration (S1P1); SMS=3 with no in-plane acceleration (S3P1); SMS=3 with IPA=2 (S3P2); S6P1; and S6P2. The number of diffusion directions and b-values was kept constant such that acquisition times varied from 21:28 to 3:56. We found that diffusion metrics were highly sensitive to acceleration factor, with a trend towards higher fractional anisotropy (FA) and lower orientation dispersion (OD) with acceleration. The differences between accelerated and unaccelerated acquisitions could be partly explained by the noise amplification (g-factor) and reduced motion. Intraclass correlations (ICCs) of FA and OD in white matter were excellent in both S1P1 and S3P1 (median >0.8), good but lower in S3P2 and S6P1 (medians around 0.70), and poor to fair in S6P2 (medians 0.46 and 0.57). In-plane acceleration decreased ICC, including areas of high susceptibility distortion. In a comparison of mild cognitive impairment versus healthy controls, acceleration tended to reduce group differences, particularly in the fornix, with greater costs in OD than FA. Our results provide guidance regarding the costs of acceleration (possible biases and reduced effect sizes) while also characterizing the benefits (reduced motion, good reliability at higher multiband with no in-plane).
Target gene regulatory network of miR-497 in angiosarcoma
Authors: Benton Annaleigh , Terwilliger Emma , Moriarty Noah M. , Liu Bozhi , Murphy Ant , Maluvac Hannah , Shu Mae , Gartenhaus Lauren E. , Janson Nimod D. , Pfeffer Claire M. , Utturkar Sagar M. , Parkinson Elizabeth I. , Lanman Nadia A. , Hanna Jason A.
Published: September 2023

Angiosarcoma (AS) is a vascular sarcoma that is highly aggressive and metastatic. Due to its rarity, treatment options for patients are limited, therefore more research is needed to identify possible therapeutic vulnerabilities. We previously found that conditional deletion ofDicer1drives AS development in mice. Given the role of DICER1 in canonical microRNA (miRNA) biogenesis, this suggests that miRNA loss is important in AS development. After testing miRNAs previously suggested to have a tumor-suppressive role in AS, microRNA-497-5p (miR-497) suppressed cell viability most significantly. We also found that miR-497 overexpression led to significantly reduced cell migration and tumor formation. To understand the mechanism of miR-497 in tumor suppression, we identified clinically relevant target genes using a combination of RNA-sequencing data in an AS cell line, expression data from AS patients, and target prediction algorithms. We validated miR-497 direct regulation of CCND2, CDK6, and VAT1. One of these genes, VAT1, is an understudied protein that has been suggested to promote cell migration and metastasis in other cancers. Indeed, we find that pharmacologic inhibition of VAT1 with the natural product Neocarzilin A reduces AS migration. This work provides insight into the mechanisms of miR-497 and its target genes in AS pathogenesis.
The determinants of the rarity of nucleic and peptide short sequences in nature
Authors: Chantzi Nikol , Mouratidis Ioannis , Mareboina Manvita , Konnaris Maxwell A. , Montgomery Austin , Georgakopoulos-Soares Ilias
Published: September 2023

The prevalence of nucleic and peptide short sequences across organismal genomes and proteomes has not been thoroughly investigated. Here we examined 45,785 reference genomes and 21,871 reference proteomes, spanning archaea, bacteria, viruses and eukaryotes to calculate the rarity of short sequences in them. To capture this, we developed a metric of the rarity of each sequence in nature, the Anti-Kardashian index. We find that the frequency of certain dipeptides in rare oligopeptide sequences is hundreds of times lower than expected, which is not the case for any dinucleotides. We also generate predictive regression models that infer the rarity of nucleic and proteomic sequences in nature. For six-mer peptide kmers the R2performance of the regression models based on amino acid and dipeptide content is 0.816, whereas models based on physicochemical features achieve an R2of 0.788. For twelve-mer nucleic kmers the R2performance of our models based on mono and dinucleotides is 0.481. Our results indicate that the mono and dinucleotide composition of nucleic sequences and the amino acids, dipeptides and physicochemical properties of peptide sequences can explain a significant proportion of the variance in their frequencies between organisms in nature.
The genetic architecture of polygenic local adaptation and its role in shaping barriers to gene flow
Authors: Zwaenepoel Arthur , Sachdeva Himani , Fraïsse Christelle
Published: September 2023

We consider how the genetic architecture underlying locally adaptive traits determines the strength of a barrier to gene flow in a mainland-island model. Assuming a general life cycle, we derive an expression for the effective migration rate when local adaptation is due to a polygenic trait under directional selection on the island, allowing for arbitrary fitness and dominance effects across loci. We show how the effective migration rate can be combined with classical single-locus diffusion theory to accurately predict multilocus differentiation between the mainland and island at migration-selection-drift equilibrium and determine the migration rate beyond which local adaptation collapses, while accounting for genetic drift and weak linkage. Using our efficient numerical tools, we then present a detailed study of the effects of dominance on barriers to gene flow, showing that when total selection is sufficiently strong, more recessive local adaptation generates stronger barriers to gene flow. We show that details of the haplodiplontic life cycle can be captured using a set of effective parameters, and consider how the relative strength of selection in the two phases affects barriers to gene flow. We then study how heterogeneous genetic architectures of local adaptation affect barriers to gene flow, characterizing adaptive differentiation at migration-selection balance for different distributions of fitness effects. We find that a more heterogeneous genetic architecture generally yields a stronger genome-wide barrier to gene flow and that the detailed genetic architecture underlying locally adaptive traits can have an important effect on observable differentiation when divergence is not too large. Lastly, we study the limits of our approach as loci become more tightly linked, showing that our predictions remain accurate over a large biologically relevant domain.
ASBAR: an Animal Skeleton-Based Action Recognition framework. Recognizing great ape behaviors in the wild using pose estimation with domain adaptation
Authors: Fuchs Michael , Genty Emilie , Zuberbühler Klaus , Cotofrei Paul
Published: September 2023

To date, the investigation and classification of animal behaviors have mostly relied on direct human observations or video recordings with posthoc analysis, which can be labor-intensive, time-consuming, and prone to human bias. Recent advances in machine learning for computer vision tasks, such as pose estimation and action recognition, thus have the potential to significantly improve and deepen our understanding of animal behavior. However, despite the increased availability of open-source toolboxes and large-scale datasets for animal pose estimation, their practical relevance for behavior recognition remains under-explored. In this paper, we propose an innovative framework,ASBAR, forAnimal Skeleton-Based Action Recognition, which fully integrates animal pose estimation and behavior recognition. We demonstrate the use of this framework in a particularly challenging task: the classification of great ape natural behaviors in the wild. First, we built a robust pose estimator model leveraging OpenMonkeyChallenge, one of the largest available open-source primate pose datasets, through a benchmark analysis on several CNN models from DeepLabCut, integrated into our framework. Second, we extracted the great ape’s skeletal motion from the PanAf dataset, a large collection of in-the-wild videos of gorillas and chimpanzees annotated for natural behaviors, which we used to train and evaluate PoseConv3D from MMaction2, a second deep learning model fully integrated into our framework. We hereby classify behaviors into nine distinct categories and achieve a Top 1 accuracy of 74.98%, comparable to previous studies using video-based methods, while reducing the model’s input size by a factor of around 20. Additionally, we provide an open-source terminal-based GUI that integrates our full pipeline and release a set of 5,440 keypoint annotations to facilitate the replication of our results on other species and/or behaviors. All models, code, and data can be accessed at:https://github.com/MitchFuchs/asbar.

Author summary

The study of animal behaviors has mostly relied on human observations and/or video analysis traditionally. In this paper, we introduce a new framework calledASBAR(forAnimal Skeleton-Based Action Recognition) that integrates recent advances in machine learning to classify animal behaviors from videos. Compared to other methods that use the entire video information, our approach relies on the detection of the animal’s pose (e.g., position of the head, eyes, limbs) from which the behavior can be recognized. We demonstrate its successful application in a challenging task for computers as it classifies nine great ape behaviors in their natural habitat with high accuracy. To facilitate its use for other researchers, we provide a graphical user interface (GUI) and annotated data to replicate our results for other animal species and/or behaviors.
Knowledge, Attitudes, and Practices Related to Avian Influenza (H5N1) After the Outbreak in Rural, Cambodia
Authors: Vang Daraden , Chau Darapheak , Vutha Kimim , Um Samnang
Published: September 2023

From 2003 to 25 February 2023, the avian influenza (H5N1) virus was confirmed in 59 human infections, including 39 deaths (∼66% case-fatality rate) reported in 13 of 25 provinces in Cambodia. We aimed to assess current knowledge, attitude, and practice toward changes in poultry handling behaviors, poultry consumption, and poultry mortality reporting among rural villagers in areas affected by Avian influenza (H5N1) in Cambodia. A cross-section survey was conducted in August 2023. There were 208 participants residing in Prey Veng province who were invited to be interviewed face-to-face. Descriptive statistics were performed using STATA V17. The participants’ average age was 55 years old (SD=13.3 years), 78.4% were female, 59% had completed primary school, 56.7% were farmers, 68.3% raised chickens in their backyards, and 10.2% raised ducks, 23% of participants cooked sick or dead birds for their families, 32% knowing information about avian influenza virus was a lower proportion from healthcare providers, 10.6% from village health support groups were, and 2% from village animal health workers were only, 49% have been reported poultry illness and deaths to local authorities. The avian influenza epidemic in Cambodia is a genuine threat to animals and a possible concern to humans. To prevent and control this, we strongly advise everyone who works with poultry or wild game birds always to be prepared to follow appropriate hygiene standards and to cook poultry meat properly.
Improving the cost efficiency of preventive chemotherapy: impact of new diagnostics on stopping decisions for control of schistosomiasis
Authors: Coffeng Luc E. , Graham Matthew , Browning Raiha , Kura Klodeta , Diggle Peter J. , Denwood Matthew , Medley Graham F. , Anderson Roy M , de Vlas Sake J.
Published: September 2023

Background

Control of several neglected tropical diseases (NTDs), including schistosomiasis, relies on the regular distribution of preventive chemotherapy (PC) over many years. For the sake of sustainable NTD control, a decision must be made at some stage to scale down or stop PC. These ‘stopping decisions’ are based on population surveys that assess whether infection levels are sufficiently low (typically less than 1%). For schistosomiasis control, concerns have been raised regarding the limited sensitivity of the currently-used diagnostic (Kato-Katz or KK) to detect low intensity infections. The use of new, more sensitive, molecular diagnostics has been proposed.

Methods

Through statistical analysis ofSchistosoma mansoniegg counts collected from Burundi and a simulation study using an established transmission model for schistosomiasis, we investigated the extent to which more sensitive diagnostics can improve decision making regarding stopping or continuing PC for the control ofS. mansoni.

Results

We found that KK-based strategies perform reasonably well for determining when to stop PC at a local scale. Use of more sensitive diagnostics only leads to a marginally improved health impact (person-years lived with heavy infection) and comes at a cost of continuing PC for longer, unless the decision threshold for stopping PC is adapted upwards. However, if this threshold is set too high, PC may be stopped prematurely, resulting in a rebound of infection levels.

Conclusions

We conclude that the potential value of more sensitive diagnostics lies more in the reduction of survey-related costs than in the direct health impact of improved parasite control.

summary

Compared to Kato-Katz faecal thick smears, model-based analyses suggest that the use of more sensitive tests only marginally changes the impact of decisions to locally stop preventive chemotherapy against schistosomiasis in terms of disease burden (person-years lived with heavy infection).
Deacetylation by sirtuins is important forAspergillus fumigatuspathogenesis and virulence
Authors: Wassano Natália Sayuri , da Silva Gabriela Bassi , Reis Artur Honorato , Gerhardt Jaqueline A. , Antoniel Everton P. , Akiyama Daniel , Rezende Caroline Patini , Neves Leandro Xavier , Vasconcelos Elton , Figueiredo Fernanda L. , Almeida Fausto , de Castro Patrícia Alves , Pinzan Camila Figueiredo , Goldman Gustavo H. , Leme Adriana F. P. , Fill Taicia P. , Moretti Nilmar S. , Damasio André
Published: September 2023

Protein acetylation is a crucial post-translational modification that controls gene expression and a variety of biological processes. Sirtuins, a prominent class of NAD+-dependent lysine deacetylases, serve as key regulators of protein acetylation and gene expression in eukaryotes. In this study, six single knockout strains of fungal pathogenAspergillus fumigatuswere constructed, in addition to a strain lacking all predicted sirtuins (SIRTKO). Phenotypic assays suggest that sirtuins are involved in cell wall integrity, secondary metabolite production, thermotolerance, and virulence.AfsirEdeletion resulted in attenuation of virulence, as demonstrated in murine andGalleriainfection models. The absence of AfSirE leads to altered acetylation status of proteins, including histones and non-histones, resulting in significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combatA. fumigatusinfections or in combination therapy with available antifungals.
QPPLab: A generally applicable software package for detecting, analyzing, and visualizing large-scale quasiperiodic spatiotemporal patterns (QPPs) of brain activity
Authors: Xu Nan , Yousefi Behnaz , Anumba Nmachi , LaGrow Theodore J. , Zhang Xiaodi , Keilholz Shella
Published: September 2023

Quasi-periodic patterns (QPPs) are prominent spatiotemporal brain dynamics observed in functional neuroimaging data, reflecting the alternation of high and low activity across brain regions and their propagation along cortical gradients. QPPs have been linked to neural processes such as attention, arousal fluctuations, and cognitive function. Despite their significance, existing QPP analysis tools are limited by study-specific parameters and complex workflows. To address these challenges, we presentQPPLab, an open-source MATLAB-based toolbox for detecting, analyzing, and visualizing QPPs from fMRI time series. QPPLab integrates correlation-based iterative algorithms, supports customizable parameter settings, and features automated workflows to simplify analysis. Processing times vary depending on dataset size and the selected mode, with the fast detection mode completing analyses that can be 4–6 times faster than the robust detection mode. Results include spatiotemporal templates of QPPs, sliding correlation time courses, and functional connectivity maps. By reducing manual parameter adjustments and providing user-friendly tools, QPPLab enables researchers to efficiently study QPPs across diverse datasets and species, advancing our understanding of intrinsic brain dynamics.

Metadata
CNTD1 plays crucial roles in prophase I progression and crossover designation during female meiosis and is critical for establishing the ovarian reserve
Authors: Wood Anna J. , Ahmed Rania M. , Simon Leah E. , Bradley Rachel A. , Wolff Ian D. , Cohen Paula E.
Published: September 2023

In meiotic prophase I, hundreds of double-strand breaks (DSBs) are formed throughout the genome. A majority of these breaks are repaired as non-crossovers (NCOs), while a minor subset are repaired as crossovers (CO). COs are essential for the faithful segregation of homologous chromsomes at the end of prophase I and errors in CO designation can result in aneuploidy, germ cell death, birth defects, or infertility. These errors are more evident in female meiosis compared to males and suggests that the events of meiotic prophase I are sexually dimorphic with respect to CO formation, placement, resolution, and/or surveillance. Here, we demonstrate a critical role for Cyclin N-Terminal Domain Containing 1 (CNTD1) protein in ensuring appropriate CO frequency and distribution across the genome during meiosis in females. We find that CNTD1 localizes with the heterodimer, MutLγ, which marks the majority of CO that emerge in pachynema of prophase I, implicating CNTD1 in late-stage CO designation and/or maturation. Accordingly, loss ofCntd1in oocytes results in failure to load MutLγ and thus results in a catastrophic loss of chiasmata and sterility. Further investigation yielded a distinct phenotype in which the primordial follicles that form upon dictyate arrest are steadily lost from birth onwards, a temporal loss of follicles that is different to that seen in other CO mutants. We find that this follicle loss inCntd1mutants is dependent on the checkpoint kinase CHK2. Thus, in females, loss ofCntd1appears to result in phenotypes that are temporally disconnected from early and late CO mutants such as MutSγ and MutLγ, which show early prophase I disruption and ablation of ovary structure, and no prophase I disruption and an appearance of wildtype ovaries, respectively. These data suggest novel dual roles for CNTD1 in CO designation and faithful progression of oocytes into dictyate arrest at late pachynema, the latter being critical for establishing the ovarian reserve in female mice.