bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-household environments make a major contribution to dengue transmission: Implications for vector control
Authors: Peña-García Víctor Hugo , LaBeaud A. Desiree , Ndenga Bryson A. , Mutuku Francis M. , Bisanzio Donal , Andrews Jason R. , Mordecai Erin A.
Published: January 2024

The incidence of Aedes-borne pathogens has been increasing despite vector control efforts. Control strategies typically target households, where Aedes mosquitoes breed in household containers and bite indoors. However, our study in Kenyan cities Kisumu and Ukunda (2019-2022) reveals high Aedes abundance in public spaces, prompting the question: how important are non-household (NH) environments for dengue transmission and control? Using field data and human activity patterns, we developed an agent-based model simulating transmission across household (HH) and five NH environments, which was then used to evaluate preventive (before an epidemic) and reactive (after an epidemic commences) vector control scenarios. Our findings estimate over half of infections occur in NH settings, particularly workplaces, markets, and recreational sites. Control efforts in NH areas proved more effective than HH, contradicting the current global focus. Greater reductions in dengue cases occurred with early, high-coverage interventions, especially in NH locations. Additionally, local ecological factors, such as uneven water container distribution, influence control outcomes. This study underscores the importance of vector control in both household and non-household environments in endemic settings. It highlights a specific approach to inform evidence-based decision making to target limited vector control resources for optimal control
An Ensemble Model for Acute Myeloid Leukemia Risk Stratification Recommendations by Combining Machine Learning with Clinical Guidelines
Authors: Chang Ming-Siang , Tsai Xavier Cheng-Hong , Chou Wen-Chien , Tien Hwei-Fang , Hou Hsin-An , Chen Chien-Yu
Published: January 2024

Acute Myeloid Leukemia (AML) is a complex disease requiring accurate risk stratification for effective treatment planning. This study introduces an innovative ensemble machine learning model integrated with the European LeukemiaNet (ELN) 2022 recommendations to enhance AML risk stratification. The model demonstrated superior performance by utilizing a comprehensive dataset of 1,213 patients from National Taiwan University Hospital (NTUH) and an external cohort of 2,113 patients from UK-NCRI trials. On the external cohort, it improved a concordance index (c-index) from 0.61 to 0.64 and effectively distinguished three different risk levels with median hazard ratios ranging from 18% to 50% improved. Key insights were gained from the discovered significant features influencing risk prediction, including age, genetic mutations, and hematological parameters. Notably, the model identified specific cytogenetic and molecular alterations likeTP53, IDH2, SRSF2, STAG2, KIT, TET2, and karyotype (-5, -7, -15, inv(16)), alongside age and platelet counts. Additionally, the study explored variations in the effectiveness of hematopoietic stem cell transplantation (HSCT) across different risk levels, offering new perspectives on treatment effects. In summary, this study develops an ensemble model based on the NTUH cohort to deliver improved performance in AML risk stratification, showcasing the potential of integrating machine learning techniques with medical guidelines to enhance patient care and personalized medicine.
The longitudinal role of overweight and obesity women in mammographic breast screening participation: retrospective cohort study using linked data
Authors: McBride K.A. , Munasinghe S. , Sperandei S. , Page A.
Published: January 2024

Objectives

This study investigated the association between prospective changes in BMI and longitudinal adherence to mammographic screening among overweight or obese women residing in New South Wales, Australia

Methods

This was a retrospective cohort study of women participating in the Australian Longitudinal Study on Women’s Health (ALSWH), with subsequent screening participation enumerated via BreastScreen New South Wales, Australia clinical records over the period 1996-2016. The association between BMI and subsequent adherence to screening was investigated in a series of marginal structural models, incorporating a range of socio-demographic, clinical, and health behaviour confounders. Models were also stratified by proxy measures of socio-economic status (private health insurance and educational achievement).

Results

Participants who had overweight/obesity were more likely to be non-adherent to mammography screening, compared to normal or underweight participants (OR=1.29, [95% CI=1.07, 1.55). The association between overweight/obesity and non-adherence was slighter stronger among those who ever had private health insurance (OR=1.30, [95% CI=1.05, 1.61) compared to those who never had private health insurance (OR=1.19, [95% CI=0.83, 1.71), and among those with lower educational background (OR=1.38, [95% CI=1.08, 1.75) compared to those with higher educational background (OR=1.27, [95% CI=0.93, 1.73).

Conclusion

Findings show long-term impacts on screening participation with higher BMI women being less likely to participate in routinely organised breast screening. Women with a higher BMI should be a focus of efforts to improve breast screening participation, particularly given their increased risk of post-menopausal breast cancer and the association of higher BMI with more aggressive clinical presentations and histopathology of breast cancers.

Key messages

Overweight and obesity increase risk of breast cancer, poorer prognostic features and worse outcomes.

Long-term impacts on screening participation are evident among higher BMI women who are less likely to participate in routinely organised breast screening.

This relationship is stronger among women of lower educational attainment.

Women with a higher BMI should be a focus of targeted efforts to improve their breast screening participation
Effects of Alzheimer’s disease plasma marker levels on multilayer centrality in healthy individuals
Authors: García-Colomo Alejandra , López-Sanz David , Taguas Ignacio , Carrasco-Gómez Martín , Spuch Carlos , Comis-Tuche María , Maestú Fernando
Published: January 2024

Finding early and non-invasive biomarkers that help identify individuals in the earliest stages of the Alzheimer’s disease continuum is paramount. Electrophysiology and plasma biomarkers are great candidates in this pursuit. Furthermore, the combination of functional connectivity metrics with graph-theory analyses allows for a deeper understanding of network alterations. Despite this, this is the first MEG study to assess multilayer centrality considering inter-band connectivity in an unimpaired population at high risk of Alzheimer’s disease. Our objective is twofold. First, to address the relationship between a compound centrality score designed to overcome previous inconsistencies stemming from the use of various individual metrics, and plasma pathology markers of Alzheimer’s disease in unimpaired individuals with elevated levels of the latter. Lastly, to evaluate whether hubs’ centrality is more affected by the pathology.

33 individuals with available MEG recordings and elevated plasma pathology markers were included. A compound centrality score for each brain source of every subject was calculated combining widely used centrality metrics, considering intra- and inter-band connections.

Spearman correlations were carried out to address the association between each node’s centrality score and biomarkers levels. Next, to test whether greater associations were found in hubs, a correlation between the obtained rho and the grand-average of the centrality score was carried out.

Increasing concentrations of p-tau231 were associated with greater centrality within the network of posterior areas, which increased their connectedness in the theta range with the remaining areas, regardless of the latter’s frequency range. The opposite relationship was found for left areas, that decreased their connectedness in the gamma frequency range. Hubs’ centrality was significantly more affected by p-tau231 levels.

Our results expand previous literature demonstrating early network reorganizations associated with elevated plasma p-tau231 in cognitively unimpaired individuals. Multilayer centrality increases in the theta band in posterior regions are congruent with previous results and theoretical models, that predict a longitudinal evolution towards a loss of centrality. On the other hand, the changes in multilayer centrality found in the gamma band could be associated with inhibitory neuron dysfunction, classical in AD pathology. Lastly, hubs were more likely to increase their centrality in association to p-tau231, thus corroborating hubs’ vulnerability.
Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer’s Disease
Authors: Bansal Vibhavari Aysha , Tan Jia Min , Soon Hui Rong , Zainolabidin Norliyana , Saito Takashi , Ch’ng Toh Hean
Published: January 2024

The emergence of Aβ pathology is one of the hallmarks of Alzheimer’s disease (AD), but the mechanisms and impact of Aβ in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope and its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of Aβ on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (AppNL-G-F/NL-G-F) that expresses Aβ in young animals. Our studies revealed that a time-dependent accumulation of intracellular Aβ corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunctionAppKI neurons become more vulnerable to inflammation-induced necroptosis – a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates Aβ in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.
Sound-seeking before and after hearing loss in mice
Authors: Mai Jessica , Gargiullo Rowan , Zheng Megan , Esho Valentina , Hussein Osama E , Pollay Eliana , Bowe Cedric , Williamson Lucas M , McElroy Abigail F , Goolsby William N , Brooks Kaitlyn A , Rodgers Chris C
Published: January 2024

How we move our bodies affects how we perceive sound. For instance, we can explore an environment to seek out the source of a sound and we can use head movements to compensate for hearing loss. How we do this is not well understood because many auditory experiments are designed to limit head and body movements. To study the role of movement in hearing, we developed a behavioral task called sound-seeking that rewarded mice for tracking down an ongoing sound source. Over the course of learning, mice more efficiently navigated to the sound. We then asked how auditory behavior was affected by hearing loss induced by surgical removal of the malleus from the middle ear. An innate behavior, the auditory startle response, was abolished by bilateral hearing loss and unaffected by unilateral hearing loss. Similarly, performance on the sound-seeking task drastically declined after bilateral hearing loss and did not recover. In striking contrast, mice with unilateral hearing loss were only transiently impaired on sound-seeking; over a recovery period of about a week, they regained high levels of performance, increasingly reliant on a different spatial sampling strategy. Thus, even in the face of permanent unilateral damage to the peripheral auditory system, mice recover their ability to perform a naturalistic sound-seeking task. This paradigm provides an opportunity to examine how body movement enables better hearing and resilient adaptation to sensory deprivation.
Structured behavioral data format: An NWB extension standard for task-based behavioral neuroscience experiments
Authors: Ly Ryan , Avaylon Matthew , Wulf Michael , Kepecs Adam , Rübel Oliver
Published: January 2024

Understanding brain function necessitates linking neural activity with corresponding behavior. Structured behavioral experiments are crucial for probing the neural computations and dynamics underlying behavior; however, adequately representing their complex data is a significant challenge. Currently, a comprehensive data standard that fully encapsulates task-based experiments, integrating neural activity with the richness of behavioral context, is lacking. We designed a data model, as an extension to the NWB neurophysiology data standard, to represent structured behavioral neuroscience experiments, spanning stimulus delivery, timestamped events and responses, and simultaneous neural recordings. This data format is validated through its application to a variety of experimental designs, showcasing its potential to advance integrative analyses of neural circuits and complex behaviors. This work introduces a comprehensive data standard designed to capture and store a spectrum of behavioral data, encapsulating the multifaceted nature of modern neuroscience experiments.
A Quantum Computing Pipeline for Real World Drug Discovery: From Algorithm to Quantum Hardware
Authors: Li Weitang , Yin Zhi , Li Xiaoran , Ma Dongqiang , Yi Shuang , Zhang Zhenxing , Zou Chenji , Bu Kunliang , Dai Maochun , Yue Jie , Chen Yuzong , Zhang Xiaojin , Zhang Shengyu
Published: January 2024

Quantum computing, with its superior computational capabilities compared to classical approaches, holds the potential to revolutionize numerous scientific domains, including pharmaceuticals. However, the application of quantum computing for drug discovery has primarily been limited to proof-of-concept studies, which often fail to capture the intricacies of real-world drug development challenges. In this study, we diverge from conventional investigations by developing an advanced quantum computing pipeline tailored to address genuine drug design problems. Our approach underscores the pragmatic application of quantum computation and propels it towards practical industrial adoption. We specifically construct our versatile quantum computing pipeline to address two critical tasks in drug discovery: the precise determination of Gibbs free energy profiles for prodrug activation involving covalent bond cleavage, and the accurate simulation of covalent bond interactions. This work serves as a pioneering effort in benchmarking quantum computing against veritable scenarios encountered in drug design, especially the covalent bonding issue present in both of the case studies, thereby transitioning from theoretical models to tangible applications. Our results demonstrate the potential of a quantum computing pipeline for integration into real world drug design workflows.
Elephants in a teacup: Ranging and Habitat-use of Asian elephantsElephas maximusin a Plantation Dominated Landscape in Southern Western Ghats, India
Authors: Vijayakrishnan Sreedhar , Raghunathan Ganesh , Ananda Kumar Mavatur , Sinha Anindya
Published: January 2024

Ranging patterns of four focal herds using a plantation-forest matrix of the Valparai plateau was studied by following the individuals on a regular basis, recording all possible sightings, for five years. Although surrounded by a network of protected areas, the focal herds were found to use the plateau extensively. There was minimal spatial overlap observed between the four herds, except between two, PTH and MON, which showed a fairly large overlap of 130 sq.km. The observed ranges of elephants were smaller (119.71 ± 24.11 sq.km) compared to previous studies on the species in India, but were comparable with those from Sri Lanka. Possible risk avoidance strategy is observed in their use of the landscape, as evidenced by the use of high intensity human activity areas mostly during night than day. Compared to previous studies from the same landscape, there is also an observed increase in the use of natural vegetation (in the form of rainforest fragments) than the plantation and monoculture habitats, indicating the importance of forest remnants for elephants on the plateau. The observations indicate importance of anthropogenic areas outside protected areas as potential habitats and, not just as movement pathways or as temporary refugia. Conservation planning should therefore consider such areas while initiating landscape-level management strategies for the species. The study also highlights the importance of longitudinal observation-based studies in ascertaining ranging, in the absence of logistically challenging techniques such as radio telemetry.
Role of microstructure of cellulosic mucilage in seed anchorage: A mechanical interpretation
Authors: Bhaskaran Krithika , Saveri Puchalapalli , Deshpande Abhijit P. , Varughese Susy
Published: January 2024

Cellulosic, hemicellulosic and pectinaceous mucilages produced by certain angiosperms as adaptation inmyxodiasporyare investigated in the past for seed dispersal. The present understanding ofzoochoryandtelechoryare based on mucilage amount, state of hydration and to a limited extent, role of mucilage microstructure studied using adhesion and friction. Pectinaceous mucilages have less adhesion and supports dispersal byzoochory. However, in the case of cellulosic mucilages, the role played by the cellulosic fibrils in seed dispersal is not clear, especially, since they have a negative correlation withendozoochory. Using fresh cellulosic seed mucilages from, sweet basil (Ocimum basilicum) and chia (Salvia hispanica) we investigate the role of microstructure of the mucilage in two key behaviours: anchoring and adhesion properties of the seeds through rheology. We report a special large deformation mechanism triggered through ‘strain stiffening’ operational in these cellulosic mucilages. In many biopolymers semi-flexible polymer chains and other aligning elements contribute to the strain stiffening. However, the strain stiffening and strong wet adhesion observed in these mucilages have a significant role from the cellulosic components. This behaviour is more pronounced in basil seeds and presents a plausible structure-property mechanism foranti-telechoryfavoured by plant species found in arid habitats.
Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states
Authors: Wang Huikun , Flores Rodolfo J. , Yarur Hector E. , Limoges Aaron , Bravo-Rivera Hector , Casello Sanne M. , Loomba Niharika , Enriquez-Traba Juan , Arenivar Miguel , Wang Queenie , Ganley Robert , Ramakrishnan Charu , Fenno Lief E , Kim Yoon , Deisseroth Karl , Or Grace , Dong Chunyang , Hoon Mark A. , Tian Lin , Tejeda Hugo A.
Published: January 2024

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.

Highlights

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vmPFCDynneurons are activated by threats and threat-predictive cues

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Characterization of a genetically-encoded kappa-opioid receptor sensor

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vmPFCDynneurons rapidly release Dyn in response to threats and their predictors

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vmPFCDynsignaling opposes threat-induced passive defensive behaviors

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Dyn signaling promotes threat-evoked state transitions in vmPFC networks
Single cell transcriptomics of vomeronasal neuroepithelium reveals a differential endoplasmic reticulum environment amongst neuronal subtypes
Authors: G V S Devakinandan , Terasaki Mark , Dani Adish
Published: January 2024

Specialized chemosensory signals elicit innate social behaviors in individuals of several vertebrate species, a process that is mediated via the accessory olfactory system (AOS). The AOS comprising the peripheral sensory vomeronasal organ has evolved elaborate molecular and cellular mechanisms to detect chemo signals. To gain insight into the cell types, developmental gene expression patterns and functional differences amongst neurons, we performed single cell transcriptomics of the mouse vomeronasal sensory epithelium. Our analysis reveals diverse cell types with gene expression patterns specific to each, which we made available as a searchable web resource accessed from www.scvnoexplorer.com. Pseudo-time developmental analysis indicates that neurons originating from common progenitors diverge in their gene expression during maturation with transient and persistent transcription factor expression at critical branch points. Comparative analysis across two of the major neuronal subtypes that express divergent GPCR families and the G-protein subunits Gnai2 or Gnao1, reveals significantly higher expression of endoplasmic reticulum (ER) associated genes within Gnao1 neurons. In addition, differences in ER content and prevalence of cubic membrane ER ultrastructure revealed by electron microscopy, indicate fundamental differences in ER function.
Lateral Flow Assays Biotesting by Utilizing Plasmonic Nanoparticles Made of Inexpensive Metals – Replacing Colloidal Gold
Authors: Lorca Veronica A. Bahamondes , Ávalos-Ovando Oscar , Sikeler Christoph , Ijäs Heini , Santiago Eva Yazmin , Skelton Eli , Wang Yong , Yang Ruiqi , Cimatu Katherine Leslee A. , Baturina Olga , Wang Zhewei , Liu Jundong , Slocik Joseph M. , Wu Shiyong , Ma Dongling , Pastukhov Andrei I. , Kabashin Andrei V. , Kordesch Martin E. , Govorov Alexander O.
Published: January 2024

Nanoparticles (NPs) can be conjugated with diverse biomolecules and employed in biosensing to detect target analytes in biological samples. This proven concept was primarily used during the COVID-19 pandemic with gold NPs-based lateral flow assays (LFAs). Considering the gold price and its worldwide depletion, here we show that novel plasmonic nanoparticles (NPs) based on inexpensive metals, titanium nitride (TiN) and copper covered with a gold shell (Cu@Au), perform comparable or even better than gold nanoparticles. After conjugation, these novel nanoparticles provided high figures of merit for LFA testing, such as high signals and specificity and robust naked-eye signal recognition. To the best of our knowledge, our study represents the 1st application of laser-ablation-fabricated nanoparticles (TiN) in the LFA and dot-blot biotesting. Since the main cost of the Au NPs in commercial testing kits is in the colloidal synthesis, our development with TiN is very exciting, offering potentially very inexpensive plasmonic nanomaterials for various bio-testing applications. Moreover, our machine learning study showed that the bio-detection with TiN is more accurate than that with Au.
The J-Like Protein ARC6 Regulates Chloroplast FtsZ-Ring Assembly through Fine-tuning ARC3 Activity in Arabidopsis
Authors: Du Wenbin , Cao Lingyan , Zhou Yuelong , Jackson Shanelle , Naeem Maryam , Yang Yue , Glynn Jonathan M. , Porter Katie J. , He Qian , Xu Jie , Liang Wanqi , Osteryoung Katherine W. , Chen Cheng
Published: January 2024

Chloroplast division is initiated by the establishment of the stromal FtsZ ring (Z ring). Assembly and positioning of the Z ring are governed by the chloroplast Min system, which inhibits Z-ring formation everywhere but the middle of the chloroplast. ACCUMULATION AND REPLICATION OF CHLOROPLASTS3 (ARC3), the core component of this system, is a direct inhibitor of Z-ring assembly. Regulation of ARC3 activity is vital thus for chloroplast division. Here, we report that ARC6, which localizes on the chloroplast inner envelope membrane, interacts with ARC3 and acts upstream of ARC3 during chloroplast division. We show that the C-terminal MORN domain of ARC3, demonstrated previously to prevent ARC3-FtsZ interaction, binds to the J-like domain (JLD) of ARC6, enabling full-length ARC3 to interact with FtsZ proteins and activating the inhibitory activity of ARC3 on the assembly of FtsZ filaments. Overexpression of a JLD-deleted version of ARC6 causes disruption of Z-ring formation in an ARC3-dependent manner. Finally, we reveal that ARC6 recruits ARC3 to the middle of the chloroplast. Our findings suggest a model whereby ARC6 regulates the assembly and positioning of the Z ring through fine-tuning the inhibitory activity of ARC3 at the chloroplast division site.

One Sentence Summary

The chloroplast membrane protein ARC6 recruits ARC3 to the chloroplast division site and regulates the assembly of the FtsZ ring by fine-tuning ARC3 activity through its J-like domain.

The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is: Cheng Chen (cgchen@sjtu.edu.cn).
High-Throughput DNA melt measurements enable improved models of DNA folding thermodynamics
Authors: Ke Yuxi , Sharma Eesha , Wayment-Steele Hannah K. , Becker Winston R. , Ho Anthony , Marklund Emil , Greenleaf William J.
Published: January 2024

DNA folding thermodynamics are central to many biological processes and biotechnological applications involving base-pairing. Current methods for predicting stability from DNA sequence use nearest-neighbor models that struggle to accurately capture the diverse sequence-dependency of elements other than Watson-Crick base pairs, likely due to insufficient experimental data. We introduce a massively parallel method, Array Melt, that uses fluorescence-based quenching signals to measure equilibrium stability of millions of DNA hairpins simultaneously on a repurposed Illumina sequencing flow cell. By leveraging this dataset of 27,732 sequences with two-state melting behavior, we derived a refined NUPACK-compatible nearest-neighbor model, a richer parameterization nearest-neighbor model that exhibits higher accuracy, and a graph neural network (GNN) model that identifies relevant interactions within DNA beyond nearest neighbors. All models provide improved accuracy in predicting DNA folding thermodynamics, providing improvements relevant forin silicodesign of qPCR primers, oligo hybridization probes, and DNA origami.
Protein SUMOylation promotes cAMP-independent EPAC1 activation
Authors: Yang Wenli , Mei Fang C. , Lin Wei , White Mark A. , Li Li , Li Yue , Pan Sheng , Cheng Xiaodong
Published: January 2024

Exchange protein directly activated by cAMP (EPAC1) mediates the intracellular functions of a critical stress-response second messenger, cAMP. Herein, we report that EPAC1 is a cellular substrate of protein SUMOylation, a prevalent stress-response posttranslational modification. Site-specific mapping of SUMOylation by mass spectrometer leads to identifying K561 as a primary SUMOylation site in EPAC1. Sequence and site-directed mutagenesis analyses reveal a functional SUMO-interacting motif required for cellular SUMOylation of EPAC1. SUMO modification of EPAC1 mediates its heat shock-induced Rap1/2 activation in a cAMP-independent manner. Structural modeling and molecular dynamics simulation studies demonstrate that SUMO substituent on K561 of EPAC1 promotes Rap1 interaction by increasing the buried surface area between the SUMOylated receptor and its effector. Our studies identify a functional SUMOylation site in EPAC1 and unveil a novel mechanism in which SUMOylation of EPAC1 leads to its autonomous activation. The findings of SUMOylation-mediated activation of EPAC1 not only provide new insights into our understanding of cellular regulation of EPAC1 but also will open up a new field of experimentation concerning the cross-talk between cAMP/EPAC1 signaling and protein SUMOylation, two major cellular stress response pathways, during cellular homeostasis.
scDirect: key transcription factor identification for directing cell state transitions based on single-cell multi-omics data
Authors: Li Chen , Chen Sijie , Chen Yixin , Bian Haiyang , Hao Minsheng , Wei Lei , Zhang Xuegong
Published: January 2024

Cell state transitions are complicated processes that occur in various life activities. Understanding and artificially manipulating them have been longstanding challenges. Substantial experiments reveal that the transitions could be directed by several key transcription factors (TFs). Here we present scDirect, a computational framework to identify key TFs based on single-cell RNA-seq and ATAC-seq data. scDirect models the TF identification task as a linear inverse problem, and solve it with gene regulatory networks enhanced by a graph attention network. Through a benchmarking on a single-cell human embryonic stem cell atlas, we demonstrate the robustness and superiority of scDirect against alternative analysis methods on TF identification. We apply scDirect on various datasets, and scDirect exhibits high capability in identifying key TFs in cell differentiation and somatic cell conversion. Furthermore, scDirect can efficiently identify TF combinations for cell reprogramming, many of which have been experimentally validated. We envision that scDirect can utilize rapidly increasing single-cell datasets to identify key TFs for directing cell state transitions and may become an effective tool to facilitate cell engineering and regenerative medicine.
A 39.8kb flavi-like virus uses a novel strategy for overcoming the RNA virus error threshold
Authors: Petrone Mary E. , Grove Joe , Mifsud Jonathon C. O. , Parry Rhys H. , Marzinelli Ezequiel M. , Holmes Edward C.
Published: January 2024

It is commonly held that there is a fundamental relationship between genome size and error rate, manifest as a notional “error threshold” that sets an upper limit on genome sizes. The genome sizes of RNA viruses, which have intrinsically high mutation rates due to a lack of mechanisms for error correction, must therefore be small to avoid accumulating an excessive number of deleterious mutations that will ultimately lead to population extinction. The proposed exceptions to this evolutionary rule are RNA viruses from the orderNidovirales(such as coronaviruses) that encode an error correcting exonuclease, enabling them to reach genome lengths greater than 40kb. The recent discovery of large genome flavi-like viruses (Flaviviridae), which comprise genomes up to 27kb in length yet seemingly do not encode exonuclease domains, has led to the proposal that a proofreading mechanism is required to facilitate the expansion of RNA virus genomes above 30kb. Herein, we describe a 39.8kb flavi-like virus identified in aHaliclonasponge metatranscriptome that does not encode an exonuclease. Structural analysis revealed that this virus may have instead captured bacterial domains associated with nucleic acid metabolism that have not been previously found in RNA viruses. Phylogenetic analysis placed this virus as a divergent pesti-like lineage, such that we have provisionally termed it Maximus pesti-like virus. This virus represents the first instance of a flavi-like virus achieving a genome size comparable to that of theNidoviralesand demonstrates that RNA viruses have evolved multiple solutions to overcome the error threshold.
Two-photon all-optical electrophysiology for the dissection of larval zebrafish brain functional connectivity
Authors: Turrini Lapo , Ricci Pietro , Sorelli Michele , de Vito Giuseppe , Marchetti Marco , Vanzi Francesco , Pavone Francesco S.
Published: January 2024

One of the most audacious goals of modern neuroscience is unraveling the complex web of causal relations underlying the activity of neuronal populations on a whole-brain scale. This endeavor, prohibitive just a couple of decades ago, has recently become within reach owing to the advancements in optical methods and the advent of genetically encoded indicators/actuators. These techniques, applied to the translucent larval zebrafish have enabled recording and manipulation of the activity of extensive neuronal populations spanning the entire vertebrate brain. Here, we present the conception of a custom two-photon optical system, coupling light-sheet imaging and 3D excitation with acousto-optic deflectors for simultaneous high-speed volumetric recording and optogenetic stimulation. By employing a zebrafish line with pan-neuronal expression of both the calcium reporter GCaMP6s and the red-shifted opsin ReaChR, we implemented a crosstalk-free, noninvasive all-optical approach and applied it to the reconstruction of the functional connectivity of the left habenula.
Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments
Authors: Milanesi Maria , Brotzakis Z. Faidon , Vendruscolo Michele
Published: January 2024

A wide range of human disorders, including Alzheimer’s disease (AD), are characterised by the aberrant formation of amyloid fibrils. Amyloid fibrils are filamentous structures characterized by the presence of a highly-ordered cross-β core. In many cases, this core structure is flanked by disordered regions, often referred to as fuzzy coat. The structural properties of fuzzy coats, and the way in which they interact with their environments, however, have not been described in full detail to date. Here, we generated the conformational ensembles of two brain-derived amyloid filaments of Aβ42, corresponding respectively to familial and sporadic forms of AD. The approach that we used, called metadynamic electron microscopy metainference (MEMMI), enabled us to provide a characterization of the transient interactions between the fuzzy coat and the cross-β core of the filaments. These calculations indicated that the familial AD filaments are less soluble than the sporadic AD filaments, and that the fuzzy coat contributes to increasing the solubility of both types of filament. In addition, by analyzing the deviations between the density maps from cryo-EM and from the MEMMI structural ensembles, we observed a slowing down in the diffusion of water and sodium ions near the surface of the filaments, offering insight into the hydration dynamics of amyloid fibrils. These results illustrate how the metainference approach can help analyse cryo-EM maps for the characterisation of the properties of amyloid fibrils.
Dynamic fusion of genomics and functional network connectivity in UK biobank reveals static and time-varying SNP manifolds
Authors: Chen Jiayu , Iraji Armin , Fu Zening , Andrés-Camazón Pablo , Thapaliya Bishal , Liu Jingyu , Calhoun Vince D.
Published: January 2024

Many psychiatric and neurological disorders show significant heritability, indicating strong genetic influence. In parallel, dynamic functional network connectivity (dFNC) measures functional temporal coupling between brain networks in a time-varying manner and has proven to identify disease-related changes in the brain. However, it remains largely unclear how genetic risk contributes to brain dysconnectivity that further manifests into clinical symptoms. The current work aimed to address this gap by proposing a novel joint ICA (jICA)-based “dynamic fusion” framework to identify dynamically tuned SNP manifolds by linking static SNPs to dynamic functional information of the brain. The sliding window approach was utilized to estimate four dFNC states and compute subject-level state-specific dFNC features. Each state of dFNC features were then combined with 12946 SZ risk SNPs for jICA decomposition, resulting in four parallel fusions in 32861 European ancestry individuals within the UK Biobank cohort. The identified joint SNP-dFNC components were further validated for SZ relevance in an aggregated SZ cohort, and compared for across-state similarity to indicate level of dynamism. The results supported that dynamic fusion yielded “static” and “dynamic” components (i.e., high and low across-state similarity, respectively) for SNP and dFNC modalities. As expected, the SNP components presented a mixture of static and dynamic manifolds, with the latter largely driven by fusion with dFNC. We also showed that some of the dynamic SNP manifolds uniquely elicited by fusion with state-specific dFNC features complemented each other in terms of biological interpretation. This dynamic fusion framework thus allows expanding the SNP modality to manifolds in the time dimension, which provides a unique lens to elicit unique SNP correlates of dFNC otherwise unseen, promising additional insights on how genetic risk links to disease-related dysconnectivity.
Intimate partner violence in Nepal: Analysis of Nepal Demographic and Health survey 2022
Authors: Sapkota Parash Mani , Pandey Achyut Raj , Adhikari Bikram , Shrestha Grishu , Piya Reecha , Lamichhane Bipul , Garu Shristi , Joshi Deepak , Baral Sushil Chandra
Published: January 2024

Introduction

Intimate partner violence (IPV) is a major public health issue in Nepal. IPV has social and economic impacts among women, adolescent girls, wider society. In this study we aimed to determine factors associated with intimate partner violence among women aged 15-49 currently in intimate relationship.

Methods

We conducted secondary data analysis of the Nepal Demographic and Health Survey 2022. IPV was measured in three domains-experience of physical violence, emotional violence, and sexual violence. Weighted univariate and multivariate logistic regression analysis was applied to determine factors associated with intimate partner violence. The results of logistic regression were presented as odds ratio and their 95% CI.

Results

Of 3853 women, 27.2% had experienced any form of IPV. The prevalence of physical violence, emotional violence and sexual violence were 23.2%, 12.8 and 7.1% respectively. Higher odds of physical violence were reported among women aged 35-49 years (AOR: 2.13, 95%CI: 1.58-2.87), women without formal education (AOR: 1.51, 95%CI: 1.10-2.06) and women who justified wife beating (AOR: 1.23, 95%CI: 1.00-1.52). Women from poor households (AOR: 1.61, 95%CI: 1.12-2.35) and women with uneducated partners (AOR: 1.66, 95%CI: 1.08-2.58) were at higher risk of experiencing sexual violence. Women with unemployed husbands reported higher risk of physical violence (AOR: 2.72, 95%CI: 1.45-5.06) and emotional violence (AOR: 1.61, 95%CI: 1.12-2.35). Women who were afraid of their partners, women who experienced parental violence, women with partners who were sometimes or often drunk, and women with controlling partners were many folds more likely to experience all forms of IPV.

Conclusion

The prevalence of all forms of IPV were high among Nepalese women. Various sociodemographic, partner-related, and women empowerment related factors were positively associated with experiencing IPV. Acknowledging and addressing all these factors is essential to mitigating the alarming rates of IPV in this population.
Sodium Valproate Modulates Cortical Morphology in Juvenile Myoclonic Epilepsy
Authors: Pimentel Bernardo Crespo , Kuchukhidze Giorgi , Xiao Fenglai , Caciagli Lorenzo , Höfler Julia , Rainer Lucas , Kronbichler Martin , Vollmar Christian , Duncan John S , Trinka Eugen , Koepp Matthias , Wandschneider Britta
Published: January 2024

Importance

Idiopathic generalized epilepsy syndromes in are associated with cortical thinning of the premotor areas. Whether this represents an underlying disease signature, a consequence of seizure activity or is related to anti-seizure medication is unknown.

Objective

To investigate valproate-related effects on cortical morphology in people with juvenile myoclonic epilepsy (JME), one of the most common IGE syndromes.

Design

Retrospective neuroimaging case-control study.

Setting

Recruitment took place in epilepsy clinics in two European epilepsy referral centers.

Participants

We matched individuals with JME on valproate (n=36) to a group of healthy controls (n=36), as well as individuals with JME not on valproate (n=36) and a group of people with temporal lobe epilepsy (n=19) on valproate using propensity scores for age, sex, occurrence of bilateral tonic-clonic seizures and drug refractoriness.

Main outcomes and Measures

All participants underwent structural T1-weighted brain imaging and MRI-derived vertex-wise measurements of cortical thickness were calculated. Results were reported in effect-sizes using cohen’sd.

Results

Compared to healthy controls, individuals with JME on valproate demonstrated cortical thinning bilaterally in the precentral gyri (left:d= -1.0,p<.001; right: d = -1.0,p<.001). This effect was localized to the left precentral gyrus when comparing JME on VPA with individuals with JME not on valproate (d= -0.89;p<.01) or with individuals with temporal lobe epilepsy on valproate (d = -0.18, p<.001). No significant differences in cortical thickness were detected between individuals with JME not on valproate and healthy controls. Cortical thinning in precentral gyrus, postcentral gyrus and superior frontal was more marked with increasing valproate dose (left:t= -6,65,p<.0001; right:t= -5,20,p<.0001).

Conclusions and Relevance

In this cross-sectional study of 91 patients with epilepsy, valproate treatment was associated with JME-specific and dose-dependent cortical thinning of the precentral gyri. Our findings suggest a valproate-induced reorganization of disease-specific areas in JME that may not only help explain the high efficacy of this medication in IGEs but also potentially account for previously described changes of cortical thickness in this disease group.
An Analysis of Two-Spirit, Lesbian, Gay, Bisexual, Transgender and Queer Research Funded by Canadian Institutes of Health Research
Authors: Namchuk Amanda B. , Stranges Tori N. , Splinter Tallinn F.L. , Moore Katherine N. , Logie Carmen H. , Galea Liisa A.M.
Published: January 2024

Purpose

Gender identity and sexual orientation are essential factors that must be incorporated into health research to ensure we unearth comprehensive and inclusive insights about the healthcare needs and experiences of diverse people. Despite the calls for more focus on sex and gender in health research, scant attention has been paid to gender identity or sexual orientation. Past research found that 0.35% of Canadian Institutes of Health Research (CIHR) grant abstracts mentioned studying lesbian, gay, bisexual, transgender, queer and/or Two-Spirit (2S/LGBTQ+)-specific health outcomes. However, the nature of that research was not explored.

Methods

Here we examine the publicly available database of grant abstracts funded by CIHR from 2009-2020 to analyze what type of 2S/LGBTQ+-specific health outcomes would be studied.

Results

We found that 58% of awarded grant abstracts mentioned studying sexually transmitted diseases, the majority of which were on human immunodeficiency virus (HIV). Less than 7% of funded 2S/LGBTQ+ grant abstracts mentioned studying cisgender women. Almost 40% mentioned including trans women/girls, and 30% mentioned including trans men/ boys. None of the studies examined mentioned work with the Two-Spirit community.

Conclusion

These results reflect larger social and health inequities that require structural level changes in research to support lesbian, bisexual and queer women’s health.
Do Topographic Deep ANN Models of the Primate Ventral Stream Predict the Perceptual Effects of Direct IT Cortical Interventions?
Authors: Schrimpf Martin , McGrath Paul , Margalit Eshed , DiCarlo James J.
Published: January 2024

Ever-advancing artificial neural network (ANN) models of the ventral visual stream capture core object recognition behavior and the neural mechanisms underlying it with increasing precision. These models take images as input, propagate through simulated neural representations that resemble biological neural representations at all stages of the primate ventral stream, and produce simulated behavioral choices that resemble primate behavioral choices. We here extend this modeling approach to make and test predictions of neural intervention experiments. Specifically, we enable a new prediction regime for topographic deep ANN (TDANN) models of primate visual processing through the development ofperturbation modulesthat translate micro-stimulation, optogenetic suppression, and muscimol suppression into changes in modelneural activity. This unlocks the ability to predict thebehavioraleffects from particular neural perturbations. We compare these predictions with the key results from the primate IT perturbation experimental literature via a suite of nine corresponding benchmarks. Without any fitting to the benchmarks, we find that TDANN models generated via co-training with both a spatial correlation loss and a standard categorization task qualitatively predict all nine behavioral results. In contrast, TDANN models generated via random topography or via topographic unit arrangement after classification training predict less than half of those results. However, the models’ quantitative predictions are consistently misaligned with experimental data, over-predicting the magnitude of some behavioral effects and under-predicting others. None of the TDANN models were built with separate model hemispheres and thus, unsurprisingly, all fail to predict hemispheric-dependent effects. Taken together, these findings indicate that current topographic deep ANN models paired with perturbation modules are reasonable guides to predict the qualitative results of direct causal experiments in IT, but that improved TDANN models will be needed for precise quantitative predictions.
Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification
Authors: Zhang Christopher , Wu Benson , Wu Yin Fang , di Ciano-Oliveira Caterina , Soria-Bretones Isabel , Pham Nhu-An , Elia Andrew J. , Chari Raj , Lam Wan L. , Bray Mark R. , Mak Tak W. , Tsao Ming-Sound , Cescon David W. , Thu Kelsie L.
Published: January 2024

Centrosome amplification (CA), an abnormal increase in the number of centrosomes in the cell, is a recurrent phenomenon in lung and other malignancies. Although CA contributes to tumor development and progression by promoting genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. The presence of extra centrosomes leads to the formation of multipolar mitotic spindles prone to causing lethal chromosome segregation errors during cell division. To sustain the benefits of CA, malignant cells are dependent on adaptive mechanisms to mitigate its detrimental consequences, and these mechanisms represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with analyses of tumor genomic data, we identified the motor protein KIFC1 as a putative vulnerability specifically in lung cancers with CA. KIFC1 expression was positively correlated with CA in lung adenocarcinoma (LUAD) cell lines and with a gene expression signature predictive of CA in LUAD tumor tissues. HighKIFC1expression was associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells to potentiation of CA and sensitization was associated with a diminished ability of KIFC1-depleted cells to cluster extra centrosomes into pseudo-bipolar mitotic spindles. Our work suggests that KIFC1 inhibition represents a novel approach for potentiating GIN to lethal levels in LC with CA by forcing cells to divide with multipolar spindles, rationalizing the clinical development of KIFC1 inhibitors and further studies to investigate its therapeutic potential.