bluuebunny/crossref_metadata_2025 huggingface dataset:
Sampling globally and locally correct RNA 3D structures using ERNWIN, SPQR and experimental SAXS data
Authors: Thiel Bernhard C. , Bussi Giovanni , Poblete Simón , Hofacker Ivo L.
Published: July 2022

The determination of the three-dimensional structure of large RNA macromolecules in solution is a challenging task that often requires the use of several experimental and computational techniques. Small-angle X-ray spectroscopy can provide insight into some geometrical properties of the probed molecule, but this data must be properly interpreted in order to generate a three-dimensional model. Here, we propose a multiscale pipeline which introduces SAXS data into modelling the global shape of RNA in solution, which can be hierarchically refined until reaching atomistic precision in explicit solvent. The low-resolution helix model (ERNWIN) deals with the exploration of the huge conformational space making use of the SAXS data, while a nucleotide-level model (SPQR) removes clashes and disentangles the proposed structures, leading the structure to an all-atom representation in explicit solvent. We apply the procedure on five different structures up to 126 nucleotides with promising results.
Basic reproduction number projection for novel pandemics and variants. Ancestral SARS-CoV2 R0 projection
Authors: Benjamin Ryan L
Published: July 2022

The recently derived Hybrid-Incidence Susceptible-Transmissible-Removed (HI-STR) prototype is a deterministic epidemic compartment model and an alternative to the Susceptible-Infected-Removed (SIR) model prototype. The HI-STR predicts that pathogen transmission depends on host population characteristics including population size, population density and some common host behavioural characteristics.

The HI-STR prototype is applied to the ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) to show that the original estimates of the Coronavirus Disease 2019 (COVID-19) basic reproduction number ($\mathcal{R}_0$) for the United Kingdom (UK) could have been projected on the individual states of the United States of America (USA) prior to being detected in the USA.

The Imperial College London (ICL) R0 estimate for the UK is projected onto each USA state. The difference between these projections and ICL estimates for USA states is either not statistically significant on the paired student t-test or epidemiologically insignificant.

Projection provides a baseline for evaluating the real-time impact of an intervention. Sensitivity analysis was conducted because of considerable variance in parameter estimates across studies. Although the HI-STR predicts that increasing symptomatic ratio and inherently immune ratio reduce R0, relative to the uncertainty in the estimates of R0 for the ancestral SARS-CoV2, the projection is insensitive to the inherently immune ratio and the symptomatic ratio.
Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission
Authors: Cuhadar Ulku , Calzado-Reyes Lorenzo , Pascual-Caro Carlos , Aberra Aman S. , Ritzau-Jost Andreas , Aggarwal Abhi , Ibata Keiji , Podgorski Kaspar , Yuzaki Michisuke , Geis Christian , Hallerman Stefan , Hoppa Michael B. , de Juan-Sanz Jaime
Published: July 2022

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how the landscape of trans-synaptic bridges dynamically remodels to reflect functional states of the synapse. Here we developed novel optical tools to visualize in firing synapses the molecular behavior of a particular secreted trans-synaptic protein, LGI1, and its presynaptic receptor, ADAM23, and discovered that neuronal activity acutely rearranges the abundance of these proteins at the synaptic cleft. Surprisingly, LGI1 in synapses was not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitated the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Thus, our findings reveal that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical point of activity-dependent control of synaptic function.

Highlights

– Neuronal activity translocates LGI1 and ADAM23 to the presynaptic surface

– LGI1 and ADAM23 are not located in synaptic vesicles

– Stable cleft localization of LGI1 depends on the history of synaptic activity

– LGI1 abundance at the synaptic cleft controls glutamate release
CHILDHOOD DEATHS, DEPRIVATION, AND MODIFIABLE FACTORS: FINDINGS FROM THE NATIONAL CHILD MORTALITY DATABASE
Authors: Odd David , Stoianova Sylvia , Williams Tom , Odd Dawn , Kurinczuk Jennifer J , Wolfe Ingrid , Luyt Karen
Published: July 2022

Objectives

The aim of this analysis is to identify and report the patterns of social deprivation in relation to childhood mortality; and identify potential points where public health, social and education interventions or health policy may be best targeted.

Design

Decile of deprivation and underlying population distribution was derived using Office for National Statistics (ONS) data. The risk of death was then derived using a Poisson regression model, calculating the increasing risk of death for each increasing deprivation decile.

Setting

England

Participants

2688 childhood deaths in England reviewed between the April 2019 and March 2020.

Main Outcome Measures

The relationship between deprivation and risk of death; for deaths with, and without modifiable factors.

Results

There was evidence of increasing mortality risk with increase in deprivation decile (RR 1.08 (1.07 to 1.10)), with the gradient of risk stronger in children who died with modifiable factors than those without (RR 1.12 (1.09 to 1.15)) vs (RR 1.07 (1.05 to 1.08)). Deprivation sub-domains of Employment, Adult Education, Barriers to Housing and Services, and Indoor Living Environments appeared to be the most important predictors of child mortality

Conclusions

There is a clear gradient of increasing child mortality across England as measures of deprivation increase; with a striking finding that this varied little by area, age or other demographic factor. Over a fifth of all child deaths may be avoided if the most deprived half of the population had the same mortality as the least deprived. Children dying in more deprived areas may have a greater proportion of avoidable deaths. Adult employment and education, and improvements to housing, may be the most efficient place to target resources to reduce these inequalities.
Effects of Physical Exercises on Emotion Regulation: A Meta-Analysis
Authors: Liu Jie , Gao Shuqing , Zhang Liancheng
Published: July 2022

Background

At present, there are inconsistent results in the research on the effect of physical exercise on emotion regulation ability, and there is no relevant research on how to exercise scientificlc. Therefore, on the basis of previous research, this study conducted a meta-analysis on the theme of physical exercise affecting emotion regulation ability according to the statement of PRISMA, and added relevant moderator variables to clarify the effect of physical exercise on emotion regulation ability.

Objective

We identified physical exercise studies and randomized controlled trials (RCTs) of emotion regulation ability that reported overall effect, heterogeneity, and publication bias of physical exercises on emotion regulation ability.

Methods

We searched for RCT s of exercise interventions on emotion regulation ability from databases including PubMed, Web of Science, Ebsco, The Cochrane Library, CNKI (China National Knowledge Infrastructure), and Wanfang, from January 1 2000 to January 1 2022. We performed methodological quality evaluations on the included literature and graded evidence with a meta-analysis using Review Manager 5.3 software.

Results

In total, 10 RCT s were included; the overall results of the meta-analysis (936participants) indicated that physical exercises improved emotion regulation ability (standardized mean difference (SMD) = 0.47; 95% confidence interval (CI) 0.21 to 0.72; p < 0.05), sensory arousal ability (SMD = 0.70; 95% CI 0.14 to 1.27; p < 0.05), and emotion regulation strategies (SMD = 0.46; 95% CI 0.04 to 0.87; p < 0.05); Subgroup analysis showed that a single exercise of more than 30 minutes can improve emotional regulation ability, which is not affected by exercise intensity, period and the health status of the participants.

Conclusion

Physical exercises can effectively improve the emotion regulation ability. The effects are considered as moderate effect sizes. While single exercise time should be at least 30 minutes.Limited by the quantity and quality of the included studies, the above conclusions need to be verified with more high-quality studies.

PROSPERO registration number: CRD42021217978
Efficacy of Anakinra in the Management of Patients with COVID-19 Infection: A Randomized Clinical Trial
Authors: Elmekaty Eman Zeyad I. , Maklad Aya , Abouelhassan Rawan , Munir Waqar , Mohamed Ibrahim Mohamed Izham , Nair Arun , Alibrahim Rim , Iqbal Fatima , Bishawi Ahmad Al , Abdelmajid Alaaeldin , Aboukamar Mohamed , Khattab Mohammed Abu , Soub Hussam Al , Maslamani Muna Al
Published: July 2022

Background

The global pandemic of COVID-19 infections continues to grow worldwide, with rising number of deaths day by day. The hyperinflammation state contributes to the multiorgan failure associated with COVID-19 infections. This study aims to explore the efficacy and safety of anakinra in COVID-19 patients with both respiratory distress and cytokine release syndromes.

Methods

This was an open-label, multicenter, randomized clinical trial. Patients were randomized in 1:1 ratio to receive standard of care (SOC) alone, or anakinra plus SOC. Adults with confirmed COVID-19 infection with evidence of both respiratory distress and cytokine release syndrome were included. The primary outcome was treatment success at day 14, defined as WHO clinical progression score of ≤3. The primary analysis was based on intention-to-treat population, with p-value of <0.05.

Results

A total of 80 patients were enrolled in the study. The mean age was 49.9 years (SD=11.7), with 82.5% (n=66) male patients. The primary outcome was not statistically different (87.5% (n=35) in anakinra group vs. 92.5% (n=37) in SOC group, p=0.712). The majority of reported adverse events were mild in severity and not related to the study treatment. Increased aspartate aminotransferase was the only significant adverse event (35% (n=14) in anakinra group vs. 15% (n=6) in SOC group, p=0.039); yet, was not associated with treatment discontinuation.

Conclusion

In patients with severe COVID-19 infection, the addition of anakinra to SOC treatment was not associated with significant improvement in the WHO clinical progression scale. Further studies investigating patients’ subgroups that might benefit from anakinra are warranted. The trial was registered at ClinicalTrials.gov (NCT04643678).
Phylogeny analysis of whole protein-coding genes in metagenomic data detected an environmental gradient for the microbiota
Authors: Satoh Soichirou , Tanaka Rei , Yokono Makio , Endoh Daiji , Yabuki Tetsuo , Tanaka Ayumi
Published: July 2022

Environmental factors affect the growth of microorganisms and therefore alter the composition of microbiota. Correlative analysis of the relationship between metagenomic composition and the environmental gradient can help elucidate key environmental factors and establishment principles for microbial communities. However, a reasonable method to quantitatively compare whole metagenomic data and identify the primary environmental factors for the establishment of microbiota has not been reported so far. In this study, we developed a method to compare whole proteomes deduced from metagenomic shotgun sequencing data, and quantitatively display their phylogenetic relationships as metagenomic trees. We called this method Metagenomic Phylogeny by Average Sequence Similarity (MPASS). We also compared one of the metagenomic trees with dendrograms of environmental factors using a comparison tool for phylogenetic trees. The MPASS method correctly constructed metagenomic trees of simulated metagenomes and soil and water samples. The topology of the metagenomic tree of samples from the Kirishima hot springs area in Japan was highly similarity to that of the dendrograms based on previously reported environmental factors for this area. The topology of the metagenomic tree also reflected the dynamics of microbiota at the taxonomic and functional levels. Our results strongly suggest that MPASS can successfully classify metagenomic shotgun sequencing data based on the similarity of whole protein-coding sequences, and will be useful for the identification of principal environmental factors for the establishment of microbial communities.
Development of amidase-dependent pyrazinoic acid prodrugs with activity against pyrazinamide resistant Mycobacterium tuberculosis
Authors: Levine Carly , Jadhav Ravindra , Pan Yan , Tsotetsi Kholiswa , Wang Xin , Awasthi Divya , Grady Courtney , Shelke Anil , Daher Samer S. , Richmann Todd , Shrestha Riju , Sukheja Paridhi , Patel Jimmy , Barnett Pamela R. , Dikdan Ryan J. , Kim Thomas , Russo Riccardo , Hanna Jennifer , Zimmerman Matthew , Dartois Véronique , Freundlich Joel S. , Alland David , Kumar Pradeep
Published: July 2022

Rapid emergence of drug resistance in Mycobacterium tuberculosis (Mtb) is one of the most significant healthcare challenges of our time. The cause of drug resistance is multifactorial, with the long course anti-tubercular therapy required to treat tuberculosis (TB) constituting a major contributing factor. Introduction of pyrazinamide (PZA) resulted in shortening of TB treatment from twelve to six months and consequently played a critical role in curbing drug resistance that developed over long course therapy. Nevertheless, because PZA is a prodrug activated by a nonessential amidase, PncA, resistance to PZA develops and frequently results in treatment failure. Here, we leveraged a whole cell drug screening approach to identify anti-tuberculars with unconventional mechanisms of action or activation that could be further developed into compounds effective at killing Mtb resistant to PZA. We discovered an amide containing prodrug, DG160, that was activated by the amidase, Rv2888c (AmiC). This amidase was capable of metabolizing a variety of amide containing compounds including a novel pyrazinoic acid-isoquinolin-1-amine prodrug, JSF-4302, which we developed as a potential PncA-independent replacement for PZA. As predicted, AmiC activation of JSF-4302 led to the generation of POA in Mtb including in a PZA resistant clinical isolate, thereby successfully delivering the active component of PZA while bypassing the need for activation by PncA. This work provides a framework for a new approach to drug development and prodrug activation in Mtb.

SIGNIFICANCE

Pyrazinamide (PZA) is a vital component of Mycobacterium tuberculosis (Mtb) treatment since its inclusion shortened tuberculosis therapy by six months. However, PZA is a prodrug and resistance develops at a high frequency due to mutations in its activator PncA. Here, we present the discovery of amide-containing anti-tubercular prodrugs that are activated intracellularly by the Mtb amidase, AmiC. Taking advantage of this finding, we successfully designed and synthesized pyrazinoic acid (POA) prodrugs that were activated by AmiC and found that these compounds delivered intracellular POA to PZA- resistant Mtb isolates that contained a nonfunctional PncA. This new approach to prodrug development provides a method for delivering conjugated drugs into Mtb with the potential to overcome clinical drug resistance.
Adaptive delayed feedback control disrupts unwanted neuronal oscillations and adjusts to network synchronization dynamics
Authors: de Castro Domingos Leite , Aroso Miguel , Aguiar A. Pedro , Grayden David B. , Aguiar Paulo
Published: July 2022

Adaptive neuronal stimulation has a strong therapeutic potential for neurological disorders such as Parkinson’s disease and epilepsy. However, standard stimulation protocols mostly rely on continuous open-loop stimulation. We implement here, for the first time in neuronal populations, two different Delayed Feedback Control (DFC) algorithms and assess their efficacy in disrupting unwanted neuronal oscillations. DFC is a well-established closed-loop control technique but its use in neuromodulation has been limited so far to models and computational studies. Leveraging on the high spatiotemporal monitoring capabilities of specialized in vitro platforms, we show that standard DFC in fact worsens the neuronal population oscillatory behaviour and promotes faster bursting, which was never reported in silico. Alternatively, we present adaptive DFC (aDFC) that monitors ongoing oscillation periodicity and self-tunes accordingly. aDFC disrupts collective neuronal oscillations and decreases network synchrony. Furthermore, we show that the intrinsic population dynamics have a strong impact in the susceptibility of networks to neuromodulation. Experimental data was complemented with computer simulations to show how this network controllability might be determined by specific network properties. Overall, these results support aDFC as a better candidate for therapeutic neurostimulation and provide new insights regarding the controllability of neuronal systems.
Reciprocal recurrent selection based on genetic complementation: An efficient way to build heterosis in diploids due to directional dominance
Authors: Covarrubias-Pazaran Giovanny , Werner Christian , Gemenet Dorcus
Published: July 2022

Depending on the trait architecture and reproduction system, selection strategies in plant breeding focus on the accumulation of additive, dominance effects, or both. Innovation in the accumulation of dominance-effect-based heterosis has been limited since the proposal of GCA-based approaches and very few strategies to exploit it better have been proposed. We propose the use of a new surrogate of genetic complementation between genetic pools to increase accumulation of dominance effects and heterosis. We simulated breeding programs to show how reciprocal recurrent selection by genetic complementation would build the dominance-based heterosis but cheaper than GCA-based approaches and used real phenotypic data from hybrid maize to demonstrate the underlying concepts. We found reciprocal recurrent selection by genetic complementation to be an attractive and viable strategy to exploit dominance, build de novo heterotic pools and boost the current GCA-based approaches. If demonstrated in practice, we hypothesized that this approach would lower the cost of breeding drastically and contribute to food security.

Key message

Heterotic patterns can be developed quickly through genetic complementation surrogates to produce high-performance hybrids at a low cost in diploid species displaying dominance and boost GCA-based approaches in hybrid breeding.
Land-use preferences of the European green toad (Bufotes viridis) in the city of Vienna (Austria): the importance of open land in urban environments
Authors: Landler Lukas , Burgstaller Stephan , Schweiger Silke
Published: July 2022

Urban areas are increasing worldwide, which poses treats to animal wildlife. However, in certain cases cities can provide refuges for endangered animals. The European green toad (Bufotes viridis) is one of such examples, which is known from cities throughout their distribution. In contrast, considerable areas of their former (primary) habitats have been degraded. The primary habitats of this species include steppes and wild river floodplains, both characterized by dynamic changes and the presence of open areas. We used available green toad observation data (2007-2020) to model the effects of land-use types on occurrence probability in the city of Vienna. Forest and densely populated areas were highly significantly negatively associated with green toad presence, while transformation/construction site areas showed a strong positive effect. Such occurrence pattern might be characteristic for early succession species, which depend on stochastic environmental disturbances (e.g., droughts and floods) in their primary habitats. We argue that urban landscape planning should appreciate the potential ecological value of open land in cities which is either in a transition phase or a permanent wasteland. Ecological managing of such landscape could vastly increase urban biodiversity.
Uncertainty alters the balance between incremental learning and episodic memory
Authors: Nicholas Jonathan , Daw Nathaniel D. , Shohamy Daphna
Published: July 2022

A key question in decision making is how humans arbitrate between competing learning and memory systems to maximize reward. We address this question by probing the balance between the effects, on choice, of incremental trial-and-error learning versus episodic memories of individual events. Although a rich literature has studied incremental learning in isolation, the role of episodic memory in decision making has only recently drawn focus, and little research disentangles their separate contributions. We hypothesized that the brain arbitrates rationally between these two systems, relying on each in circumstances to which it is most suited, as indicated by uncertainty. We tested this hypothesis by directly contrasting contributions of episodic and incremental influence to decisions, while manipulating the relative uncertainty of incremental learning using a well-established manipulation of reward volatility. Across two large, independent samples of young adults, participants traded these influences off rationally, depending more on episodic information when incremental summaries were more uncertain. These results support the proposal that the brain optimizes the balance between different forms of learning and memory according to their relative uncertainties and elucidate the circumstances under which episodic memory informs decisions.
Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors
Authors: Fink Elissa A. , Bardine Conner , Gahbauer Stefan , Singh Isha , White Kris , Gu Shuo , Wan Xiaobo , Ary Beatrice , Glenn Isabella , O’Connell Joseph , O’Donnell Henry , Fajtová Pavla , Lyu Jiankun , Vigneron Seth , Young Nicholas J. , Kondratov Ivan S. , O’Donoghue Anthony J. , Moroz Yurii , Taunton Jack , Renslo Adam R. , Irwin John J. , García-Sastre Adolfo , Shoichet Brian K. , Craik Charles S.
Published: July 2022

Antiviral therapeutics to treat SARS-CoV-2 are much desired for the on-going pandemic. A well-precedented viral enzyme is the main protease (MPro), which is now targeted by an approved drug and by several investigational drugs. With the inevitable liabilities of these new drugs, and facing viral resistance, there remains a call for new chemical scaffolds against MPro. We virtually docked 1.2 billion non-covalent and a new library of 6.5 million electrophilic molecules against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 μM and 20 μM, respectively. Several series were optimized, resulting in inhibitors active in the low micromolar range. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. Together, these compounds reveal new chemotypes to aid in further discovery of MPro inhibitors for SARS-CoV-2 and other future coronaviruses.
Human-specific progenitor sub-domain contributes to extended neurogenesis and increased motor neuron production
Authors: Jang Sumin , Gunmit Elias , Wichterle Hynek
Published: July 2022

Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in >1000-fold more neurons in the human central nervous system. Expansion of human neocortex has been in part attributed to the population of outer radial glia and amplifying progenitors that increase the output of neurogenic lineages. However, outer radial glia appear to be absent in many regions of the developing human nervous system, prompting us to search for alternative populations of progenitors that contribute to the expansion of human neurogenesis in one such region - the developing spinal cord. To this end, we performed high-temporal resolution single-cell expression analysis of human and mouse motor neuron progenitors generated from pluripotent stem cells in vitro. Alignment of human and mouse data using canonical correlation analysis identified “human-specific” progenitor clusters characterized by early co-expression of NKX2-2 and OLIG2 that lacked an orthologous murine counterpart. A matching progenitor population has been previously described in the human embryonic spinal cord1, but its function remained unknown. Our lineage tracing analysis demonstrates that these cells function as ventral motor neuron progenitors (vpMNs), but in contrast to classical pMNs, vpMNs exhibit increased Notch activity and generate motor neurons in a delayed and protracted manner. Concomitantly, vpMNs undergo more rounds of cell division before undergoing neurogenesis, leading to ~2-fold increase in total motor neuron output, and contributing preferentially to later-born, limb-innervating motor neuron subtypes. Thus, instead of relying on transit-amplifying progenitors, human spinal cord evolved a novel progenitor subdomain that extends timescales and expands output of human motor neurogenesis.
Beyond sequence similarity: cross-phyla protein annotation by structural prediction and alignment
Authors: Ruperti Fabian , Papadopoulos Nikolaos , Musser Jacob , Mirdita Milot , Steinegger Martin , Arendt Detlev
Published: July 2022

Background

Annotating protein function is a major goal in molecular biology, yet experimentally determined knowledge is often limited to a few model organisms. In non-model species, the sequence-based prediction of gene orthology can be used to infer function, however this approach loses predictive power with longer evolutionary distances. Here we propose a pipeline for the functional annotation of proteins using structural similarity, exploiting the fact that protein structures are directly linked to function and can be more conserved than protein sequences.

Results

We propose a pipeline of openly available tools for the functional annotation of proteins via structural similarity (MorF:MorphologFinder) and use it to annotate the complete proteome of a sponge. Sponges are highly relevant for inferring the early history of animals, yet their proteomes remain sparsely annotated. MorF accurately predicts the functions of proteins with known homology in>90% cases, and annotates an additional 50% of the proteome beyond standard sequence-based methods. Using this, we uncover new functions for sponge cell types, including extensive FGF, TGF and Ephrin signalling in sponge epithelia, and redox metabolism and control in myopeptidocytes. Notably, we also annotate genes specific to the enigmatic sponge mesocytes, proposing they function to digest cell walls.

Conclusions

Our work demonstrates that structural similarity is a powerful approach that complements and extends sequence similarity searches to identify homologous proteins over long evolutionary distances. We anticipate this to be a powerful approach that boosts discovery in numerous -omics datasets, especially for non-model organisms.
High-order thalamic and motor cortex inputs integrate sublinearly into tuft dendrites of pyramidal neurons in mouse somatosensory cortex
Authors: Han Young-Eun , Choi Joon Ho , Kim Kyungsoo , Kang Seongtak , Park Hyungju , Choi Ji-Woong , Rah Jong-Cheol
Published: July 2022

Tuft dendrites of pyramidal neurons housed in layer 1 of the neocortex form extensive excitatory synaptic connections with long-range cortical and high-order thalamic axons, along with diverse inhibitory inputs. Recently, we reported that synapses from the vibrissal primary motor cortex (vM1) and posterior medial thalamic nucleus (POm) are spatially clustered together in the same set of distal dendrites, suggesting a close functional interaction. In this study, we evaluated how these two types of synapses interact with each other using in vivo two-photon Ca2+ imaging and electrophysiology. We observed that dendritic Ca2+ responses could be efficiently evoked by electrical stimulation of POm or vM1 in the overlapping set of dendritic branches, rejecting the idea of branch-wise origin-selective synaptic wiring. Surprisingly, the Ca2+ responses upon coincident POm and vM1 stimulation summed sublinearly. We attribute this sublinearity to mutual inhibition via inhibitory neurons because synaptic currents generated by POm and vM1 also integrated sublinearly, but pharmacologically isolated direct synaptic currents summed linearly. Inhibitory neurons receiving POm inputs in the superficial cortical layer negatively regulated vM1-evoked responses. Finally, POm and vM1 innervated overlapping but distinct populations of somatostatin-expressing inhibitory neurons. Thus, POm and vM1 inputs negatively modulate each other in the mouse somatosensory cortex.
Effects of Variation in Urine Sample Storage Conditions on 16S Urogenital Microbiome Analyses
Authors: Kumar Tanya , Bryant MacKenzie , Cantrell Kalen , Song Se Jin , McDonald Daniel , Tubb Helena M. , Farmer Sawyer , Lukacz Emily S. , Brubaker Linda , Knight Rob
Published: July 2022

Replicability is a well-established challenge in microbiome research with a variety of contributing factors at all stages, from sample collection to code execution. Here, we focus on voided urine sample storage conditions for urogenital microbiome analysis. Using urine samples collected from 10 healthy adult women, we investigated the microbiome preservation efficacy of AssayAssure® Genelock (as opposed to no preservative) under different temperature conditions. We varied temperature over 48 hours in order to examine the impact of conditions samples may experience with home voided urine collection and shipping to a central biorepository. The following common lab and shipping conditions were investigated: -20C, ambient temperature, 4C, a freeze-thaw cycle, and a heat cycle. At 48 hours, all samples were stored at -80C until processing. After generating 16S rRNA gene amplicon sequencing data using the highly sensitive KatharoSeq protocol, we observed individual variation in both alpha and beta diversity metrics below interhuman differences, corroborating reports of individual microbiome variability in other specimen types. While there was no significant difference in beta diversity when comparing AssayAssure® Genelock vs. no preservative, we did observe a higher concordance with AssayAssure samples shipped at colder temperatures (−20C and 4C) when compared to the samples shipped at -20C without preservative. Our results indicate that AssayAssure does not introduce a significant amount of microbial bias when used on a range of temperatures but is most effective at colder temperatures.

Importance

The urogenital microbiome is an understudied yet important human microbiome niche. Research has been stimulated by the relatively recent discovery that urine is not sterile: urinary tract microbes have been linked to health problems including urinary infections, incontinence, and cancer. The quality of life and economic impact of UTIs and urgency incontinence alone are enormous, with $3.5 billion and $82.6 billion respectively spent in the U.S. annually. Given the low biomass of urine, novelty of the field, and well-established replicability bias in microbiome studies, it is critical to study storage conditions on urine samples to minimize microbial biases. Efficient and reliable preservation methods permit home self-sample collection and shipping, increasing the accessibility of larger-scale studies. Here, we examined both buffer and temperature variation effects on 16S rRNA gene amplicon sequencing results from urogenital samples, providing data on the consequences of common storage methods on urogenital microbiome results.
Tryptophan specialized metabolism and ER body-resident myrosinases modulate root microbiota assembly
Authors: Basak Arpan Kumar , Piasecka Anna , Hucklenbroich Jana , Türksoy Gözde Merve , Guan Rui , Zhang Pengfan , Getzke Felix , Garrido-Oter Ruben , Hacquard Stephane , Strzałka Kazimierz , Bednarek Paweł , Yamada Kenji , Nakano Ryohei Thomas
Published: July 2022

Indole glucosinolates (IGs) are tryptophan (Trp)-derived sulfur-containing specialized metabolites that play a crucial role in plant-microbe interactions in plants of the order Brassicales, including Arabidopsis thaliana. Despite the growing body of evidence implicating IG biosynthetic pathways in root-microbiota interactions, how myrosinases, the enzymes that convert inert IGs into bioactive intermediate/terminal products, contribute to this process remains unknown. Here, we describe the roles of the PYK10 and BGLU21 myrosinases in root-microbiota assembly partly via metabolites secreted from roots into the rhizosphere. PYK10 and BGLU21 localize to the endoplasmic reticulum (ER) body, an ER-derived organelle observed in plants of the family Brassicaceae. We investigated the root microbiota structure of mutants defective in the Trp metabolic (cyp79b2b3 and myb34/51/122) and ER body (nai1 and pyk10bglu21) pathways and found that these factors together contribute to the assembly of root microbiota. Microbial community composition in soils as well as in bacterial synthetic communities (SynComs) treated with root exudates axenically collected from pyk10bglu21 and cyp79b2b3 differed significantly from those treated with exudates derived from wild-type plants, pointing to a direct role of root-exuded compounds. We also show that growth of the pyk10bglu21 and cyp79b2b3 mutants was severely inhibited by fungal endophytes isolated from healthy A. thaliana plants. Overall, our findings demonstrate that root ER body-resident myrosinases influencing the secretion of Trp-derived specialized metabolites represent a lineage-specific innovation that evolved in Brassicaceae to regulate root microbiota structure.

Significance

ER bodies were first identified in roots of Brassicaceae plants more than 50 years ago, but their physiological functions have remained uncharacterized. A series of previous studies have suggested their possible role in root-microbe interactions. Here, we provide clear experimental evidence showing a role for ER bodies in root-microbiota interactions, which overlaps with that of root-exuded Trp-derived metabolites. Our findings delineate a plant lineage-specific innovation involving intracellular compartments and metabolic enzymes that evolved to regulate plant-microbe interactions at the root-soil interface.
Towards a mesoscale physical modeling framework for stereotactic-EEG recordings
Authors: Mercadal Borja , Lopez-Sola Edmundo , Galan-Gadea Adrià , Al Harrach Mariam , Sanchez-Todo Roser , Salvador Ricardo , Bartolomei Fabrice , Wendling Fabrice , Ruffini Giulio
Published: July 2022

Objective

Stereotactic-EEG (SEEG) and scalp EEG recordings can be modeled using mesoscale neural mass population models (NMM). However, the relationship between those mathematical models and the physics of the measurements is unclear. In addition, it is challenging to represent SEEG data by combining NMMs and volume conductor models due to the intermediate spatial scale represented by these measurements.

Approach

We provide a framework combining the multicompartmental modeling formalism and a detailed geometrical model to simulate the transmembrane currents that appear in layer 3, 5 and 6 pyramidal cells due to a synaptic input. With this approach, it is possible to realistically simulate the current source density (CSD) depth profile inside a cortical patch due to inputs localized into a single cortical layer and the induced voltage measured by two SEEG contacts using a volume conductor model. Based on this approach, we built a framework to connect the activity of a NMM with a volume conductor model and we simulated an example of SEEG signal as a proof of concept.

Main results

CSD depends strongly on the distribution of the synaptic inputs onto the different cortical layers and the equivalent current dipole strengths display substantial differences (of up to a factor of four in magnitude in our example). Thus, the inputs coming from different neural populations do not contribute equally to the electrophysiological recordings. A direct consequence of this is that the raw output of neural mass models is not a good proxy for electrical recordings. We also show that the simplest CSD model that can accurately reproduce SEEG measurements can be constructed from discrete monopolar sources (one per cortical layer).

Significance

Our results highlight the importance of including a physical model in NMMs to represent measurements. We provide a framework connecting microscale neuron models with the neural mass formalism and with physical models of the measurement process that can improve the accuracy of predicted electrophysiological recordings.
Membrane lipid reshaping underlies oxidative stress sensing by the mitochondrial proteins UCP1 and ANT1
Authors: Jovanović Olga , Chekashkina Ksenia , Škulj Sanja , Žuna Kristina , Vazdar Mario , Bashkirov Pavel V. , Pohl Elena E.
Published: July 2022

Oxidative stress and ROS are important players in the pathogenesis of several diseases. Besides the direct modification of proteins, ROS modify lipids with negative spontaneous curvature, such as phosphatidylethanolamine (PE), producing PE adducts and lysolipids. The formation of PE-adducts potentiates the protonophoric activity of the uncoupling protein 1 (UCP1), but the molecular mechanism remains obscure. Here, we connected the ROS-mediated lipid shape alteration with the membrane mechanical properties and function of UCP1 and adenine nucleotide translocase 1 (ANT1). We found that lysophosphatidylcholines (OPC and MPC) and PE adducts decrease a bending modulus in lipid bilayers and increase the protonophoric activity of both proteins. Furthermore, MD simulations revealed that modified PEs and lysolipids alter the membrane lateral pressure profile in the same direction and range, indicating that modified PEs act as lipids with positive spontaneous curvature. Both results indicate that oxidative stress decreases stored curvature elastic stress (SCES) in the lipid bilayer membrane. In conclusion, we demonstrate that UCP1 and ANT1 sense SCES and propose a new regulatory mechanism for the function of these proteins.
Dichotomous Intrinsic Properties of Adult Accumbens Medium Spiny Neurons Vanish in the Fragile X Mouse Model of Autism
Authors: Giua Gabriele , Lassalle Olivier , Makrini-Maleville Leila , Valjent Emmanuel , Chavis Pascale , Manzoni Olivier J.J.
Published: July 2022

Fragile X syndrome (FXS), the most common cause of autism and inherited intellectual disability, is caused by the mutation of a single gene, fmr1, which encodes the Fragile X mental retardation protein (FMRP). FXS patients suffer from cognitive, emotional, and social deficits indicative of dysfunction in the nucleus accumbens (NAc), a structure central to the control of social behavior. The major cell type of the NAc, medium spiny neurons (MSNs), are differentiated in two subtypes based on their expression of either dopamine D1 or D2 receptors, their connectivity, and associated behavioral functions. Understanding how the absence of FMRP differentially affects the cellular properties of MSNs is a necessary step to categorize FXS cellular endophenotypes. To address this question, we comprehensively compared the intrinsic passive and active properties of MSN subtypes identified in a novel Fmr1-/y :: Drd1a-tdTomato mouse model allowing in-situ identification of MSN subtypes in FXS mice. Although fmr1 transcripts and their gene product, FMRP, were found in both MSNs subtypes, the results suggest cell-autonomous functions for Fmr1. The opposite membrane properties and action potential kinetics that normally discriminate D1- from D2- MSNs in WT mouse is either reversed or abolished in Fmr1-/y :: Drd1a-tdTomato mice. Multivariate analysis shed light on the compound effects of Fmr1 ablation by revealing how the phenotypic traits that distinguish each cell type in WT are modified in FXS. Together these data show that in Fragile X mice the normal dichotomy that characterizes NAc D1- and D2-MSNs is thrown out of balance, leading to a uniform phenotype that could underlie selected aspects of the pathology.
Transcriptional signatures of wheat inflorescence development
Authors: VanGessel Carl , Hamilton James , Tabbita Facundo , Dubcovsky Jorge , Pearce Stephen
Published: July 2022

In order to maintain global food security, it will be necessary to increase yields of the cereal crops that provide most of the calories and protein for the world’s population, which includes common wheat (Triticum aestivum L.). An important factor contributing to wheat yield is the number of grain-holding spikelets which form on the spike during inflorescence development. Characterizing the gene regulatory networks controlling the timing and rate of inflorescence development will facilitate the selection of natural and induced gene variants that contribute to increased spikelet number and yield.

In the current study, co-expression and gene regulatory networks were assembled from a temporal wheat spike transcriptome dataset, revealing the dynamic expression profiles associated with the progression from vegetative meristem to terminal spikelet formation. Consensus co-expression networks revealed enrichment of several transcription factor families at specific developmental stages including the sequential activation of different classes of MIKC-MADS box genes. This gene regulatory network highlighted interactions among a small number of regulatory hub genes active during terminal spikelet formation. Finally, the CLAVATA and WUSCHEL gene families were investigated, revealing potential roles for TaCLE13, TaWOX2, and TaWOX7 in wheat meristem development. The hypotheses generated from these datasets and networks further our understanding of wheat inflorescence development.
Somatostatin interneurons in auditory cortex regulate sensory representations and contribute to auditory perception
Authors: Chai Ruiming , Zhang Yuan , Xin Yu , Deng Li , Xu Ning-long
Published: July 2022

As a major class of inhibitory neurons in the mammalian neocortex, somatostatin (SOM)-expressing GABAergic interneurons receive diverse inputs and target multiple types of local cortical neurons, representing a critical circuit component. Yet, the precise contribution of SOM interneurons to cortical circuit function and behavioral performance remains unclear. Here we address this using cell-type specific imaging and perturbation during an auditory perceptual decision task. Two-photon calcium imaging reveals that SOM interneurons exhibit task enhanced responses and stimulus category selectivity. Simultaneous optogenetic inactivation and two-photon imaging show that SOM interneurons exert divergent effects of either sharpening the sensory tuning or scaling down the tuning peak on different proportions of auditory cortical neurons. At behavioral level, inactivation of SOM interneurons reveals a specific contribution to perceptual discriminability. Our data delineate the role of SOM interneurons in cortical processing and auditory perception, linking cell-type specific cortical circuit computations with perceptual functions.
Making memories last: The peripheral effect of direct current stimulation on strengthening memories
Authors: Luckey Alison M. , McLeod S. Lauren , Huang Yuefeng , Mohan Anusha , Vanneste Sven
Published: July 2022

Most memories that are formed are forgotten, while others are retained longer and are subject to memory stabilization. We show that non-invasive transcutaneous electrical stimulation of the greater occipital nerve (NITESGON) using direct current during learning elicited a long-term memory effect. However, it did not trigger an immediate effect on learning. A neurobiological model of long-term memory proposes a mechanism by which memories that are initially unstable can be strengthened through subsequent novel experiences. In a series of studies, we demonstrate NITESGON’s capability to boost the retention of memories when applied shortly before, during or shortly after the time of learning by enhancing memory consolidation via activation and communication in and between the locus coeruleus pathway and hippocampus by modulating dopaminergic input. These findings may have a significant impact for neurocognitive disorders that inhibit memory consolidation such as Alzheimer’s disease.
Highly accurate quantification of allelic gene expression for population and disease genetics
Authors: Saukkonen Anna , Kilpinen Helena , Hodgkinson Alan
Published: July 2022

Analysis of allele-specific gene expression (ASE) is a powerful approach for studying gene regulation, particularly when sample sizes are small, such as for rare diseases, or when studying the effects of rare genetic variation. However, detection of ASE events relies on accurate alignment of RNA sequencing reads, where challenges still remain, particularly for reads containing genetic variants or those that align to many different genomic locations. We have developed the Personalised ASE Caller (PAC), a tool that combines multiple steps to improve the quantification of allelic reads, including personalized (i.e., diploid) read alignment with improved allocation of multimapping reads. Using simulated RNA sequencing data, we show that PAC outperforms standard alignment approaches for ASE detection, reducing the number of sites with incorrect biases (>10%) by ∼80% and increasing the number of sites that can be reliably quantified by ∼3%. Applying PAC to real RNA sequencing data from 670 whole-blood samples, we show that genetic regulatory signatures inferred from ASE data more closely match those from population-based methods that are less prone to alignment biases. Finally, we use PAC to characterize cell type–specific ASE events that would be missed by standard alignment approaches, and in doing so identify disease relevant genes that may modulate their effects through the regulation of gene expression. PAC can be applied to the vast quantity of existing RNA sequencing data sets to better understand a wide array of fundamental biological and disease processes.