bluuebunny/crossref_metadata_2025 huggingface dataset:
High prevalence of an alpha variant lineage with a premature stop codon in ORF7a in Iraq, winter 2020-2021
Authors: Al-Rashedi Nihad A.M , Alburkat Hussein , Hadi Abas O. , Munahi Murad G. , Jasim Ali , Hameed Alaa , Oda Basel Saber , Lilo Kareem Moamin , AlObaidi Laith A.H. , Vapalahti Olli , Sironen Tarja , Smura Teemu
Published: October 2021

Background

Since the first reported case of coronavirus disease 2019 (COVID-19) in China, SARS-CoV-2 has been spreading worldwide. Genomic surveillance of SARS-CoV-2 has had a critical role in tracking the emergence, introduction, and spread of new variants, which may affect transmissibility, pathogenicity, and escape from infection or vaccine-induced immunity. As anticipated, the rapid increase in COVID-19 infections in Iraq in February 2021 is due to the introduction of variants of concern during the second wave of the COVID-19 pandemic.

Aim

To understand the molecular epidemiology of SARS-CoV-2 during the second wave in Iraq (2021),

Method

We sequenced 76 complete SARS-CoV-2 genomes using NGS technology and identified genomic mutations and proportions of circulating variants among these. Also, we performed an in silico study to predict the effect of the truncation of NS7a protein (ORF7a) on its function

Results

We detected nine different lineages of SARS-CoV-2. The B.1.1.7 lineage was predominant (78.9%) from February to May 2021, while only one B.1.351 strain was detected. Interestingly, the phylogenetic analysis showed that multiple strains of the B.1.1.7 lineage clustered closely with those from European countries. A high frequency (88%) of stop codon mutation (NS7a Q62stop) was detected among the B.1.1.7 lineage sequences. In silico analysis of NS7a with Q62stop found that this stop codon had no significant effect on the function of NS7a.

Conclusion

This work provides molecular epidemiological insights into the spread variants of SARS-CoV-2 in Iraq, which are most likely imported from Europe.
Markerless mouse tracking for social experiments
Authors: Le Van Anh , Sterley Toni-Lee , Cheng Ning , Bains Jaideep S. , Murari Kartikeya
Published: October 2021

Automated behavior quantification requires accurate tracking of animals. Simultaneous tracking of multiple animals, particularly those lacking visual identifiers, is particularly challenging. Problems of mistaken identities and lost information on key anatomical features are common in existing methods. Here we propose a markerless video-based tool to simultaneously track two socially interacting mice of the same appearance. It incorporates conventional handcrafted tracking and deep learning based techniques, which are trained on a small number of labeled images from a very basic, uncluttered experimental setup. The output consists of body masks and coordinates of the snout and tail-base for each mouse. The method was tested on a series of cross-setup videos recorded under commonly used experimental conditions including bedding in the cage and fiberoptic or headstage implants on the mice. Results obtained without any human intervention showed the effectiveness of the proposed approach, evidenced by a near elimination of identities switches and a 10% improvement in tracking accuracy over a pure deep-learning-based keypoint tracking approach trained on the same data. Finally, we demonstrated an application of this approach in studies of social behaviour of mice, by using it to quantify and compare interactions between pairs of mice in which some are anosmic, i.e. unable to smell. Our results indicated loss of olfaction impaired typical snout-directed social recognition behaviors of mice, while non-snout-directed social behaviours were enhanced. Together, these results suggest that the hybrid approach could be valuable for studying group behaviors in rodents, such as social interactions.
Endoplasmic Reticulum Chaperone Genes Encode Effectors of Long-Term Memory
Authors: Chatterjee Snehajyoti , Bahl Ethan , Mukherjee Utsav , Walsh Emily N. , Shetty Mahesh Shivarama , Yan Amy L. , Vanrobaeys Yann , Lederman Joseph D. , Giese K. Peter , Michaelson Jacob , Abel Ted
Published: October 2021

The mechanisms underlying memory loss associated with Alzheimer’s disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of a group of genes encoding chaperones that localize to the endoplasmic reticulum (ER), which function to traffic plasticity-related proteins to the cell surface during long lasting forms of synaptic plasticity and memory. Nr4a transcription factors and ER chaperones are linked to ADRD in human samples as well as mouse models, and overexpressing Nr4a1 or the ER chaperone Hspa5 ameliorates the long-term memory deficits in a tau-based mouse model of ADRD, pointing towards novel therapeutic approaches for treating memory loss. Thus, our findings establish protein folding in the ER as a novel molecular concept underlying long-term memory, providing new insights into the mechanistic basis of cognitive deficits in dementia.

One-Sentence Summary

Molecular approaches establish protein folding in the endoplasmic reticulum as a novel molecular concept underlying synaptic plasticity and memory, serving as a switch to regulate protein folding and trafficking, and driving cognitive deficits in neurodegenerative disorders.
Moran Process Version of the Tug-of-War Model: Complex Behavior Revealed by Mathematical Analysis and Simulation Studies
Authors: Bobrowski Adam , Kimmel Marek , Kurpas Monika K. , Ratajczyk Elżbieta
Published: October 2021

Abstract

In a series of publications McFarland and co-authors introduced the tug-of-war model of evolution of cancer cell populations. The model is explaining the joint effect of rare advantageous and frequent slightly deleterious mutations, which may be identifiable with driver and passenger mutations in cancer. In this paper, we put the Tug-of-War model in the framework of a denumerable-type Moran process and use mathematics and simulations to understand its behavior. The model is associated with a time-continuous Markov Chain (MC), with a generator that can be split into a sum of the drift and selection process part and of the mutation process part. Operator semigroup theory is then employed to prove that the MC does not explode, as well as to characterize a strong-drift limit version of the MC which displays “instant fixation” effect, which was an assumption in the original McFarland’s model. Mathematical results are fully confirmed by simulations of the complete and limit versions. They also visualize complex stochastic transients and genealogies of clones arising in the model.
Mining of thousands of prokaryotic genomes reveals high abundance of prophage signals
Authors: López-Leal Gamaliel , Camelo-Valera Laura Carolina , Hurtado-Ramírez Juan Manuel , Verleyen Jérôme , Castillo-Ramírez Santiago , Reyes-Muñoz Alejandro
Published: October 2021

Phages and prophages are one of the principal modulators of microbial populations. However, much of their diversity is still poorly understood. Here, we extracted 33,624 prophages from 13,713 complete prokaryotic genomes in order to explore the prophage diversity and their relationships with their host. Our results reveal that prophages were present in 75% of the genomes studied. In addition, Enterobacterales were significantly enriched in prophages. We also found that pathogens are a significant reservoir of prophages. Finally, we determined that the prophage relatedness and the range of genomic hosts were delimited by the evolutionary relationships of their hosts. On a broader level, we got insights into the prophage population, identified in thousands of publicly available prokaryotic genomes, by comparing the prophage distribution and relatedness between them and their hosts.
First characterisation of antimicrobial susceptibility and resistance of Neisseria gonorrhoeae isolates in Qatar, 2017-2020
Authors: Al-Maslamani Muna , Ibrahim Elmagboul Emad Bashier , Puthiyottil Aslam , Chemaitelly Hiam , Varghese Manoj Kizhakkepeedikayil , Al Romaihi Hamad Eid , Al-Thani Mohamed H. , Khal Abdullatif Al , Unemo Magnus , Abu-Raddad Laith J.
Published: October 2021

Limited data are available regarding antimicrobial resistance in Neisseria gonorrhoeae strains circulating in WHO Eastern Mediterranean Region (EMR). We investigated the antimicrobial susceptibility/resistance of N. gonorrhoeae isolates to five antimicrobials (ceftriaxone, azithromycin, ciprofloxacin, tetracycline, and benzylpenicillin) currently or previously used for gonorrhoea treatment in Qatar, 2017-2020. Minimum inhibitory concentrations (MICs; mg/L) of antimicrobials were determined using Etest on gonococcal isolates collected during January 1, 2017-August 30, 2020 at Hamad Medical Corporation, a national public healthcare provider. During 2017-2020, resistance in isolates from urogenital sites of 433 patients was 64.7% (95% CI: 59.5-69.6%; range: 43.9-78.7%) for ciprofloxacin, 50.7% (95% CI: 45.3-56.1%; range: 41.3-70.4%) for tetracycline, and 30.8% (95% CI: 26.3-35.6%; range: 26.7-35.8%) for benzylpenicillin. Percentage of isolates non-susceptible to azithromycin was 4.1% (95% CI: 2.0-7.4%; range: 2.7-4.8%) and all (100%) isolates were susceptible to ceftriaxone. Two (1.6%) isolates from 2019 and one (2.2%) isolate from 2020 had high-level resistance to azithromycin (MIC≥256 mg/L). Overall, 1.0% (4/418) of isolates had a ceftriaxone MIC of 0.25 mg/L, which is at the ceftriaxone susceptibility breakpoint (MIC≤0.25 mg/L). Treatment with ceftriaxone 250 mg plus azithromycin 1 g can continuously be recommended for gonorrhoea therapy in Qatar. Continued quality-assured gonococcal AMR surveillance is warranted in EMR.
Using a novel echo-marker to identify high mortality risk patients with moderate aortic stenosis
Authors: Chao Chieh-Ju , Agasthi Pradyumma , Barry Timothy , Girardo Marlene , Seri Amith R. , Shanbhag Anusha , Wang Yuxiang , Lester Steven J. , Alsidawi Said , Freeman William K , Naqvi Tasneem Z. , Eleid Mackram , Fortuin David , Sweeney John P. , Pollak Peter , Sabbagh Abdallah El , Sell-Dottin Kristen , Majdalany David , Larsen Carolyn , Holmes David R , Oh Jae K. , Appleton Christopher P. , Arsanjani Reza
Published: October 2021

Background

Recent studies have shown that patients with moderate aortic stenosis and reduced left ventricular ejection fraction may benefit from earlier intervention instead of periodic surveillance. Identifying patients at higher risk is therefore warranted concerning the possibility of expanding aortic valve replacement indication.

Objective

We aim to investigate the usefulness of a novel echo-marker, augmented mean arterial pressure (AugMAP), in identifying high-risk patients with moderate aortic stenosis.

Methods

Adult patients with moderate aortic stenosis (aortic valve area 1.0-1.5 cm2) at Mayo Clinic sites in 1/2010-12/2020 were identified. Baseline demographics, echocardiography, and all-cause mortality data were retrieved. Patients were grouped into higher and lower AugMAP groups using a cutoff of 80 mmHg for analysis. Kaplan-Meier and Cox regression analyses were used to assess the performance of AugMAP.

Results

A total of 4,563 patients with moderate aortic stenosis were included. The mean age was 73.7±12.5 years and 60.5 % were male. The median follow-up was 2.5 years, and 36.0% of patients died. The mean LVEF was 60.1 ± 11.4%, and the mean AugMAP was 99.1 ± 13.1 mmHg. Patients in the lower AugMAP group, with either preserved or reduced LVEF, had significantly worse survival performance (all p< 0.0001). Multivariate Cox regression showed that AugMAP was independently associated with all-cause mortality after adjusting for age, sex, and LVEF (HR: 0.99 per unit increase, 95%CI: 0.978-0.996, p=0.01).

Conclusion

AugMAP is a simple and effective echo-maker beyond LVEF to identify high-risk moderate aortic stenosis patients who may benefit more from earlier intervention.

Condensed abstract

Patients with moderate aortic stenosis and reduced left ventricular ejection fraction may benefit from earlier intervention. We aim to validate the usefulness of a novel echo-marker, augmented mean arterial pressure (AugMAP), in identifying high-risk patients with moderate aortic stenosis. AugMAP can identify patients at higher mortality risk within the first two years after the diagnosis of moderate aortic stenosis, regardless of LVEF. AugMAP was also independently associated with all-cause mortality after adjusting for age, sex, and LVEF. AugMAP is a simple and effective novel echo-maker beyond LVEF to identify high-risk moderate aortic stenosis patients who may benefit from earlier intervention.
Spatiotemporal epidemiology of HIV between 1997 and 2020 in Kerman, Iran
Authors: Mirzaei Hossein , Mirzazadeh Ali , Barooni Mohsen , Ranjbar Ebrahim , Eybpoosh Sana , Sharifi Hamid
Published: October 2021

Objectives: We assessed the epidemiological and spatiotemporal patterns of HIV cases reported between 1997 and 2020 in Kerman, Iran.
Method: We compared the age, gender, modes of transmission, and spatial distribution of newly diagnosed HIV infected people over time (1997-2004, 2005-2012, and 2013-2020). We also mapped the services and spatial distribution for people who were living with HIV in 2020. The nearest neighbor index and kernel density were used to identify the spatial distribution of HIV cases. Chi square for trend, one-sample t-test, and Kruskal Wallis H tests were used to compare the differences over time. Stata 17 and ArcGIS 10.3 were used for HIV surveillance data analysis.
Results: A total of 459 (25.6% women) people were diagnosed with HIV during 1997-2020. The proportion of women (from 9.3% in 1997-2004 to 48.3% in 2013-2020, P < 0.001), those infected with HIV through sexual contacts (from 11.6% in 1997-2004 to 50.3% in 2013-2020, P < 0.001), proportion of HIV infected children under 5 years of age (0.8% in 1997-2004 to 5.4% in 2013-2020, P = 0.01), and mean age at diagnosis among men (from 34.9 in 1997-2004 to 39.8 years in 2013-2020, P = 0.004) significantly increased over time. The mean age at diagnosis among women (34.5 years in 2013-2020), and the proportion who diagnosed with CD4 count <200 (36.2% in 2013-2020) did not change significantly over time. The density map of residents with HIV infection had the highest density in the northern and southern edges of the city in 2005-2012. The HIV clusters in 2020 matched with the locations of fixed and mobile services.
Conclusion: We observed important changes in HIV epidemiology regarding gender, modes of transmission, number of pediatric cases, and density maps over time which should be considered for precise targeting of HIV prevention, treatment, and outreach programs in this city.
Molecular-scale 3D visualisation of the cardiac ryanodine receptor clusters and the molecular-scale fraying of dyads
Authors: Sheard Thomas M. D. , Hurley Miriam E. , Smith Andrew J. , Colyer John , White Ed , Jayasinghe Izzy
Published: October 2021

Clusters of ryanodine receptor calcium channels (RyRs) form the primary molecular machinery in cardiomyocytes. Various adaptations of super-resolution microscopy have revealed intricate details of the structure, molecular composition and locations of these couplons. However, most optical super-resolution techniques lack the capacity for three-dimensional (3D) visualisation. Enhanced Expansion Microscopy (EExM) offers resolution (in-plane and axially) sufficient to spatially resolve individual proteins within peripheral couplons and within dyads located in the interior. We have combined immunocytochemistry and immunohistochemistry variations of EExM with 3D visualisation to examine the complex topologies, geometries and molecular sub-domains within RyR clusters. We observed that peripheral couplons exhibit variable co-clustering ratios and patterns between RyR and the structural protein, junctophilin-2 (JPH2). Dyads possessed sub-domains of JPH2 which occupied the central regions of the RyR cluster, whilst the poles were typically devoid of JPH2 and broader, and likely specialise in turnover and remodelling of the cluster. In right ventricular myocytes from rats with monocrotaline-induced right ventricular failure, we observed hallmarks of RyR cluster fragmentation accompanied by similar fragmentations of the JPH2 sub-domains. We hypothesise that the frayed morphology of RyRs in close proximity to fragmented JPH2 structural sub-domains may form the primordial foci of RyR mobilisation and dyad remodelling.
Population genomics of ancient and modernTrichuris trichiura
Authors: Doyle Stephen R. , Søe Martin Jensen , Nejsum Peter , Betson Martha , Cooper Philip J. , Peng Lifei , Zhu Xing-Quan , Sanchez Ana , Matamoros Gabriela , Fontecha Sandoval Gustavo Adolfo , Cutillas Cristina , Tchuenté Louis-Albert Tchuem , Mekonnen Zeleke , Ame Shaali M. , Namwanje Harriet , Levecke Bruno , Berriman Matthew , Fredensborg Brian Lund , Outzen Kapel Christian Moliin
Published: October 2021

The neglected tropical disease trichuriasis is caused by the whipwormTrichuris trichiura, a soil-transmitted helminth that has infected humans for millennia. Today,T. trichiurainfects as many as 500 million people, predominantly in communities with poor sanitary infrastructure enabling sustained faecal-oral transmission. Using whole-genome sequencing of geographically distributed worms collected from human and other primate hosts, together with ancient samples preserved in archaeologically-defined latrines and deposits dated up to one thousand years old, we present the first population genomics study ofT. trichiura. We describe the continent-scale genetic structure between whipworms infecting humans and baboons relative to those infecting other primates. Admixture and population demographic analyses support a stepwise distribution of genetic variation that is highest in Uganda, consistent with an African origin and subsequent translocation with human migration. Finally, genome-wide analyses between human samples and between human and non-human primate samples reveal local regions of genetic differentiation between geographically distinct populations. These data provide insight into zoonotic reservoirs of human-infectiveT. trichiuraand will support future efforts toward the implementation of genomic epidemiology of this globally important helminth.
Within-generation and transgenerational social plasticity interact during rapid adaptive evolution
Authors: Sturiale Samantha L. , Bailey Nathan W.
Published: October 2021

The role of within-generation phenotypic plasticity (WGP) versus transgenerational plasticity (TGP) during evolutionary adaptation are not well understood, particularly for socially-cued TGP.

We tested how genetics, WGP, and TGP jointly influence expression of fitness traits facilitating adaptive evolution in the field cricketTeleogryllus oceanicus. A male-silencing mutation (“flatwing”) spread to fixation in ca. 50 generations in a Hawaiian cricket population attacked by acoustically-orienting parasitoids. This rapid loss of song caused the social environment to dramatically change.

Juveniles carrying theflatwing(fw) genotype exhibited greater locomotive activity than those carrying thenormal-wing(nw) allele, consistent with genetic coupling of increased locomotion withfw.

Consistent with adaptive WGP, homozygousfwfemales developing in the absence of song showed reduced body condition and reproductive investment at adulthood.

Adult but not juvenile offspring exhibited TGP in response to maternal social environment for structural size, somatic condition, and reproductive investment, whereas adult locomotion and flight was only influenced by WGP. WGP and TGP interacted to shape multiple traits at adulthood, though effect sizes were modest.

Interactions between genetic effects and social plasticity within and across generations are likely to have influenced the evolutionary spread of flatwing crickets. However, interactions among these effects can be complex, and it is notable that TGP manifested most strongly later in development. Our findings stress the importance of evaluating trait plasticity at different developmental stages and across generations when studying phenotypic plasticity’s role in evolution.
Autopolyploid establishment depends on life history strategy and the mating outcomes of clonal architecture
Authors: Van Drunen Wendy E. , Friedman Jannice
Published: October 2021

Polyploidy is a significant component in the evolution of many taxa, particularly plant groups. However, the mechanisms promoting or preventing initial polyploid establishment in natural populations are often unclear. We develop spatially explicit agent-based simulation models to explore how perennial life history and clonal propagation influence the early stages of polyploid establishment. Our models show that polyploid establishment is unlikely among short-lived plants. Polyploids have increased establishment probability when both diploid and polyploid lifespans are long, especially when unreduced gamete production is non-zero. Further, polyploids that combine sexual and clonal reproduction can establish across a wide range of life history strategies. Polyploid genets containing many, far spreading ramets are most successful, but genets with tightly clumped ramets have similar establishment probability when pollen dispersal is local and rates of self-fertilization are high. Clonal architecture has a substantial impact on the spatial structure of the mixed cytotype population during establishment; altering patterns of mating within or between cytotypes, the mechanisms through which polyploid establishment proceeds, and the final composition of the polyploid population after successful establishment. Overall, our findings provide insight into the complex relationship between polyploidy, perenniality, and clonal reproduction, and offer testable predictions for future empirical work.
Readers move their eyes mindlessly using midbrain visuo-motor principles
Authors: Vitu Françoise , Adeli Hossein , Zelinsky Gregory J.
Published: October 2021

Saccadic eye movements rapidly shift our gaze over 100,000 times daily, enabling countless tasks ranging from driving to reading. Long regarded as a window to the mind1and human information processing2, they are thought to be cortically/cognitively controlled movements aimed at objects/words of interest3–10. Saccades however involve a complex cerebral network11–13wherein the contribution of phylogenetically older sensory-motor pathways14–15remains unclear. Here we show using a neuro-computational approach16that mindless visuo-motor computations, akin to reflexive orienting responses17in neonates18–19and vertebrates with little neocortex15,20, guide humans’ eye movements in a quintessentially cognitive task, reading. These computations occur in the superior colliculus, an ancestral midbrain structure15, that integrates retinal and (sub)cortical afferent signals13over retinotopically organized, and size-invariant, neuronal populations21. Simply considering retinal and primary-visual-cortex afferents, which convey the distribution of luminance contrast over sentences (visual-saliency map22), we find that collicular population-averaging principles capture readers’ prototypical word-based oculomotor behavior2, leaving essentially rereading behavior unexplained. These principles reveal that inter-word spacing is unnecessary23–24, explaining metadata across languages and writing systems using only print size as a predictor25–26. Our findings demonstrate that saccades, rather than being a window into cognitive/linguistic processes, primarily reflect rudimentary visuo-motor mechanisms in the midbrain that survived brain-evolution pressure27.
A novel Pan-viral prophylaxis strategy using vaccine adjuvant CAF09b protects against influenza virus infection
Authors: Zimmermann Julie , Schmidt Signe Tandrup , Trebbien Ramona , Cox Rebecca Jane , Zhou Fan , Follmann Frank , Pedersen Gabriel Kristian , Christensen Dennis
Published: October 2021

The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF®09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I related gene expression. When CAF09b was administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although virus was still detectable in the lungs. However, when CAF09b was administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.
Roosting ecology and the evolution of bat landing maneuvers
Authors: Boerma David B. , Swartz Sharon M.
Published: October 2021

Biomechanics is poised at the intersection of organismal form, function, and ecology, and forms a practical lens through which to investigate evolutionary linkages among these factors. We conducted the first evolutionary analysis of bat flight dynamics by examining the phylogenetic patterning of landing mechanics. We discovered that bats perform stereotyped maneuvers that are correlated with landing performance quantified as impact force, and that these are linked with roosting ecology, a critical aspect of bat biology. Our findings suggest that bat ancestors performed simple, four-limbed landings, similar to those performed by gliding mammals, and that more complex landings evolved in association with novel roost types. This explicit connection between ecology and biomechanics presents the opportunity to identify traits that are associated with a locomotor behavior of known ecological relevance, thus laying the foundation for a broader understanding of the evolution of flight and wing architecture in this extraordinarily successful mammalian lineage.
Mitochondrial fission process 1 (MTFP1) controls bioenergetic efficiency and prevents inflammatory cardiomyopathy and heart failure in mice
Authors: Donnarumma Erminia , Kohlhaas Michael , Vimont Elodie , Kornobis Etienne , Chaze Thibault , Giai Gianetto Quentin , Matondo Mariette , Moya-Nilges Maryse , Maack Christoph , Wai Timothy
Published: October 2021

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.
An in-vivo digital atlas of the spatially reliable cerebral vasculature in mice
Authors: Hinz Rukun , Malekzadeh Meriam , Peeters Lore M. , Vanreusel Verdi , Verhoye Marleen , Van der Linden Annemie , Keliris Georgios A.
Published: October 2021

Cerebral vascular abnormalities can have a large impact on brain function and have been frequently detected as a comorbidity in various neuropathologies. The mouse is the most common pre-clinical animal model used to investigate neuropathologies and thus cerebral vascular atlases of this species are indispensable. In particular, an atlas derived from multiple animals and that can address inter-subject variability is still absent. The current study presents a mouse cerebral vascular atlas developed from MR 2D-TOF angiograms acquired from a relatively high number (N=21) of 12 weeks old male C57BL/6 mice. The vascular atlas we present depicts large arteries, veins and sinuses that are more spatially reliable across animals than smaller vessels. The atlas is available for download and contains multiple datasets: i) a cerebral vascular atlas; ii) a digital segmentation of large vessels (arteries and veins); iii) a high resolution T2 anatomical background aligned to the atlas; iv) a skeletonized vascular atlas; and v) a vascular graph model. We suggest that these components provide a very potent analysis tool for mouse fMRI data and that the atlas can be used as a template for multimodal brain imaging studies. To this end, we also demonstrate an explicit application of the atlas for the investigation of vascular influences in resting-state fMRI.
Incorporating Target-Specific Pharmacophoric Information Into Deep Generative Models For Fragment Elaboration
Authors: Hadfield Thomas E. , Imrie Fergus , Merritt Andy , Birchall Kristian , Deane Charlotte M.
Published: October 2021

Despite recent interest in deep generative models for scaffold elaboration, their applicability to fragment-to-lead campaigns has so far been limited. This is primarily due to their inability to account for local protein structure or a user’s design hypothesis. We propose a novel method for fragment elaboration, STRIFE that overcomes these issues. STRIFE takes as input Fragment Hotspot Maps (FHMs) extracted from a protein target, and processes them to provide meaningful and interpretable structural information to its generative model, which in turn is able to rapidly generate elaborations with complementary pharmacophores to the protein. In a large-scale evaluation, STRIFE outperforms existing, structure-unaware, fragment elaboration methods in proposing highly ligand efficient elaborations. In addition to automatically extracting pharmacophoric information from a protein target’s FHM, STRIFE optionally allows the user to specify their own design hypotheses.
Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types
Authors: Shekhar Karthik , Whitney Irene E. , Butrus Salwan , Peng Yi-Rong , Sanes Joshua R.
Published: October 2021

The genesis of broad neuronal classes from multipotential neural progenitor cells has been extensively studied, but less is known about the diversification of a single neuronal class into multiple types. We used single-cell RNA-seq to study how newly-born (postmitotic) mouse retinal ganglion cell (RGC) precursors diversify into ~45 discrete types. Computational analysis provides evidence that RGC type identity is not specified at mitotic exit, but acquired by gradual, asynchronous fate restriction of postmitotic multipotential precursors. Some types are not identifiable until a week after they are generated. Immature RGCs may be specified to project ipsilaterally or contralaterally to the rest of the brain before their type identity has been determined. Optimal transport inference identifies groups of RGC precursors with largely non-overlapping fates, distinguished by selectively expressed transcription factors that could act as fate determinants. Our study provides a framework for investigating the molecular diversification of discrete types within a neuronal class.
Impact of various preservation and storage methods on the viability of mycoplasma field strains isolated in Mali
Authors: Sery Amadou , Sidibe Cheick Abou Kounta , Kone Mamadou , Sacko Bekaye , Awuni Joseph , Amafu William , Niang Mamadou
Published: October 2021

The survival of five mycoplasma strains was studied in different storage media (Mycoplasma complet media without cryopreservative agent, Mycoplasma complete media with addition of horse serum, Mycoplasma complete media with addition of glycerol and lyophilized cultures without stabilizer) under different temperatures (+37°C, +4°C, −20°C, −85°C) during 24 months. Five Mycoplasma strains, Mycoplasma mycoides subsp mycoides (Mmm), Mycoplasma bovis (Mb), Mycoplasma agalactiae (Ma), Mycoplasma gallisepticum (Mg) and Mycoplasma synoviae (Ms) were isolated from various parts of the country. The initial titers of the strains determined by the agar plate count before storage were 42.4×107 UFC/ml (8.6 log UFC/ml) for Mmm strain; 32.4×108 UFC/ml (9.51 log UFC/ml) for M.bovis strain; 12.4×109 UFC/ml (10.09 log UFC/ml) for Ma strain; 2.4×109 UFC/ml (9.38 log UFC/ml) for Mg and 2.8×109 UFC/ml (9.45 log UFC/ml) for Ms strain. After 3 weeks of storage, no viable mycoplasmas were detected in all the conservation media at +37°C and after 3 months of storage at +4°C except for the lyophilized cultures in which an average viability rate of 17.81% was observed. Overall, the mycoplasma strains remained viable at freezing temperatures after 24 months regardless of the storage medium, but with decreasing titers, which was noticeable with mycoplasma complete media, and mycoplasma media with horse serum. Conversely, at −20°C the average viability rates after 24 months of storage were 84.36% (with glycerol) and 90.04% (lyophilized cultures). At −85°C after 24 months of storage, this was 87.98% (with glycerol) and 91.44% (lyophilized cultures). These findings suggest that, in the absence of the lysophylisation process, the addition of glycerol may be recommended for long-term storage of frozen mycoplasma isolates.
Mining transcriptomic data to identifySaccharomyces cerevisiaesignatures related to improved and repressed ethanol production under fermentation
Authors: Sazegari Sima , Niazi Ali , Zinati Zahra , Eskandari Mohammad Hadi
Published: October 2021

Saccharomyces cerevisiaeis known for its outstanding ability to produce ethanol in industry. Identifying the dynamic of gene expression inS. cerevisiaein response to fermentation is required for the establishment of any ethanol production improvement program. The goal of this study was to identify the discriminative genes between improved and repressed ethanol production as well as clarifying the molecular responses to this process through mining the transcriptomic data. Through 11 machine learning based algorithms from RapidMiner employed on available microarray datasets related to yeast fermentation performance under Mg2+and Cu2+supplementation, 172 probe sets were identified by at least 5 AWAs. Some have been identified as being involved in carbohydrate metabolism, oxidative phosphorylation, and ethanol fermentation. Principal component analysis (PCA) and heatmap clustering were also validated the top-ranked selective probe sets. According to decision tree models, 17 roots with 100% performance were identified.OLI1andCYC3were identified as the roots with the best performance, demonstrated by the most weighting algorithms and linked to top two significant enriched pathways including porphyrin biosynthesis and oxidative phosphorylation.ADH5andPDA1are also recognized as differential top-ranked genes that contribute to ethanol production. According to the regulatory clustering analysis,Tup1has a significant effect on the top-ranked target genesCYC3andADH5genes. This study provides a basic understanding of theS. cerevisiaecell molecular mechanism and responses to two different medium conditions (Mg2+and Cu2+) during the fermentation process.
Hybridisation and chloroplast capture between ancient Themeda triandra ecotypes in Australia
Authors: Dunning Luke T. , Oloffson Jill K. , Papadopulos Alexander S.T. , Baleeiro Paulo C. , Ntshangase Sinethemba , Barker Nigel , Jobson Richard W.
Published: October 2021

Ecotypes are distinct populations within a species which are adapted to specific environmental conditions. Understanding how these ecotypes become established, and how they interact when reunited, is fundamental to elucidating how ecological adaptations are maintained. This study focuses on Themeda triandra, a dominant grassland species across Asia, Africa and Australia. It is the most widespread plant in Australia, where it has distinct ecotypes that are usually restricted to either wetter and cooler coastal regions or the drier and hotter interior. We use whole genome sequencing for over 80 Themeda accessions to reconstruct the evolutionary history of T. triandra and related taxa. A chloroplast phylogeny confirms that Australia was colonised by T. triandra twice, with the division between ecotypes predating their arrival in Australia. The nuclear genome provides evidence of gene-flow among the ecotypes, largely restricted to two geographic areas. In northern Queensland there appears to be a hybrid zone with admixed nuclear genomes and shared plastid haplotypes. Conversely, in the cracking claypans of Western Australia, there is cytonuclear discordance with individuals possessing the coastal plastid and interior clade nuclear genomes. This chloroplast capture is potentially a result of adaptive introgression, with selection detected in the rpoC2 gene which is associated with water use efficiency. A stable hybrid zone in the east, and the displacement of one ecotype in the west, highlights the unpredictable nature of hybrid zones, with repeated contacts between the same ecotypes producing different outcomes.
Unlocking the functional potential of polyploid yeasts
Authors: Mozzachiodi Simone , Krogerus Kristoffer , Gibson Brian , Nicolas Alain , Liti Gianni
Published: October 2021

Breeding and domestication have generated widely exploited crops, animals and microbes. However, many Saccharomyces cerevisiae industrial strains have complex polyploid genomes and are sterile, preventing genetic improvement strategies based on breeding. Here, we present a novel strain improvement approach based on the budding yeasts’ property to promote genetic recombination when meiosis is interrupted and cells return-to-mitotic-growth (RTG). We demonstrated that two unrelated sterile industrial strains with complex triploid and tetraploid genomes were RTG-competent and developed a visual screening for easy and high-throughput identification of recombined RTG clones based on colony phenotypes. Sequencing of the evolved clones revealed unprecedented levels of RTG-induced genome-wide recombination. We generated and extensively phenotyped a RTG library and identified clones with superior biotechnological traits. Thus, we propose the RTG-framework as a fully non-GMO workflow to rapidly improve industrial yeasts that can be easily brought to the market.
Effects of Oncohistone Mutations and PTM Crosstalk on the N-terminal Acetylation Activities of NatD
Authors: Ho Yi-Hsun , Huang Rong
Published: October 2021

Acetylation at the α-N-terminus (Nα) is one of the most abundant modifications detected on histone H4 and H2A, which is catalyzed by N-terminal acetyltransferase D (NatD). NatD substrate recognition motif, N-terminal SGRGK, is enriched with frequent oncohistone mutations and post-translational modifications (PTMs). However, there is no information on how oncohistone mutations and other PTMs affect NatD-catalyzed acetylation. Herein, we determined how changes of local chemical environment on the N-terminal SGRGK sequence regulate NatD-catalyzed Nα acetylation on histone H4/H2A. Our studies indicate that all oncohistone mutations at SGRG suppressed the catalytic efficiency of NatD. Meanwhile, H4 serine 1 phosphorylation and arginine 3 methylation also negatively affect the NatD activity, but the lysine 5 acetylation has a marginal effect on NatD. This work reveals the impacts of oncohistone mutations on NatD activity and unravels the crosstalk between NatD and PTMs. To our knowledge, this is the first report on the potential regulatory mechanism of NatD, highlighting different revenues to interrogate the NatD-mediated pathway in the future.
Structural analysis of the lncRNA SChLAP1 reveals protein binding interfaces and a conformationally heterogenous retroviral insertion
Authors: Falese James P. , McFadden Emily J. , D’Inzeo Christopher A. , Hargrove Amanda E.
Published: October 2021

The lncRNA Second Chromosome Locus Associated with Prostate 1 (SChLAP1) was previously identified as a predictive biomarker and potential driver of aggressive prostate cancer. Recent work suggests that SChLAP1 may bind the SWI/SNF chromatin remodeling complex to promote prostate cancer metastasis, though the exact role of SWI/SNF recognition is debated. To date, there are no detailed biochemical studies ofapoSChLAP1 or SChLAP1:protein complexes. Herein, we report the first secondary structure model of SChLAP1 using SHAPE-MaPinvitro,in cellulo, andex cellulo(protein-free). Comparison of theex celluloandin cellulodata via ΔSHAPE identified putative protein binding sites within SChLAP1. In addition, we identified primate conserved exons of SChLAP1 as well as regions that appear to have been incorporated through retroviral insertion. In particular, we characterized a complex structural landscape in a protein binding region at the 3′—end of SChLAP1 derived from a THE1B-type retroviral insertion, suggesting a role for an exapted RNA structure in SChLAP1:protein recognition and prostate cancer progression. This work lays the foundation for future efforts to selectively target and disrupt the SChLAP1:protein interface and to develop new therapeutic avenues in prostate cancer treatment.
Non-monotonic fibril surface occlusion by GFP tags from coarse-grained molecular simulations
Authors: Shillcock Julian C. , Hastings Janna , Riguet Nathan , Lashuel Hilal
Published: October 2021

The pathological growth of amyloid fibrils in neurons underlies the progression of neurodegenerative diseases including Alzheimer’s and Parkinson’s disease. Fibrils form when soluble monomers oligomerise in the cytoplasm. Their subsequent growth occurs via nucleated polymerization mechanisms involving the free ends of the fibrils augmented by secondary nucleation of new oligomers at their surface. Amyloid fibrils possess a complex interactome with diffusing cytoplasmic proteins that regulates many aspects of their growth, seeding capacity, biochemical activity and transition to pathological inclusions in diseased brains. Changes to their surface are also expected to modify their interactome, pathogenicity and spreading in the brain. Many assays visualise fibril formation, growth and inclusion formation by decorating monomeric proteins with fluorescent tags such as GFP. Recent studies from our group suggest that tags with sizes comparable to the fibril radius may modify the fibril surface accessibility and thus their PTM pattern, interactome and ability to form inclusions. Using coarse-grained molecular simulations of a single alpha synuclein fibril tagged with GFP we find that thermal fluctuations of the tags create a non-monotonic, size-dependent sieve around the fibril that perturbs its interactome with diffusing species. Our results indicate that experiments using tagged and untagged monomers to study the growth and interactome of fibrils should be compared with caution, and the confounding effects of the tags are more complex than a reduction in surface accessibility. The prevalence of fluorescent tags in amyloid fibril growth experiments suggests this has implications beyond the specific alpha synuclein fibrils we model here.
Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
Authors: Muto Yoshiharu , Dixon Eryn E. , Yoshimura Yasuhiro , Wu Haojia , Omachi Kohei , King Andrew J. , Olson Eric N. , Gunawan Marvin G. , Kuo Jay J. , Cox Jennifer , Miner Jeffrey H. , Seliger Stephen L. , Woodward Owen M. , Welling Paul A. , Watnick Terry J. , Humphreys Benjamin D.
Published: October 2021

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease and is characterized by the formation and progressive expansion of kidney cysts. Most ADPKD cases arise from mutations in either the PKD1 or PKD2 gene but the precise downstream signaling pathways driving cyst growth are not well understood, and relatively few studies investigate human cystic kidney due to sample scarcity. In order to better understand the cell types and states driving human ADPKD progression, we analyzed eight ADPKD and five healthy human kidney samples, generating a single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. The integrated datasets identified 11 primary cell clusters including most epithelial cell types as well as large endothelial and fibroblast cell clusters. Proximal tubular cells from ADPKD kidneys expressed a failed repair transcriptomic signature characterized by profibrotic and proinflammatory transcripts. We identified the G protein-coupled receptor GPRC5A as specifically upregulated in cyst lining cells derived from collecting duct. The principal cell subpopulation enriched for GPRC5A expression also exhibited increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptor families and we identified and validated a distal enhancer regulating GPRC5A expression containing these transcription factor binding motifs. This study establishes the single cell transcriptomic and epigenomic landscape of ADPKD, revealing previously unrecognized cellular heterogeneity.
Thalamus drives active dendritic computations in cortex
Authors: Bast Arco , Guest Jason M. , Fruengel Rieke , Narayanan Rajeevan T. , de Kock Christiaan P.J. , Oberlaender Marcel
Published: October 2021

Perception is linked to a calcium-dependent dendritic spiking mechanism that enables the major output cells of the cerebral cortex – layer 5 pyramidal tract neurons – to combine inputs from different information streams. Which circuits activate this mechanism upon sensory input is unclear. Here we found that thalamocortical axons, which provide sensory input to cortex, target specifically the dendritic domains in pyramidal tract neurons that initiate calcium spikes. Sensory input thereby enables distal dendritic inputs preceding the stimulus to transform the first responses that leave cortex into bursts of action potentials. Thus, thalamus can drive active dendritic coupling of sensory with prestimulus information streams to modulate cortical output. Our findings indicate that thalamocortical coupling is first in a cascade of mechanisms that transform sensory input into perception.