bluuebunny/crossref_metadata_2025 huggingface dataset:
Chloride-dependent mechanisms of multimodal sensory discrimination and neuropathic sensitization in Drosophila
Authors: Himmel Nathaniel J. , Sakurai Akira , Letcher Jamin M. , Patel Atit A. , Bhattacharjee Shatabdi , Benson Maggie N. , Gray Thomas R. , Cymbalyuk Gennady S. , Cox Daniel N.
Published: December 2021

Individual sensory neurons can be tuned to many stimuli, each driving unique, stimulus-relevant behaviors, and the ability of multimodal nociceptor neurons to discriminate between potentially harmful and innocuous stimuli is broadly important for organismal survival. Moreover, disruptions in the capacity to differentiate between noxious and innocuous stimuli can result in neuropathic pain. Drosophila larval Class III (CIII) neurons are peripheral noxious cold nociceptors and gentle touch mechanosensors; high levels of activation drive cold-evoked contraction (CT) behavior, while low levels of activation result in a suite of touch-associated behaviors. However, it is unknown what molecular factors underlie CIII multimodality. Here, we show that the TMEM16/anoctamins subdued and white walker (wwk; CG15270) are required for cold-evoked CT, but not for touch-associated behavior, indicating a conserved role for anoctamins in nociception. We also evidence that CIII neurons make use of atypical depolarizing chloride currents to encode cold, and that overexpression of ncc69—a fly homologue of NKCC1—results in phenotypes consistent with neuropathic sensitization, including behavioral hypersensitization and spontaneous nociceptor activity, making Drosophila CIII neurons a candidate system for future studies of the basic mechanisms underlying neuropathic pain.
Single-fiber nucleosome density shapes the regulatory output of a mammalian chromatin remodeling enzyme
Authors: Abdulhay Nour J , Hsieh Laura J , McNally Colin P , Ketavarapu Mythili , Kasinathan Sivakanthan , Nanda Arjun S , Ostrowski Megan S , Wu Ke , Moore Camille M , Goodarzi Hani , Narlikar Geeta J , Ramani Vijay
Published: December 2021

ATP-dependent chromatin remodelers regulate the DNA accessibility required of virtually all nuclear processes. Biochemical studies have provided insight into remodeler action at the nucleosome level, but how these findings translate to activity on chromatin fibers in vitro and in vivo remains poorly understood. Here, we present a massively multiplex single-molecule platform allowing high-resolution mapping of nucleosomes on fibers assembled on mammalian genomic sequences. We apply this method to distinguish between competing models for chromatin remodeling by the essential ISWI ATPase SNF2h: linker-length-dependent dynamic positioning versus fixed-linker-length static clamping. Our single-fiber data demonstrate that SNF2h operates as a density-dependent, length-sensing chromatin remodeler whose ability to decrease or increase DNA accessibility depends on single-fiber nucleosome density. In vivo, this activity manifests as different regulatory modes across epigenomic domains: at canonically-defined heterochromatin, SNF2h generates evenly-spaced nucleosome arrays of multiple nucleosome repeat lengths; at SNF2h-dependent accessible sites, SNF2h slides nucleosomes to increase accessibility of motifs for the essential transcription factor CTCF. Overall, our generalizable approach provides molecularly-precise views of the processes that shape nuclear physiology. Concurrently, our data illustrate how a mammalian chromatin remodeling enzyme can effectively sense nucleosome density to induce diametrically-opposed regulatory effects within the nucleus.
Artificial intelligence for diagnosis and prognosis in neuroimaging for dementia; a systematic review
Authors: Borchert R , Azevedo T , Badhwar A , Bernal J , Betts M , Bruffaerts R , Burkhart MC , Dewachter I , Gellersen HM , Low A , Machado L , Madan CR , Malpetti M , Mejia J , Michopoulou S , Muñoz-Neira C , Peres M , Phillips V , Ramanan S , Tamburin S , Tantiangco H , Thakur L , Tomassini A , Vipin A , Tang E , Newby D , Ranson J , Llewellyn D.J. , Veldsman M , Rittman T
Published: December 2021

Introduction

Recent developments in artificial intelligence (AI) and neuroimaging offer new opportunities for improving diagnosis and prognosis of dementia. To synthesise the available literature, we performed a systematic review.

Methods

We systematically reviewed primary research publications up to January 2021, using AI for neuroimaging to predict diagnosis and/or prognosis in cognitive neurodegenerative diseases. After initial screening, data from each study was extracted, including: demographic information, AI methods, neuroimaging features, and results.

Results

We found 2709 reports, with 252 eligible papers remaining following screening. Most studies relied on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n=178) with no other individual dataset used more than 5 times. Algorithmic classifiers, such as support vector machine (SVM), were the most commonly used AI method (47%) followed by discriminative (32%) and generative (11%) classifiers. Structural MRI was used in 71% of studies with a wide range of accuracies for the diagnosis of neurodegenerative diseases and predicting prognosis. Lower accuracy was found in studies using a multi-class classifier or an external cohort as the validation group. There was improvement in accuracy when neuroimaging modalities were combined, e.g. PET and structural MRI. Only 17 papers studied non-Alzheimer’s disease dementias.

Conclusion

The use of AI with neuroimaging for diagnosis and prognosis in dementia is a rapidly emerging field. We make a number of recommendations addressing the definition of key clinical questions, heterogeneity of AI methods, and the availability of appropriate and representative data. We anticipate that addressing these issues will enable the field to move towards meaningful clinical translation.
Genomics-informed outbreak investigations of SARS-CoV-2 using civet
Authors: O’Toole Áine , Hill Verity , Jackson Ben , Dewar Rebecca , Sahadeo Nikita , Colquhoun Rachel , Rooke Stefan , McCrone JT , McHugh Martin P , Nicholls Sam , Poplawski Radoslaw ,   The COVID-19 Genomics UK (COG-UK) Consortium,   COVID-19 Impact Project (Trinidad & Tobago Group), Aanensen David , Holden Matt , Connor Tom , Loman Nick , Goodfellow Ian , Carrington Christine V. F. , Templeton Kate , Rambaut Andrew
Published: December 2021

The scale of data produced during the SARS-CoV-2 pandemic has been unprecedented, with more than 5 million sequences shared publicly at the time of writing. This wealth of sequence data provides important context for interpreting local outbreaks. However, placing sequences of interest into national and international context is difficult given the size of the global dataset. Often outbreak investigations and genomic surveillance efforts require running similar analyses again and again on the latest dataset and producing reports. We developed civet (cluster investigation and virus epidemiology tool) to aid these routine analyses and facilitate virus outbreak investigation and surveillance. Civet can place sequences of interest in the local context of background diversity, resolving the query into different ’catchments’ and presenting the phylogenetic results alongside metadata in an interactive, distributable report. Civet can be used on a fine scale for clinical outbreak investigation, for local surveillance and cluster discovery, and to routinely summarise the virus diversity circulating on a national level. Civet reports have helped researchers and public health bodies feedback genomic information in the appropriate context within a timeframe that is useful for public health.
Relationship Between Alcohol Consumption and Telecommuting Preference-Practice Mismatch During the COVID-19 Pandemic
Authors: Watanabe Chihiro , Konno Yusuke , Yoshimura Reiji , Tateishi Seiichiro , Hino Ayako , Tsuji Mayumi , Ogami Akira , Nagata Masako , Muramatsu Keiji , Fujino Yoshihisa ,   for the CORoNaWork project
Published: December 2021

Introduction

This study examined the association between increased alcohol consumption and telecommuting, comparing employees who expressed a preference for telecommuting and those who did not.

Methods

We conducted an internet monitor survey. Responses from 20,395 of the 33,302 participants were included in the final sample. Participants were asked about their desire for and frequency of telecommuting, and about changes in alcohol consumption under the COVID-19 pandemic. Data were analyzed by logistic regression analysis.

Results

Participants who telecommuted despite preferring not to do so reported significantly increased alcohol consumption, as revealed by a multivariate analysis (OR=1.62, 95% CI 1.25-2.12). Participants who expressed a preference for telecommuting showed no such increase.

Conclusions

Under the COVID-19 pandemic, telecommuting that involves a mismatch with employee preference for way of working may be a new risk factor for problematic drinking.
LKB1 Is Physiologically Required for Sleep from Drosophila to the Mouse
Authors: Liu Ziyi , Jiang Lifen , Li Chaoyi , Li Chengang , Yang Jingqun , Wang Dan , Mao Renbo , Rao Yi
Published: December 2021

LKB1 is known as a master kinase for 14 kinases related to the adenosine monophosphate (AMP)-activated protein kinase (AMPK). Two of them (SIK3 and AMPKα) have previously been implicated in sleep regulation. We generated loss-of-function (LOF) mutants for Lkb1 in both Drosophila and mice. Sleep was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography (EEG) analysis showed that non-rapid eye movement (NREM) sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that LKB1 plays a physiological role in sleep regulation conserved from flies to mice.
AutoMicroED: A semi-automated MicroED processing pipeline
Authors: Powell Samantha M. , Novikova Irina V. , Kim Doo Nam , Evans James E.
Published: December 2021

Despite rapid adaptation of micro-electron diffraction (MicroED) for protein and small molecule structure determination to sub-angstrom resolution, the lack of automation tools for easy MicroED data processing remains a challenge for expanding to the broader scientific community. In particular, automation tools, which are novice user friendly, compatible with heterogenous datasets and can be run in unison with data collection to judge the quality of incoming data (similar to cryosparc LIVE for single particle cryoEM) do not exist. Here, we present AutoMicroED, a cohesive and semi-automatic MicroED data processing pipeline that runs through image conversion, indexing, integration and scaling of data, followed by merging of successful datasets that are pushed through phasing and final structure determination. AutoMicroED is compatible with both small molecule and protein datasets and creates a straightforward and reproducible method to solve single structures from pure samples, or multiple structures from mixed populations. The immediate feedback on data quality, data completeness and more parameters, aids users to identify whether they have collected enough data for their needs. Overall, AutoMicroED permits efficient structure elucidation for both novice and experienced users with comparable results to more laborious manual processing.
An intrinsic endothelial dysfunction causes cerebral small vessel disease
Authors: Quick Sophie , Procter Tessa V. , Moss Jonathan , Lawson Angus , Baker Serena , Walton Marc , Mohammad Mehreen , Mungall Will , Onishi Ami , Tobola Zuzanna , Stringer Michael , Jansen Maurits A. , Vallatos Antoine , Giarratano Ylenia , Bernabeu Miguel O. , Wardlaw Joanna M. , Williams Anna C.
Published: December 2021

Small Vessel Disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes(1, 2). The disease is characterised by cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. Classically, the microvascular and tissue damage has been considered secondary to extrinsic factors, such as hypertension, consisting of microvessel stiffening, impaired vasoreactivity and blood-brain barrier dysfunction identified in human sporadic SVDs. However, increasing evidence points to an underlying vulnerability to SVD-related brain damage, not just extrinsic factors. Here, in a novel normotensive transgenic rat model where the phospholipase flippase Atp11b is deleted, we show pathological, imaging and behavioural changes typical of those in human sporadic SVD, but that occur without hypertension. These changes are due to an intrinsic endothelial cell dysfunction, identified in vessels of the brain white matter and the retina, with pathological evidence of vasoreactivity and blood-brain barrier deficits, which precipitate a secondary maturation block in oligodendroglia and myelin disruption around the small vessels. This highlights that an intrinsic endothelial dysfunction may underlie vulnerability to human sporadic SVD, providing alternative therapeutic targets to prevent a major cause of stroke and dementia.
Spike initiation properties in the axon support high-fidelity signal transmission
Authors: Kamaleddin Mohammad Amin , Abdollahi Nooshin , Ratté Stéphanie , Prescott Steven A
Published: December 2021

The axon initial segment (AIS) converts graded depolarization into all-or-none spikes that are transmitted by the axon to downstream neurons. Analog-to-digital transduction and digital signal transmission call for distinct spike initiation properties (filters) and those filters should, therefore, differ between the AIS and distal axon. Here we show that unlike the AIS, which spikes repetitively during sustained depolarization, the axon spikes transiently and only if depolarization reaches threshold before KV1 channels activate. Rate of depolarization is critical. This was shown by optogenetically evoking spikes in the distal axon of CA1 pyramidal neurons using different photostimulus waveforms and pharmacological conditions while recording antidromically propagated spikes at the soma, thus circumventing the prohibitive difficulty of patching intact axons. Computational modeling shows that KV1 channels in the axon implement a high-pass filter that is matched to the axial current waveform associated with spike propagation, thus maximizing the signal-to-noise ratio to ensure high-fidelity transmission of spike-based signals.
Transcriptomics reveal stretched human pluripotent stem cell-derived cardiomyocytes as an advantageous hypertrophy model
Authors: Pohjolainen Lotta , Ruskoaho Heikki , Talman Virpi
Published: December 2021

Left ventricular hypertrophy, characterized by hypertrophy of individual cardiomyocytes, is an adaptive response to an increased cardiac workload that eventually leads to heart failure. Previous studies using neonatal rat ventricular myocytes (NRVMs) and animal models have revealed several genes and signaling pathways associated with hypertrophy and mechanical load. However, these models are not directly applicable to humans. Here, we studied the effect of cyclic mechanical stretch on gene expression of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using RNA sequencing. hiPSC-CMs showed distinct hypertrophic changes in gene expression at the level of individual genes and in biological processes. We also identified several differentially expressed genes that have not been previously associated with cardiomyocyte hypertrophy and thus serve as attractive targets for future studies. When compared to previously published data attained from stretched NRVMs and human embryonic stem cell-derived cardiomyocytes, hiPSC-CMs displayed a smaller number of changes in gene expression, but the differentially expressed genes revealed more pronounced enrichment of hypertrophy-related biological processes and pathways. Overall, these results establish hiPSC-CMs as a valuable in vitro model for studying human cardiomyocyte hypertrophy.

Non-standard Abbreviations and Acronyms

ET-1, endothelin-1; GO, gene ontology; hESC-CM, human embryonic stem cell-derived cardiomyocyte; hiPSC, human induced pluripotent stem cell; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; MAPK, mitogen-activated protein kinase; MEK1/2, mitogen-activated protein kinase kinase 1/2; NRVM, neonatal rat ventricular myocyte; PKC, protein kinase C; PBS, phosphate-buffered saline; RB+, RPMI 1640 supplemented with B-27; RB-, RPMI 1640 medium supplemented with B-27 without insulin; RT, room temperature; TF, transcription factor
Identifying Protein Features and Pathways Responsible for Toxicity using Machine learning, CANDO, and Tox21 datasets: Implications for Predictive Toxicology
Authors: Moukheiber Lama , Mangione William , Maleki Saeed , Falls Zackary , Gao Mingchen , Samudrala Ram
Published: December 2021

Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning methods have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational model using machine learning for selecting the most important proteins representing features in predicting the toxicity of the compounds in the Tox21 dataset using the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) platform for therapeutic discovery. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For our computational model, we employed a random forest (RF) with the combination of Synthetic Minority Oversampling Technique (SMOTE) and Edited Nearest Neighbor (ENN) method, aka SMOTE+ENN, which is resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR), toxicity mediating transcription factor, and mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were passed into enrichment analysis to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with NR-AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong, with twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints.
Prolactin maintains parental responses and alters reproductive axis gene expression, but not courtship behaviors, in both sexes of a biparental bird
Authors: Farrar Victoria S. , Flores Laura , Viernes Rechelle C. , Pereira Laura Ornelas , Mushtari Susan , Calisi Rebecca M.
Published: December 2021

Prolactin, a hormone involved in vertebrate parental care, is hypothesized to inhibit reproductive hypothalamic-pituitary-gonadal (HPG) axis activity during parenting, thus maintaining investment in the current brood as opposed to new reproductive efforts. While prolactin underlies many parental behaviors in birds, its effects on other reproductive behaviors, such as courtship, remain unstudied. How prolactin affects neuropeptide and hormone receptor expression across the avian HPG axis also remains unknown. To address these questions, we administered ovine prolactin (oPRL) or a vehicle control to both sexes in experienced pairs of the biparental rock dove (Columba livia), after nest removal at the end of incubation. We found that oPRL promoted parental responses to novel chicks and stimulated crop growth compared to controls, consistent with other studies. However, we found that neither courtship behaviors, copulation rates nor pair maintenance differed with oPRL treatment. Across the HPG, we found oPRL had little effect on gene expression in hypothalamic nuclei, but increased expression ofFSHBand hypothalamic hormone receptor genes in the pituitary. In the gonads, oPRL increased testes size and gonadotropin receptor expression, but did not affect ovarian state or small white follicle gene expression. However, the oviducts of oPRL-treated females were smaller and had lower estrogen receptor expression compared with controls. Our results highlight that some species, especially those that show multiple brooding, may be able to maintain mating behavior despite elevated prolactin. Thus, mechanisms may exist for prolactin to promote investment in parental care without concurrent inhibition of reproductive function or HPG axis activity.
Native SAD Phasing at Room Temperature
Authors: Greisman Jack B. , Dalton Kevin M. , Sheehan Candice J. , Klureza Margaret A. , Hekstra Doeke R.
Published: December 2021

Abstract

Single-wavelength anomalous diffraction (SAD) is a routine method for overcoming the phase problem when solving a new macromolecular structure. This technique requires the accurate measurement of intensities to sensitively determine differences across Bijvoet pairs, making it a stringent test for the reliability of a data collection method. Although SAD experiments are commonly conducted at cryogenic temperatures to mitigate the effects of radiation damage, such temperatures can alter the conformational ensemble of the protein crystal and may impede the merging of data from multiple crystals due to non-uniform freezing. Here, we propose a data collection strategy to obtain high-quality data from room temperature samples. To illustrate the strengths of this approach we use native SAD phasing at 6.5 keV to solve four structures of three model systems at 295 K. The resulting datasets allow for automatic phasing and model building, and exhibit alternate conformations that are well-supported by the electron density. The high-redundancy data collection method demonstrated here enables the routine collection of high-quality, room-temperature diffraction to improve the study of protein conformational ensembles.
A Multiscale computational model of YAP signaling in epithelial fingering behaviour
Authors: Mukhtar Naba , Cytrynbaum Eric N , Edelstein-Keshet Leah
Published: December 2021

In epithelial-mesenchymal transition (EMT), cells organized into sheets break away and become motile mesenchymal cells. EMT plays a crucial role in wound healing, embryonic development, and cancer metastasis. Intracellular signaling in response to mechanical, topographic, or chemical stimuli can promote EMT. We present a multiscale model for EMT downstream of the protein YAP, which suppresses the cell-cell adhesion protein E-cadherin and activates the GTPase Rac1 that enhances cell migration. We first propose an ODE model for YAP/Rac1/E-cadherin interactions. The model dynamics are bistable, accounting for motile loose cells as for adherent slower cells. We implement this model in a cellular Potts model simulation of 2D wound-healing using the open source platform Morpheus. We show that, under suitable stimuli (depicting topographic cues) the sheet exhibits finger-like projections and EMT. Morphological, as well as quantitative differences in YAP levels as well as cell speed across the sheet are consistent with preexisting experimental observations of epithelial sheets grown on topographic features in vitro. The simulation is also consistent with experiments that knockdown or over-express YAP, inhibit Rac1, or block E-cadherin.

SIGNIFICANCE

In normal wound-healing, cell in an epithelium divide, grow, and migrate so as to seal a gap. In some pathological states, epithelial-mesenchymal transition (EMT) can lead to abnormal morphology, including fingering, breakage of single cells or multicellular clusters from the sheet edge. The mechanochemical control of this behaviour by cell signaling circuits (YAP, Rac1, and E-cadherin) reveals how the competition between cell adhesion and cell migration contributes to the process. We use the open-source computational platform Morpheus to investigate a multiscale model for the interactions of the proteins inside cells and the resulting morphology of the cell sheet. Results are consistent with experimental results in the literature.
Trends in Pacific Canadian groundfish stock status
Authors: Anderson Sean C. , Connors Brendan M. , English Philina A. , Forrest Robyn E. , Haigh Rowan , Holt Kendra R.
Published: December 2021

We assembled estimated biomass (B) time series from stock assessments for 24 Pacific Canadian groundfish stocks and modelled average and stock status through 2020 based on biomass relative to each stock’s (1) Limit Reference Point (B/LRP), (2) Upper Stock Reference (B/USR), and (3) biomass at maximum sustainable yield (B/BMSY). The overall mean B/LRP in 2020 was 3.2 (95% credible interval [CI]: 2.6–3.9). The overall mean B/USR and B/BMSY in 2020 was 1.5 (95% CI: 1.3–1.9) and 1.4 (95% CI: 1.1–1.7), respectively. Average stock status declined from 1950 to around 2000 and has remained relatively stable since then. The change around 2000 followed the implementation of ITQs (individual transferable quotas) for the trawl fleet and the commencement of the synoptic trawl surveys. As of their last assessment, four stocks (Strait of Georgia Lingcod [Area 4B], coastwide Bocaccio, and inside and outside Quillback Rockfish) had a greater than 5% probability of being below their LRP (i.e., in the “ critical zone”); Pacific Cod in Area 3CD had a 4.6% probability. Roughly one-third of stocks had a greater than 1 in 4 chance of being below their USR (i.e., in the “ cautious zone”). Conversely, two-thirds of assessed groundfish stocks had a high (>75%) probability of being above the USR (i.e., in the “ healthy zone”).
Milking it for all it’s worth: The effects of environmental enrichment on maternal nurturance, lactation quality, and offspring social behavior
Authors: DeRosa Holly , Caradonna Salvatore G. , Tran Hieu , Marrocco Jordan , Kentner Amanda C.
Published: December 2021

Breastfeeding confers robust benefits to offspring development in terms of growth, immunity, and neurophysiology. Similarly, improving environmental complexity (i.e., environmental enrichment; EE) contributes developmental advantages to both humans and laboratory animal models. However, the impact of environmental context on maternal care and milk quality has not been thoroughly evaluated, nor are the biological underpinnings of EE on offspring development understood. Here, Sprague-Dawley rats were housed and bred in either EE or standard-housed (SD) conditions. EE dams gave birth to a larger number of pups, and litters were standardized and cross-fostered across groups on postnatal day (P)1. Maternal milk samples were then collected on P1 (transitional milk phase) and P10 (mature milk phase) for analysis. While EE dams spent less time nursing, postnatal enrichment exposure was associated with heavier offspring bodyweights. Milk from EE mothers had increased triglyceride levels, a greater microbiome diversity, and a significantly higher abundance of bacterial families related to bodyweight and energy metabolism. These differences reflected comparable transcriptomic changes at the genome-wide level. In addition to changes in lactational quality, we observed elevated levels of cannabinoid receptor 1 in the hypothalamus of EE dams, and sex- and time-dependent effects of EE on offspring social behavior. Together, these results underscore the multidimensional impact of the combined neonatal and maternal environments on offspring development and maternal health. Moreover, they highlight potential deficiencies in the use of “gold standard” laboratory housing in the attempt to design translationally relevant animal models in biomedical research.

Significance Statement

Maternal care quality is different between environmentally enriched (EE) and standard laboratory housed (SD) dams. SD rat dams spend more time nursing their young. This may result in overfeeding which can program offspring neural stress responses. Alternatively, metabolic differences in milk may affect neurodevelopmental outcomes, which are different between EE and SD animals. To test this, we evaluated milk and offspring behavior. Milk from EE dams had elevated triglyceride levels and microbiome diversity. EE offspring had heavier body weights and increased social behavior which was lost with crossfostering into SD housing. These data identify potential deficiencies in the quality of “gold standard” laboratory housing and its impact on the welfare and design of translationally relevant animal models in biomedical research.
High-performance Saccharomyces cerevisiae-based biosensor for heavy metal detection
Authors: Fan Cong , Zhang Danli , Mo Qiwen , Yuan Jifeng
Published: December 2021

Heavy metals, i.e., Cu(II), are harmful to the environment. There is an increasing demand to develop inexpensive detection methods for heavy metals. Here, we developed a yeast biosensor with reduced-noise and improved signal output for potential on-site copper ion detection. The copper-sensing circuit was achieved by employing a secondary genetic layer to control the galactose-inducible (GAL) system in Saccharomyces cerevisiae. The reciprocal control of the Gal4 activator and Gal80 repressor under copper-responsive promoters resulted in a low-noise and ultrasensitive yeast biosensor for the copper ion detection. Furthermore, we developed a betaxanthin-based colorimetric assay, as well as 2-phenylethanol and styrene-based olfactory outputs for the copper ion detection. Notably, our engineered yeast sensor confers a narrow range switch-like behavior, which can give a “yes/no” response when coupled with betaxanthin-based visual phenotype. Taken together, we envision that the design principle established here might be applicable for developing other sensing systems for various chemical detections.

IMPORTANCE

The accumulation of heavy metals in the environment led to an imbalance with environmental and ecological impacts, and there is an increasing demand for inexpensive methods that permit on-site detection of heavy metals. In this study, a yeast biosensor with reduced-noise and improved signal output was developed. We used a betaxanthin-based colorimetric assay for monitoring the copper contamination in water samples, which confers a switch-like behavior with a “yes/no” response. In addition, we also explored the 2-phenylethanol and styrene-based outputs for copper detection, which might be useful for olfactory detection of heavy metals.
Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis
Authors: Heseding Hannah Marie , Jahn Kirsten , Eberlein Christian K. , Wieting Jelte , Maier Hannah B. , Proskynitopoulos Phileas , Glahn Alexander , Bleich Stefan , Frieling Helge , Deest Maximilian
Published: December 2021

Background

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of usually paternally expressed, maternally imprinted genes located on chromosome 15q11-q13. Individuals with PWS display a specific behavioral phenotype and have a higher susceptibility than the general population for certain psychiatric conditions, especially psychosis. An impairment of the oxytocin system has been described in Prader-Willi syndrome, but has not yet been investigated on the epigenetic level. Recent studies have pointed out altered methylation patterns of the oxytocin receptor gene (OXTR) in various psychiatric disorders, including psychosis.

Methods

In this study, we investigated methylation rates of CpG dinucleotides in the promoter region of the oxytocin receptor gene via bisulfite-sequencing using DNA extracted from peripheral blood samples of 31 individuals with PWS and 14 controls matched for age, sex and BMI.

Results

Individuals with PWS show significantly lower methylation in the intron 1 region of the OXTR than neurotypical controls (p=0.012). Furthermore, male PWS subjects with psychosis show significantly lower methylation of the OXTR exon 1 region than those without psychosis (p=0.002). Transcription factor binding site analysis revealed E2F1 as a transcription factor potentially binding to the exon 1 region. E2F1 is physiologically regulated by Necdin, an anti-apoptotic protein whose corresponding gene is located within the PWS locus.

Conclusion

This study provides evidence of a disruption of the Oxytocin system on an epigenetic level in PWS in general and in individuals with PWS and psychosis.
Selection-driven adaptation to the extreme Antarctic environment in the Emperor penguin
Authors: Pirri Federica , Ometto Lino , Fuselli Silvia , Fernandes Flávia A. N. , Ancona Lorena , Le Bohec Céline , Zane Lorenzo , Trucchi Emiliano
Published: December 2021

The eco-evolutionary history of penguins is profoundly influenced by their shift from temperate to cold environments. Breeding only in Antarctica during the winter, the Emperor penguin appears as an extreme outcome of this process, with unique features related to insulation, heat production and energy management. However, whether this species actually diverged from a less cold-adapted ancestor, thus more similar in ecology to its sister species, the King penguin, is still an open question. As the Antarctic niche shift likely resulted in vast changes in selective pressure experienced by the Emperor penguin, the identification and relative quantification of the genomic signatures of selection, unique to each of these sister species, could answer this question. Applying a suite of phylogeny-based methods on 7,651 orthologous gene alignments of seven penguins and 13 other birds, we identified a set of candidate genes showing significantly different selection regimes either in the Emperor or in the King penguin lineage. Our comparative approach unveils a more pervasive selection shift in the Emperor penguin, supporting the hypothesis that its extreme cold adaptation is a derived state from a more King penguin-like ecology. Among the candidate genes under selection in the Emperor penguin, four genes (TRPM8, LEPR, CRB1, and SFI1) were identified before in other cold adapted vertebrates, while, on the other hand, 161 genes can be assigned to functional pathways relevant to cold adaptation (e.g., cardiovascular system, lipid, fatty acid and glucose metabolism, insulation, etc.). Our results show that extreme cold adaptation in the Emperor penguin largely involved unique genetic options which, however, affect metabolic and physiological traits common to other cold-adapted homeotherms.
A comprehensive examination of ACE-2 receptor and prediction of spike glycoprotein and ACE-2 interaction based on in silico analysis of ACE-2 receptor
Authors: Özgentürk Nehir Özdemir , Aktaş Emre
Published: December 2021

ACE-2 receptor plays a vital role not only in the SARS-CoV-induced epidemic but also in some diseases. Studies have been carried out on the interactions of ACE-2-SARS-CoV proteins. However, comprehensive research has not been conducted on ACE2 protein by using bioinformatic tools. The present study especially two places, G104 and L108 points, which are effective in protecting the structure of the ACE-2 protein, play a critical role in the biological functioning of this protein, and play an essential role in determining the chemicalphysical properties of this protein, and play a crucial role for ACE-2 protein-SARS CoV surface glycoprotein, were determined. It was also found that the G104 and L108 regions were more prone to possible mutations or deletions than the other ACE-2 protein regions. Moreover, it was determined that all possible mutations or deletions in these regions affect the chemical-physical properties, biological functions, and structure of the ACE-2 protein. Having a negative GRAVY value, one transmembrane helix, a significant molecular weight, a long-estimated half-life as well as most having unstable are results of G104 and L108 points mutations or deletions. Finally, it was determined that LQQNGSSVLS, which belong to the ACE-2 protein, may play an active role in binding the spike protein of SARS-CoV. All possible docking score results were estimated. It is thought that this study will bring a different perspective to ACE-2 _SARS-CoV interaction and other diseases in which ACE-2 plays an important role and will also be an essential resource for studies on ACE-2 protein.
From Deer-to-Deer: SARS-CoV-2 is efficiently transmitted and presents broad tissue tropism and replication sites in white-tailed deer
Authors: Martins Mathias , Boggiatto Paola M. , Buckley Alexandra , Cassmann Eric D. , Falkenberg Shollie , Caserta Leonardo C. , Fernandes Maureen H.V. , Kanipe Carly , Lager Kelly , Palmer Mitchell V. , Diel Diego G.
Published: December 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) in humans, has a broad host range, and is able to infect domestic and wild animal species. Notably, white-tailed deer (WTD, Odocoileus virginianus), the most widely distributed cervid species in the Americas, were shown to be highly susceptible to SARS-CoV-2 in challenge studies and reported natural infection rates approaching 40% in free-ranging WTD in the U.S. Thus, understanding the infection and transmission dynamics of SARS-CoV-2 in WTD is critical to prevent future zoonotic transmission to humans and for implementation of effective disease control measures. Here, we demonstrated that following intranasal inoculation with SARS-CoV-2, WTD fawns shed infectious virus up to day 5 post-inoculation (pi), with high viral loads shed in nasal and oral secretions. This resulted in efficient deer-to-deer transmission on day 3 pi. Consistent a with lack of infectious SARS-CoV-2 shedding after day 5 pi, no transmission was observed to contact animals added on days 6 and 9 pi. We have also investigated the tropism and sites of SARS-CoV-2 replication in adult WTD. Infectious virus was recovered from respiratory-, lymphoid-, and central nervous system tissues, indicating broad tissue tropism and multiple sites of virus replication. The study provides important insights on the infection and transmission dynamics of SARS-CoV-2 in WTD, a wild animal species that is highly susceptible to infection and with the potential to become a reservoir for the virus in the field.

Author summary

The high susceptibility of white-tailed deer (WTD) to SARS-CoV-2, their ability to transmit the virus to other deer, and the recent findings suggesting widespread SARS-CoV-2 infection in wild WTD populations in the U.S. underscore the need for a better understanding of the infection and transmission dynamics of SARS-CoV-2 in this potential reservoir species. Here we investigated the transmission dynamics of SARS-CoV-2 over time and defined the major sites of virus replication during the acute phase of infection. Additionally, we assessed the evolution of the virus as it replicated and transmitted between animals. The work provides important information on the infection dynamics of SARS-CoV-2 in WTD, an animal species that - if confirmed as a new reservoir of infection - may provide many opportunities for exposure and potential zoonotic transmission of the virus back to humans.
The effect of constraining mediolateral ankle moments and foot placement on the use of the counter-rotation mechanism during walking
Authors: van den Bogaart Maud , Bruijn Sjoerd M. , Spildooren Joke , van Dieën Jaap H. , Meyns Pieter
Published: December 2021

Stability during walking can be maintained by shifts of the Center of Pressure through modulation of foot placement and ankle moments (CoP-mechanism). An additional mechanism to stabilize gait, is the counter-rotation mechanism i.e. changing the angular momentum of segments around the Center of Mass (CoM) to change the direction of the ground reaction force. It is unknown if and how humans use the counter-rotation mechanism to control the CoM during walking and how this interacts with the CoP-mechanism. Thirteen healthy adults walked on a treadmill, while full-body kinematic and force plate data were obtained. The contributions of the CoP and the counter-rotation mechanisms to control the CoM were calculated during steady-state walking, walking on LesSchuh, i.e. constraining mediolateral CoP shifts underneath the stance foot and walking on LesSchuh at 50% of normal step width, constraining both foot placement and ankle mechanisms (LesSchuh50%). A decreased magnitude of within-stride control by the CoP-mechanism was compensated for by an increased magnitude of within-stride control by the counter-rotation mechanism during LesSchuh50% compared to steady-state walking. This suggests that the counter-rotation mechanism is used to stabilize gait when needed. However, the mean contribution of the counter-rotation mechanism over strides did not increase during LesSchuh50% compared to steady-state walking. The CoP-mechanism was the main contributor to the total CoM acceleration. The use of the counter-rotation mechanism may be limited because angular accelerations ultimately need to be reversed and because of interference with other task constraints, such as head stabilization and preventing interference with the gait pattern.
Adaptive strategies under prolonged starvation and role of slow growth in bacterial fitness
Authors: Nandy Pabitra
Published: December 2021

1.

Adaptive evolution has the power to illuminate genetic mechanisms under a pre-defined set of selection factors in a controlled environment. Laboratory evolution of bacteria under long-term starvation has gained importance in recent years because of its ability to uncover adaptive strategies to overcome prolonged nutrient limitation- a condition thought to be encountered often by natural microbial isolates. In this evolutionary paradigm, bacteria are maintained in an energy-restricted environment in the growth phase called as long-term stationary phase or LTSP. This phase is characterized by a stable viable population size and highly dynamic genetic changes. Multiple independent iterations of LTSP evolution experiments have given rise to mutants that are slow-growing compared to the ancestor. Although the antagonistic regulation between rapid growth and stress response is fairly well-known in bacteria (especiallyEscherichia coli), the reason behind the growth deficit of many LTSP-adapted mutants has not been explored in detail. In this review, I revisit the trade-off between growth and stress response and delve into the regulatory mechanisms currently known to control growth under nutrient deficiency. Focusing on the theme of “sigma-factor competition” I try to search for the evolutionary reasoning of slow growth amongst mutants adapted to prolonged starvation. Additionally, I present novel experimental data indicating the dynamics of four such slow-growing variants that evolved during a 30-day long LTSP evolution experiment withEscherichia coli.
Population genomic analysis of the speckled dace species complex (Rhinichthys osculus) identifies three species-level lineages in California
Authors: Su Yingxin , Moyle Peter B. , Campbell Matthew A. , Finger Amanda J. , O’Rourke Sean M. , Baumsteiger Jason , Miller Michael R.
Published: December 2021

The speckled dace (Rhinichthys osculus) is small cyprinid fish that is widespread in the Western USA. Currently treated as a single species, speckled dace consists of multiple evolutionary lineages that can be recognized as species and subspecies throughout its range. Recognition of taxonomic distinctiveness of speckled dace populations is important for developing conservation strategies. In this study, we collected samples of speckled dace from 38 locations in the American West, with a focus on California. We used RAD sequencing to extract thousands of SNPs across the genome from samples to identify genetic differences among seven California populations informally recognized as speckled dace subspecies: Amargosa, Owens, Long Valley, Lahontan, Klamath, Sacramento, and Santa Ana speckled dace. We performed principal component analysis, admixture analysis, estimated pairwise Fst, and constructed a phylogeny to explore taxonomic relationships among these groups and test if these subspecies warrant formal recognition. Our analyses show that the seven subspecies fit into three major lineages equivalent to species: western (Sacramento-Klamath), Santa Ana, and Lahontan speckled dace. Death Valley speckled dace were determined to be two lineages (Amargosa and Long Valley) within Lahontan speckled dace. Western and Lahontan speckled dace lineages had branches that can be designated as subspecies. These designations fit well with the geologic history of the region which has promoted long isolation of populations. This study highlights the importance of genetic analysis for conservation and management of freshwater fishes.
RNA binding protein RBM3 augments kissing loop formation with lncRNAs to enhance translational control
Authors: Sayed Afreen Asif Ali , Choudhury Sonali , Subramaniam Dharmalingam , Gunewardena Sumedha , Ponnurangam Sivapriya , Dandawate Prasad , Tawfik Ossama , Standing David , Padhye Subhash B. , Li Linheng , Iwakuma Tomoo , Umar Shahid , Jensen Roy A. , Thomas Sufi Mary , Anant Shrikant
Published: December 2021

It is becoming apparent that translational regulation involves the coordinated actions of RNA binding proteins (RBPs) and non-coding RNAs. For efficient translation, mRNA needs to be circularized, which is catalyzed by RNA binding proteins and translation factors. However, the role of lncRNAs in the process is not yet defined. We first performed RNA-seq and RNA- immunoprecipitation coupled-Seq and identified LSAMP-3 and Flii-1. Moreover, modeling studies suggest enhanced kissing loop interactions including of transcripts that encode angiogenesis and epithelial mesenchymal transition. While intestinal epithelial cell specific RBM3 transgenic mice showed increased LSAMP-3 and Flii-1, this was reduced in knockout mice. Also, RBM3 overexpression increased tumor xenograft growth, this was suppressed by knockdown of the lncRNAs. Also, knockdown of endogenous RBM3 reduced lncRNA levels and tumor xenograft growth. In addition, it reduced colitis-associated cancers. We propose that RBPs such as RBM3 mediate their function through regulatory lncRNAs that enable circularization to control translation.
Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses
Authors: Sander Anna-Lena , Moreira-Soto Andres , Yordanov Stoian , Toplak Ivan , Balboni Andrea , Ameneiros Ramón Seage , Corman Victor , Drosten Christian , Drexler Jan Felix
Published: December 2021

The furin cleavage site in SARS-CoV-2 is unique within the Severe acute respiratory syndrome–related coronavirus (SrC) species. We re-assessed diverse SrC from European horseshoe bats and reveal molecular determinants such as purine richness, RNA secondary structures and viral quasispecies potentially enabling furin cleavage. Furin cleavage thus likely emerged from the SrC bat reservoir via molecular mechanisms conserved across reservoir-bound RNA viruses, supporting a natural origin of SARS-CoV-2.