bluuebunny/crossref_metadata_2025 huggingface dataset:
Rare variant analyses validate known ALS genes in a multi-ethnic population and identifiesANTXR2as a candidate in PLS
Authors: Pottinger Tess D. , Motelow Joshua E. , Povysil Gundula , Moreno Cristiane A. Martins , Ren Zhong , Phatnani Hemali ,   The New York Genome Center ALS Sequencing Consortium, Aitman Timothy J. , Santoyo-Lopez Javier ,   Scottish Genomes Partnership, Mitsumoto Hiroshi ,   ALS COSMOS Study Group,   PLS COSMOS Study Group,   GTAC Investigators, Goldstein David B. , Harms Matthew B.
Published: October 2023

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 30,000 people in the United States. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms, such as antisense oligonucleotides, continue to develop, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

Methods

Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger cohort of 6,970 ALS patients from a large multi-ethnic cohort as well as 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

Results

A gene based collapsing model showed significant associations withSOD1,TARDBP, andTBK1(OR=19.18, p = 3.67 × 10−39; OR=4.73, p = 2 × 10−10; OR=2.3, p = 7.49 × 10−9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene,ALKBH3(p = 4.88 × 10−7), was protective for ALS in this model. An intolerant domain based collapsing model showed a significant improvement in identifying regions inTARDBPthat associated with ALS (OR=10.08, p = 3.62 × 10−16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment inANTXR2(p=8.38 × 10−6).

Conclusions

In a large multi-ethnic cohort of 6,970 ALS patients, rare variant burden testing validated known ALS genes and identified a novel potentially protective gene,ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations inANTXR2.
Scaling use of the rust fungusPuccinia punctiformisfor biological control of Canada thistle (Cirsium arvense(L.) Scop.): First report on a U.S. statewide effort
Authors: Bean Dan W. , Gladem Kristi , Rosen Karen , Blake Alexander , Clark Robert E. , Henderson Caitlin , Kaltenbach John , Price Joel , Smallwood Emily L. , Berner Dana K. , Young Stephen L. , Schaeffer Robert N.
Published: October 2023

Canada thistle (Cirsium arvense(L.) Scop., CT) is one of the worst weeds threatening temperate regions of the world. A host-specific rust fungus,Puccinia punctiformis(F. Strauss) Rohl., is known to cause systemic disease of CT, ultimately killing individuals and reducing stand densities. In 2013, it was demonstrated that fall inoculation of rosettes with coarsely ground leaves bearingP. punctiformistelia can successfully initiate epiphytotics. In the same year, a cooperative project between the Colorado Department of Agriculture and United States Department of Agriculture was initiated, in which CT patches across the state of Colorado (USA) were inoculated and tracked over subsequent years for changes in stem density. Here, we report our findings from 8 years (2014-2021) of monitoring effort. At most sites (N= 87), CT stem densities declined, from a mean (± SE) of 87.9 (± 6.5) stems to 44.7 (± 4.2). These declines however were spatially-autocorrelated, and likely attributable to local growing conditions, as mean annual daily maximum temperature and standard deviation of elevation, as well as climatic conditions around the times of both treatment and monitoring, were found to be important predictors of CT decline. Further, we observed that the amount of inoculum deployed, timing since last release, and method in which it was spread locally at a site were also associated with the magnitude of CT stem decline. These results are indicative of the value ofP. punctiformisas a CT biological control agent. The nameCirsium arvensedieback (CADB) is proposed herein to describe the agriculturally important decline in CT stem densities attributable to this previously un-named systemic disease.
75 years of anthropogenic change and its impact on Canadian butterfly taxonomic and phylogenetic diversity
Authors: Lewthwaite J.M.M , Mooers A.Ø
Published: October 2023

Previous studies have documented very little net change in average quadrat-level species richness and phylogenetic diversity. However, although the average remains centered around 0, there is much variation around this mean and many outliers. The relative contribution of anthropogenic drivers (such as climate change or land use change) to these outliers remains unclear. Traits may dictate species responses to these changes, and if relatedness is correlated with trait similarity, then the impacts of anthropogenic change may be clustered on the phylogeny. We build the first regional phylogeny of all Canadian butterfly species in order to examine change in community phylogenetic structure in response to two main documented drivers of change -- climate change and land use change -- across 265 species, 75 years and 96 well-sampled quadrats. We find no evidence that, on average, communities are becoming more or less clustered than one would expect. However, there is much variation depending on the magnitude and type of anthropogenic change occurring within a quadrat. We find that climate change as well as agricultural development is reducing species richness within a quadrat, and these species that are lost tend to be scattered across the phylogeny. However, agricultural abandonment is having the opposite effect: we find increasing species richness in the years immediately following it and decreasing distance between species in quadrats with the highest rates of abandonment, such that the species that colonize these plots tend to be close relatives of those already present and thus contribute little novel phylogenetic diversity to an assemblage. Consistent with previous work, small changes in local species richness may conceal simultaneous change in other facets of biodiversity.
Osteocyte Nicotinic Acetylcholine Receptors Impact Bone Mechanoadaptation in a Sexually Dimorphic Manner
Authors: Mora-Antoinette Macy , Garcia-Ortiz Andrea , Obaji Mariam , Saffari Alexander , Matthews Melia D. , Lewis Karl J.
Published: October 2023

Recent evidence suggests acetylcholine has a positive influence on bone mechanotransduction. Indeed, osteocytes express components for nicotinic acetylcholine receptors (nAChRs), which are known for mediating calcium signaling and may impact mechanosensitivity. Here, we use novel fluorescent imaging approaches to provide the first evidence of direct interaction between osteocytes and cholinergic nerve fibers in cortical bone in vivo. Moreover, we show that osteocytes are functional targets of cholinergic signaling for bone mechanoadaptation. We report sexually dimorphic patterns in bone structure and mechanobiology based on nAChR function. In females, osteocyte mechanosensitivity was decreased at small force magnitudes and tissue level deficits were recovered with anabolic loading. In males, osteocyte mechanosensitivity was increased in some groups and anabolic loading had very little effect on tissue architecture. This work establishes a new signaling paradigm wherein osteocytes interface with cholinergic nerves and bone mechanotransduction is regulated by osteocyte cholinergic signaling in a sexually dimorphic way.
RVE based Finite Element Modelling of the Contact Mechanics Between Skin and Indenter
Authors: Pardeshi Rushabh , Dingari Naga Neehar , Rai Beena
Published: October 2023

The nature of contact between human skin and external object (such as medical device, personal care device, fabric and so on) significantly influences the tactile perception and/or the functionality of the object. The contact mechanics depends strongly on the indenter properties and the mechanical properties of skin. Further, the topmost layer i.e., stratum corneum plays the most important role in tactile perception. In this study we use a representative volume element (RVE) based FEM model including the four layers of skin - stratum corneum, epidermis, dermis, and hypodermis - to simulate the contact mechanics between skin and a spherical indenter. The RVE model captures the mechanical properties of the microscopic constituents of the stratum corneum, which is the topmost layer of skin. We found that the RVE model can be used to simulate a variety of stratum corneum conditions (for example, dry and wet stratum corneum) and compositions. Using the RVE model in conjunction with an FEM model, we compute the frictional stress between skin and an indenter, as a function of stratum corneum microstructure, indentation depth, and local coefficient of friction. Both, the RVE model and the contact mechanics model predictions show good qualitative agreement with experimental findings in literature. Such studies will be very useful in in-silico design and optimization of devices that interact with skin. The current framework gives control over several parameters like skin microstructure, indenter or skin geometry and hence can be used to augment/substitute experimental testing.
BloodDDIT4andTRIM13transcript levels mark the early stages of Machado-Joseph disease
Authors: Ferreira Ana F. , Raposo Mafalda , Shaw Emily D. , Vasconcelos João , Kay Teresa , Bettencourt Conceição , Saraiva-Pereira Maria Luiza , Jardim Laura Bannach , do Carmo Costa Maria , Lima Manuela
Published: October 2023

Machado-Joseph disease (MJD) is a rare late-onset polyglutamine neurodegenerative disease caused by the expansion of a CAG repeat in theATXN3gene encoding the ataxin- 3 (ATXN3) protein. Several studies have identified changes in the abundance of select transcripts and proteins in blood samples of MJD mutation carriers. Here, we aimed to: 1) identify blood transcriptional changes that could be potential biomarkers of MJD from preclinical to symptomatic disease stages; 2) correlate levels of differentially expressed transcripts in blood of MJD carriers with demographic, genetics, and clinical features; and 3) evaluate whether the identified differential abundance of selected transcripts in blood of MJD subjects is preserved in post-mortem brains of MJD patients. Using real- time quantitative PCR, we observed consistent dysregulation ofDDIT4,TRIM13andP2RY13transcript levels in blood samples of MJD subjects from different disease stages (from preclinical to symptomatic), and of patients from two cohorts with different backgrounds (Azores and Brazil). Importantly, combined bloodDDIT4andTRIM13transcript levels display a very high accuracy to discriminate MJD carriers in preclinical stage, early-stage patients, and patients with more than five years of disease duration from respective controls (AUC=1.00, AUC=0.96, and AUC=0.90, respectively). Moreover, in the combined group of Azorean and Brazilian patients, blood levels ofP2RY13transcript correlate with age at onset, and abundance ofDDIT4andTRIM13transcripts correlate with the CAG repeat size of the expandedATXN3allele. In the subgroup of early-stage Azorean patients, blood levels ofTRIM13transcripts correlate with age at disease onset. Interestingly, abundance of DDIT4, TRIM13 and P2RY13 proteins is also altered in brains of MJD patients. In summary, this work shows that bloodDDIT4andTRIM13transcript levels are potentially blood-based biomarkers of MJD of special usefulness in marking preclinical and early stages of the disease, and points for common dysregulated processes involvingDDIT4,TRIM13andP2RY13in the blood and the brain of MJD subjects.
BBQ methods: Streamlined workflows for Bacterial Burden Quantification in infected cells by confocal microscopy
Authors: Augenstreich Jacques , Shuster Michael , Fan Yongqiang , Lyu Zhihui , Ling Jiqiang , Briken Volker
Published: October 2023

Accurate quantification of bacterial burden within macrophages, termed Bacterial Burden Quantification (BBQ), is crucial for understanding host-pathogen interactions. Various methods have been employed, each with strengths and weaknesses. This article addresses limitations in existing techniques and introduces two novel automated methods for BBQ within macrophages based on confocal microscopy data analysis. The first method refines total fluorescence quantification by incorporating filtering steps to exclude uninfected cells, while the second method calculates total bacterial volume per cell to mitigate potential biases in fluorescence-based readouts. These workflows utilize PyImageJ and Cellpose software, providing reliable, unbiased, and rapid quantification of bacterial load. The proposed workflows were validated using Salmonella enterica serovar Typhimurium and Mycobacterium tuberculosis models, demonstrating their effectiveness in accurately assessing bacterial burden. These automated workflows offer valuable tools for studying bacterial interactions within host cells and provide insights for various research applications.
Overlap and divergence of neural circuits mediating distinct behavioral responses to sugar
Authors: Jacobs Ruby V. , Wang Crystal X. , Lozada-Perdomo Fiorella V. , Nguyen Lam , Deere Julia U. , Uttley Hannah A. , Devineni Anita V.
Published: October 2023

A single sensory cue can elicit diverse behavioral responses. For example, the taste of sugar robustly promotes feeding1, 2but also influences other behaviors, such as altering locomotor patterns to maximize food-finding3, 4or conferring a rewarding value onto associated contexts or cues.5–7Here, we investigate how sweet taste elicits multiple appetitive behaviors inDrosophila. Are different sugar-evoked behaviors coordinately regulated? At what point does the sugar circuit diverge into different pathways that drive distinct behaviors? We first established an optogenetic paradigm to study the effects of sugar taste on locomotion, spatial preference, and associative learning. We then tested how different sugar-evoked behaviors were modulated by internal and external factors, including hunger, diet, or the presence of an aversive taste. Different behaviors were generally modulated in similar ways, but we also observed some differences that reveal selective modulation of specific behavioral pathways. Finally, we investigated where the sugar taste circuit diverges into different behavioral pathways. A recent study identified a sensory-motor circuit comprising five layers of neurons that drives the initiation of feeding in response to sugar.8By individually manipulating each of these neurons, we show that circuits mediating different innate responses to sugar are partially overlapping and begin to diverge at the level of second- and third-order neurons, whereas circuits for innate versus learned behaviors may diverge at the first synapse. Connectomic analyses reveal distinct subcircuits that mediate different behaviors. Together, these studies provide insight into how neural circuits are organized to elicit diverse behavioral responses to a single stimulus.
Astrocyte-specific inhibition of primary cilium functions improves cognitive impairment during neuroinflammation by suppressing A1 astrocyte differentiation
Authors: Muhamad Nor Atiqah , Furukawa Shota , Yuri Shunsuke , Toriyama Michinori , Masutani Kohei , Matsumoto Chuya , Itoh Seiya , Shinagawa Yuichiro , Isotani Ayako , Toriyama Manami , Itoh Hiroshi
Published: October 2023

A1 astrocytes play a neurotoxic role in various neurodegenerative diseases. While inhibiting the differentiation of A1 astrocytes can slow disease progression, the mechanisms controlling A1 astrocyte differentiation are largely unknown. The primary cilium is a cellular organelle that receives extracellular signals and regulates cell proliferation, differentiation, and maturation. To elucidate the physiological function of the primary cilium in A1 astrocytes, we utilized primary astrocytes and an inflammation mouse model. We found that the length of the primary cilium was increased in astrocytes, and the inhibition of primary cilium formation inhibited their differentiation into A1 astrocytes. Since mice with systemic ciliogenesis defects exhibit embryonic lethality, the function of the primary cilium in adults has remained largely unclear. Therefore, we established conditional knockout (cKO) mice that specifically inhibit primary cilium function in astrocytes upon drug stimulation. In a neuroinflammation mouse model in which lipopolysaccharide (LPS) was intraperitoneally injected into wild-type mice, increases in A1 astrocyte number and primary cilium length were observed in the brain. In contrast, cKO mice exhibited a reduction in the proportions of A1 astrocytes and apoptotic cells in the brain. Additionally, the novel object recognition (NOR) score observed in the cKO mice was higher than that observed in the neuroinflammation model mice. These results suggest that the primary cilium in astrocytes is essential for A1 astrocyte differentiation, which leads to a decline brain function. We propose that regulating astrocyte-specific primary cilium signalling may be a novel strategy for the suppression of neuroinflammation.
The Subcortical Default Mode Network and Alzheimer’s Disease: A systematic review and Activation Likelihood Estimation Meta-Analysis
Authors: Seoane Sara L , van den Heuvel Martijn , Acebes Ángel , Janssen Niels
Published: October 2023

The default mode network is a central cortical brain network suggested to play a major role in several disorders, and to be particularly vulnerable to the neuropathological hallmarks of Alzheimer’s disease. Subcortical involvement in the default mode network and its alteration in Alzhimer’s disease remains largely unknown. We performed a systematic review, meta-analysis, and empirical validation of the subcortical default mode network in healthy adults, combined with a systematic review, meta-analysis, and network analysis of the involvement of subcortical default mode areas in Alzheimer’s disease. Our results show that, besides the well-known cortical default mode network brain regions, the default mode network consistently includes subcortical regions, namely the thalamus, lobule and vermis IX and right Crus I/II of the cerebellum, and the amygdala. Network analysis also suggests the involvement of the caudate nucleus. In Alzheimer’s disease, we observed a left-lateralized cluster of decrease in functional connectivity which covered the medial temporal lobe and amygdala and showed overlap with the default mode network in a portion covering parts of the left anterior hippocampus and left amygdala. An increase in functional connectivity was also found in the right anterior insula. These results confirm the consistency of subcortical contributions to the default mode network in healthy adults and highlight the relevance of the subcortical default mode network alteration in Alzheimer’s disease.
Impact of digital assistive technologies on the quality of life for people with dementia: A scoping review
Authors: Schneider Charlotte , Nißen Marcia , Kowatsch Tobias , Vinay Rasita
Published: October 2023

Background

Digital assistive technologies (DATs) have emerged as promising tools to support the daily life of people with dementia (PWD) by offering support in various aspects of daily life. Quality of life (QOL) is an important consideration when discussing the care of PWD in relation to their autonomy. Current research tends to concentrate either on specific categories of DATs, or provide a generic view. Therefore, it would be of essence to provide a review of the different kinds of DATs, and how they contribute to improving QOL for PWD.

Objective

This scoping review aimed to review DATs and their impact on QOL for PWD.

Method

For this scoping review a broad literature search was performed in Cochrane, Embase, PubMed, Scopus, and Web of Science, covering scientific literature from January 2013 and May 2023. Screening and data extraction were conducted, followed by quantitative and qualitative analysis using thematic analysis principles and Digital Therapeutics (DTx) Alliance categories for DAT grouping.

Results

The literature search identified 6’083 records, with 1’056 duplicates. After screening, 4’560 full-texts were excluded, yielding 122 studies of different designs. The DATs were categorized intodigital therapeutics(n=109),patient monitoring(n=30),digital diagnostics(n=2),care support(n=2), andhealth system clinical software (n=1). These categories were identified to impact various aspects of QOL: preserving autonomy, engagement, and social interaction, health monitoring and promotion, improving activities of daily living, improving cognition, maintaining dignity, managing behavioral and psychological symptoms of dementia (BPSD), and safety/surveillance.

Conclusions

Various DATs offer extensive support, elevating the QOL of PWD.Digital therapeuticsare predominantly used for aging-in-place and independent living through assistance with daily tasks. Future research should focus on less-represented DHT categories, such ascare support, health & wellnessorsoftwaresolutions. Observing ongoing DAT developments and their long-term effects on QOL remains essential.

Strengths and limitations of this study

The study conducted an extensive search across five electronic databases spanning a decade to identify relevant literature on DATs and their impact on the QOL for PWD.

By excluding conference proceedings, book chapters, pilot, and feasibility studies, the review might have missed ongoing or planned research that could offer insights into different DATs or QOL impacts.

While the scoping review approach allowed for a broad overview, it didn’t assess the quality of included studies or intervention effectiveness, potentially introducing bias and limiting in-depth analysis.

The study’s emphasis on patient-facing DATs could have introduced bias, highlightingdigital therapeuticsin the included literature while potentially overlooking other assistive technology categories.
Antigenic drift and subtype interference shape A(H3N2) epidemic dynamics in the United States
Authors: Perofsky Amanda C , Huddleston John , Hansen Chelsea , Barnes John R , Rowe Thomas , Xu Xiyan , Kondor Rebecca , Wentworth David E , Lewis Nicola , Whittaker Lynne , Ermetal Burcu , Harvey Ruth , Galiano Monica , Daniels Rodney Stuart , McCauley John W , Fujisaki Seiichiro , Nakamura Kazuya , Kishida Noriko , Watanabe Shinji , Hasegawa Hideki , Sullivan Sheena G , Barr Ian G , Subbarao Kanta , Krammer Florian , Bedford Trevor , Viboud Cécile
Published: October 2023

Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997—2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection dynamics, presumably via heterosubtypic cross-immunity.

Impact statement:Antigenic drift in influenza’s major surface proteins – hemagglutinin and neuraminidase – contributes to variability in epidemic magnitude across seasons but is less influential than subtype interference in shaping annual outbreaks.
Mapping of multiple neurotransmitter receptor subtypes and distinct protein complexes to the connectome
Authors: Sanfilippo Piero , Kim Alexander J. , Bhukel Anuradha , Yoo Juyoun , Mirshahidi Pegah S. , Pandey Vijaya , Bevir Harry , Yuen Ashley , Mirshahidi Parmis S. , Guo Peiyi , Li Hong-Sheng , Wohlschlegel James A. , Aso Yoshinori , Lawrence Zipursky S.
Published: October 2023

Neurons express different combinations of neurotransmitter receptor (NR) subunits and receive inputs from multiple neuron types expressing different neurotransmitters. Localizing NR subunits to specific synaptic inputs has been challenging. Here we use epitope tagged endogenous NR subunits, expansion light-sheet microscopy, and EM connectomics to molecularly characterize synapses in Drosophila. We show that in directionally selective motion sensitive neurons, different multiple NRs elaborated a highly stereotyped molecular topography with NR localized to specific domains receiving cell-type specific inputs. Developmental studies suggested that NRs or complexes of them with other membrane proteins determines patterns of synaptic inputs. In support of this model, we identify a transmembrane protein associated selectively with a subset of spatially restricted synapses and demonstrate through genetic analysis its requirement for synapse formation. We propose that mechanisms which regulate the precise spatial distribution of NRs provide a molecular cartography specifying the patterns of synaptic connections onto dendrites.
A neurocomputational account of the link between social perception and social action
Authors: Bas Lisa M. , Roberts Ian D. , Hutcherson Cendri A. , Tusche Anita
Published: October 2023

People selectively help others based on perceptions of their merit or need. Here, we develop a neurocomputational account of how these social perceptions translate into social choice. Using a novel fMRI social perception task, we show that both merit and need perceptions recruited the brain’s social inference network. A behavioral computational model identified two non-exclusive mechanisms underlying variance in social perceptions: a consistent tendency to perceive others as meritorious/needy (bias) and a propensity to sample and integrate normative evidence distinguishing high from low merit/need in other people (sensitivity). Variance in people’s merit (but not need) bias and sensitivity independently predicted distinct aspects of altruism in a social choice task completed months later. An individual’s meritbiaspredictedcontext-independentvariance in people’s overall other-regard during altruistic choice, biasing people towards prosocial actions. An individual’s meritsensitivitypredictedcontext-sensitivediscrimination in generosity towards high and low merit recipients by influencing other-regard and self-regard during altruistic decision-making. This context-sensitive perception-action link was associated with activation in the right temporoparietal junction. Together, these findings point towards stable, biologically based individual differences in perceptual processes related to abstract social concepts like merit, and suggest that these differences may have important behavioral implications for an individual’s tendency toward favoritism or discrimination in social settings.
Microclimate buffering varies across forest types during an extreme heat event
Authors: John Aji , Pradhan Kavya , Case Michael J. , Ettinger Ailene K. , Hille Ris Lambers Janneke
Published: October 2023

Increasing temperatures and extreme heat episodes have become more common with climate change. While forests are known to be buffered from increasing temperatures compared to non-forested areas, whether this buffering is maintained under extreme temperature events, how such events influence forests, and how forest organisms respond to extreme heat is relatively unknown. Here we assess the effects of an extreme heat event (the Pacific Northwest (PNW) heatdome in June 2021) on forest microclimates, forests, and the organisms living within them. We first asked how the PNW heatdome affected microclimates in forests with differing canopy cover (including non-forests) and found that the buffering capacity of forests is greater under denser canopies, even under extreme heat events. We then combined this information with organismal temperature tolerance curves for 12 relevant species and found that canopy buffering can minimize the negative impacts of even extreme heat events on understory organisms, with greater canopy density providing greater microclimate moderation. Finally, we analyzed seasonal NDVI trends in recent years, and found signs of canopy stress following the extreme 2021 heat event. In all, this suggests that although forest canopies may buffer the negative effects of extreme heat events on understory organisms, a greater frequency of extreme heat events may threaten this capacity by damaging forest canopies.
Ranking of cell clusters in a single-cell RNA-sequencing analysis framework using prior knowledge
Authors: Oulas Anastasis , Savva Kyriaki , Karathanasis Nestoras , Spyrou George M
Published: October 2023

Prioritization or ranking of different cell types in a scRNA-Seq framework can be performed in a variety of ways, some of these include: i) obtaining an indication of the proportion of cell types between the different conditions under study, ii) counting the number of differentially expressed genes (DEGs) between cell types and conditions in the experiment or, iii) prioritizing cell types based on prior knowledge about the conditions under study (i.e., a specific disease). These methods have drawbacks and limitations thus novel methods for improving cell ranking are required. Here we present a novel methodology that exploits prior knowledge in combination with expert-user information to accentuate cell types from a scRNA-seq analysis that yield the most biologically meaningful results. Prior knowledge is incorporated in a standardized, structured manner, whereby a checklist is attained by querying MalaCards human disease database with a disease of interest. The checklist is comprised of pathways and drugs and, optionally, drug mode of actions (MOAs), associated with the disease. The user is prompted to “edit” this checklist by removing or adding terms (in the form of keywords) from the list of predefined terms. Our methodology has substantial advantages to more traditional cell ranking techniques and provides an informative complementary methodology that utilizes prior knowledge in a rapid and automated manner, that has previously not been attempted by other studies. The current methodology is also implemented as an R package entitled Single Cell Ranking Analysis Toolkit (scRANK) and is available for download and installation via GitHub (https://#hub.com/aoulas/scRANK)

Author Summary

Single-cell RNA Sequencing (scRNA-Seq) provides an additive resolution down to the cellular level that was previously not available from traditional “Bulk” RNA sequencing experiments. However, it is often difficult to prioritize the specific cell-types which are primarily responsible for the cause of a disease. This work presents a novel methodology that exploits prior knowledge for a disease in combination with expert-user information to accentuate cell types from a scRNA-seq analysis that are most closely related to the molecular mechanism of a disease of interest. Prior knowledge is incorporated in a standardized, structured manner, whereby a checklist is attained by querying a human disease database called MalaCards. This checklist comes in the form of pathways and drugs and, optionally, drug mode of actions (MOAs), associated with the disease. The expert-user is prompted to “edit” the prior knowledge checklist by removing or adding terms from the list of predefined terms.

This methodology has substantial advantages to more traditional cell prioritizing or ranking techniques and provides an informative complementary methodology that utilizes prior knowledge in a rapid and automated manner.
Branching architecture affects genetic diversity within an individual tree
Authors: Tomimoto Sou , Iwasa Yoh , Satake Akiko
Published: October 2023

Premise

While a tree grows over many years, somatic mutations accumulate and generate a genetically diverse individual. Trees can transmit such mutations to subsequent generations, potentially enhancing the genetic diversity of the population. We study a mathematical model to understand the relationship between within-individual genetic variation and branching architecture.

Methods

We generate branching architecture by repeatedly adding two new branches (main and lateral daughter branches) to each terminal branch (mother branch). Tree shape is determined by two key parameters: daughter-mother ratio (DM) and main-lateral ratio (ML). During branch elongation, somatic mutations accumulate in the stem cells of a shoot apical meristem (SAM) at the tip of each branch. In branching, all the stem cells are passed on from the mother to the main daughter branch, but only one stem cell is chosen for the lateral daughter branch. We evaluate genetic variation by, the mean genetic differences between all pairs of branches of a tree, and examine howvaries with DM and ML while keeping the total branch length constant.

Key results and Conclusions

(1)attains the maximum for an intermediate DM, when stem cells in the SAM are genetically homogeneous; (2)decreases monotonically with DM when stem cells are genetically heterogeneous; and (3)increases monotonically with ML. Even though the total branch length remains constant, the within-individual genetic variation differs substantially. The results demonstrate the importance of branching architecture in storing genetic diversity.
Reducing work-load of pathotype and gene detection inKlebsiella pneumoniaeby leveraging machine learning
Authors: Sanikhani Rahimeh , Kiani Kourosh Alizadeh , Soroush Mehdi , Moeinirad Mohammad , Sanikhani Seyed Ahmad , Beheshti Masoumeh , Tavakoli Sajad , Badmasti Farzad , Sadati Seyed Hossein
Published: October 2023

Background

The growing prevalence of carbapenem resistance has caused an increasing number of bacterial isolates with multi-drug resistance features, especially in theEnterobacteriaceaefamily.Klebsiella pneumoniae, as one of the important members of theEnterobacteriaceaefamily, causes serious infections, which has attracted the attention of scientists due to the emergence of hypervirulent pathotypes with increasing antibiotic resistance and has been raised as a major concern worldwide. Early detection of this new super bacterium and its antibiotic resistance is of great help in reducing mortality and costs. The lack of new antibiotic options underscores the need to optimize current diagnostics. Therefore, this study was designed to leverage machine-learning approach for optimized selection of crucial antibiotics to reduce the experiments needed for the detection of pathotypes and genes’ presence in two classical and hypervirulentK. pneumoniaepathotypes.

Methods

341 non-duplicate clinical isolates ofK. pneumoniaewere collected from five university hospitals in Tehran and Qazvin, Iran. Pathotype differentiation of classical (cKp) and hypervirulentK.pneumoniae(hvKp) was done by PCR method by two molecular biomarkers includingiucandiut. After identifying the phenotypic antibiotic resistance, the presence of antibiotic resistance genes was detected by PCR method. Then, the relevance of resistance/susceptibility of the antibiotics and presence of pathotypes, aerobactin, and beta-lactamase genes was investigated and analyzed using five supervised machine learning algorithms by selecting crucial antibiotics through feature selection methods.

Results

Among the 341K.pneumoniaeisolates, 102 and 239 isolates were hvKpand cKprespectively. The highest rate of antibiotic resistance after ampicillin (100%) was related to cefotaxime (76.2%) and the lowest rate of resistance was found in meropenem (24.3%). Imipenem, Meropenem, Aztreonam, Ceftazidime, Ceftriaxone, and Gentamicin are crucial antibiotics for detection of the pathotypes and the aerobactin genes. Moreover, Cefotaxime, Ciprofloxacin, Cefepime, Meropenem, and Imipenem are essential for detection of the beta-lactamase genes.

Conclusion

Implementing a machine learning approach including various feature selection methods and algorithms, results in less-required experiments on more limited antibiotics to detect genes and pathotypes. Our findings reveal that using machine learning in the prediction of the presence of genes and pathotypes of clinical isolates was a suitable method in terms of rapidity and cost-efficiency on top of accuracy.
IDR-induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers
Authors: Zhang Xinyan , Xiao Qian , Zeng Longhui , Hashmi Fawzaan , Su Xiaolei
Published: October 2023

Chimeric antigen receptor (CAR)-T cell-based therapies demonstrate remarkable efficacy for the treatment of otherwise intractable cancers, particularly B-cell malignancies. However, existing FDA-approved CAR-Ts are limited by low antigen sensitivity, rendering their insufficient targeting to low antigen-expressing cancers. To improve the antigen sensitivity of CAR-Ts, we engineered CARs targeting CD19, CD22, and HER2 by including intrinsically disordered regions (IDRs) that promote signaling condensation. The “IDR CARs” triggered enhanced membrane-proximal signaling in the CAR-T synapse, which led to an increased release of cytotoxic factors, a higher killing activity towards low antigen-expressing cancer cells in vitro, and an improved anti-tumor efficacy in vivo. No elevated tonic signaling was observed in IDR CAR-Ts. Together, we demonstrated IDRs as a new tool set to enhance CAR-T cytotoxicity and to broaden CAR-T’s application to low antigen-expressing cancers.
Digenic variant interpretation with hypothesis-driven explainable AI
Authors: Paoli Federica De , Nicora Giovanna , Berardelli Silvia , Gazzo Andrea , Bellazzi Riccardo , Magni Paolo , Rizzo Ettore , Limongelli Ivan , Zucca Susanna
Published: October 2023

Motivation

The digenic inheritance hypothesis holds the potential to enhance diagnostic yield in rare diseases. Computational approaches capable of accurately interpreting and prioritizing digenic combinations based on the proband’s phenotypic profiles and familial information can provide valuable assistance to clinicians during the diagnostic process.

Results

We have developed diVas, a hypothesis-driven machine learning approach that can effectively interpret genomic variants across different gene pairs. DiVas demonstrates strong performance both in classifying and prioritizing causative pairs, consistently placing them within the top positions across 11 real cases (achieving 73% sensitivity and a median ranking of 3). Additionally, diVas exploits Explainable Artificial Intelligence (XAI) to dissect the digenic disease mechanism for predicted positive pairs.

Availability and Implementation

Prediction results of the diVas method on a high-confidence, comprehensive, manually curated dataset of known digenic combinations are available atoliver.engenome.com.
Aedes aegyptiin Maryland: The need for elevated vector surveillance at the face of a dynamic climate
Authors: Faiman Roy , Goodwin Autumn , Cave-Stevens Jaykob , Schultz Alyssa , Brey Jewell , Ford Tristan
Published: October 2023

We report the collection of threeAedes aegyptiadult female mosquitoes in a Rockville, Maryland backyard in late July, 2023, followed by the emergence of 15 adults collected as larvae in a residential backyard in Baltimore, Maryland in mid-September, 2023.Aedes aegyptiis a species primarily associated with tropical and subtropical regions, known for its significance as a vector of arboviruses, including Yellow Fever, Dengue, Zika, and Chikungunya among others. In the continental United States,Ae. aegyptipopulations are mostly found in the southeast, and in several isolated locations such as southern California and Arizona. This finding raises questions about the potential establishment and survival ofAe. aegyptiin temperate climates, emphasizing the critical importance of robust vector surveillance programs in preventing potential outbreaks of vector-borne diseases in regions not traditionally considered endemic for this species.
Evolution of sex-biased gene expression during transitions to separate sexes in theSilenegenus
Authors: Prentout Djivan , Muyle Aline , Zemp Niklaus , el Filali Adil , Boussau Bastien , Touzet Pascal , Widmer Alex , Käfer Jos , Marais Gabriel A.B.
Published: October 2023

Sexual dimorphism is widespread among species with separate sexes and its extent is thought to be governed by the differential expression of thousands of genes between males and females (known as Sex-Biased Genes, hereafter SBGs). SBGs have been studied in numerous species, but rarely in a comparative way, which curtails our understanding of their evolution, especially during multiple independent transitions to separate sexes. We sequenced the transcriptomes of nine dioecious species, two gynodioecious species (separate females and hermaphrodites) and two hermaphrodite species from theSilenegenus. Our dataset provides access to three independent transitions to dioecy (dating from less than 1 Myo to about 11 Myo). We demonstrated that male-biased expression emerges first during a transition to separate sexes, later followed by female-biased genes. Furthermore, we showed that, despite a mixture of selective regimes, positive selection significantly affects the evolution of some SBGs. Overall, this study provides new insights on the causes of SBG evolution during transitions to separate sexes.

Teaser

This study describes the evolution of sex-biased gene expression during a transition to separate sexes in plants.
Global RNA interactome of nitrogen starvedEscherichia coliuncovers a conserved post-transcriptional regulatory axis required for optimal growth recovery
Authors: McQuail Josh , Matera Gianluca , Gräfenhan Tom , Bischler Thorsten , Haberkant Per , Stein Frank , Vogel Jörg , Wigneshweraraj Sivaramesh
Published: October 2023

The RNA binding protein Hfq has a central role in the post-transcription control of gene expression in many bacteria. Numerous studies have mapped the transcriptome-wide Hfq-mediated RNA-RNA interactions in growing bacteria or bacteria that have entered short-term growth-arrest. To what extent post-transcriptional regulation underpins gene expression in growth-arrested bacteria remains unknown. Here, we used nitrogen (N) starvation as a model to study the Hfq-mediated RNA interactome asEscherichia colienter, experience, and exit long-term growth arrest. We observe that the Hfq-mediated RNA interactome undergoes extensive changes during N starvation, with the conserved SdsR sRNA making the most interactions with different mRNA targets exclusively in long-term N-starvedE. coli. Taking a proteomics approach, we reveal that in growth-arrested cells SdsR influences gene expression far beyond its direct mRNA targets. We demonstrate that the absence of SdsR significantly compromises the ability of the mutant bacteria to recover growth competitively from the long-term N-starved state and uncover a conserved post-transcriptional regulatory axis which underpins this process.
Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett Syndrome Mice
Authors: Whitaker-Fornek Jessica R. , Jenkins Paul M. , Levitt Erica S.
Published: October 2023

Rett Syndrome (RTT) is a severe neurodevelopmental disorder that mainly affects girls and women due to silencing mutations in the X-linkedMECP2gene. One of the most troubling symptoms of RTT is breathing irregularity, including apneas, breath-holds, and hyperventilation. Mice with silencing mutations inMecp2exhibit breathing abnormalities similar to human patients and serve as useful models for studying mechanisms underlying breathing problems in RTT. Previous work implicated the pontine, respiratory-controlling Kölliker-Fuse (KF) in the breathing problems in RTT. The goal of this study was to test the hypothesis that inhibitory synaptic transmission is deficient in KF neurons from symptomatic male and female RTT mice. We performed whole-cell voltage-clamp recordings from KF neurons in acute brain slices to examine pharmacologically isolated, spontaneous and electrically evoked inhibitory post-synaptic currents (IPSCs) in RTT mice and age- and sex-matched wild type mice. The frequency of spontaneous IPSCs was reduced in KF neurons from male RTT mice, but not female RTT mice. In addition, electrically evoked IPSCs were less reliable in KF neurons from male RTT mice, but not female RTT mice. KF neurons from male RTT mice were also more excitable and exhibited shorter duration action potentials. Increased excitability of KF neurons from male mice was not explained by changes in axon initial segment length. These findings indicate impaired inhibitory neurotransmission and increased excitability of KF neurons in male, but not female RTT mice, and suggest that sex-dependent mechanisms contribute to breathing problems in RTT.

New and Noteworthy

Kölliker-Fuse (KF) neurons in acute brain slices from male Rett syndrome (RTT) mice receive reduced inhibitory synaptic inputs compared with wild type littermates. In female RTT mice, inhibitory transmission was not different in KF neurons compared with controls. The results from this study show that sex-specific alterations in synaptic transmission occur in the KF of RTT mice.

Graphical Abstract
Parallel nonfunctionalization of CK1δ/ε kinase ohnologs following a whole-genome duplication event
Authors: Evans-Yamamoto Daniel , Dubé Alexandre K , Saha Gourav , Plante Samuel , Bradley David , Gagnon-Arsenault Isabelle , Landry Christian R
Published: October 2023

Whole genome duplication (WGD) followed by speciation allows us to examine the parallel evolution of ohnolog pairs. In the yeast familySaccharomycetaceae,HRR25is a rare case of repeated ohnolog maintenance. This gene has reverted to a single copy inS. cerevisiaewhere it is now essential, but has been maintained as pairs in at least 7 species post WGD. InS. cerevisiae,HRR25encodes the casein kinase (CK) 1δ/ε and plays a role in a variety of functions through its kinase activity and protein-protein interactions (PPIs). We hypothesized that the maintenance of duplicatedHRR25ohnologs could be a result of repeated subfunctionalization. We tested this hypothesis through a functional complementation assay inS. cerevisiae, testing all pairwise combinations of 25 orthologs (including 7 ohnolog pairs). Contrary to our expectations, we observed no cases of pair-dependent complementation, which would have supported the subfunctionalization hypothesis. Instead, most post-WGD species have one ohnolog that failed to complement, suggesting their nonfunctionalization or neofunctionalization. The ohnologs incapable of complementation have undergone more rapid protein evolution, lost most PPIs that were observed for their functional counterparts and singletons from post and non-WGD species, and have non-conserved cellular localization, consistent with their ongoing loss of function. The analysis inN. castellishows that the non-complementing ohnolog is expressed at a lower level and has become non-essential. Taken together, our results indicate thatHRR25orthologs are undergoing gradual nonfunctionalization.