Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.
Past tree influence and prescribed fire mediate biotic interactions and community reassembly in a grassland-restoration experiment

1. Woody plant encroachment of grasslands is occurring globally, with profound ecological consequences. Attempts to restore herbaceous dominance may fail if the woody state is resilient or if intervention leads to an alternate, undesirable state. Restoration outcomes often hinge on biotic interactions – particularly on priority effects that inhibit or promote community reassembly. 2. Following experimental tree removal from conifer-invaded grasslands, we documented substantial variation in community reassembly associated with the changing abundance of the native clonal sedge Carex inops L.H. Bailey subsp. inops. We explored possible mechanisms for this variation, focusing on the nature and timing of interactions between the meadow community and Carex and on how past tree influence and prescribed fire mediate the outcomes of these interactions. 3. Meadow species increased after tree removal, but less so in burned than in unburned plots. Carex expanded dramatically after fire, particularly where past tree influence had been greater. 4. Meadow species and Carex developed an increasingly negative association over time; preemption was reciprocal, but offset in time and space. Meadow species inhibited Carex through vegetative recovery in areas of limited or recent tree influence, irrespective of fire. Carex inhibited meadow reassembly in areas of greater tree influence, but only with burning. 5. Synthesis and applications. Tree removal and fire imposed across a range of altered meadow states yielded varying outcomes, reflecting biotic interactions and species’ regenerative traits that inhibited or promoted reassembly. Fire tended to destabilize the remnant meadow community and, in areas more degraded by encroachment, stimulated release of Carex, which inhibited reassembly. Knowledge of the context dependence of biotic interactions can enhance the effectiveness of restoration by establishing the bounds within which treatments produce desirable or undesirable outcomes.
Ultrastructure of gametogenesis and sporogony of Haemogregarina (sensu lato) myoxocephali (Apicomplexa: Adeleina) in the marine leech Malmiana scorpii.

The sexual and sporogonic development of Haemogregarina (sensu lato) myoxocephali, an apicomplexan blood parasite of longhorn sculpin, Myoxocephalus octodecemspinosus, was studied by transmission electron microscopy. All stages of development were observed epicellularly within intestinal epithelial cells of the leech Malmiana scorpii. During microgametogenesis nuclear division was characterized by a transnuclear cytoplasmic channel containing the spindle microtubules. Four aflagellate microgametes were formed. During fertilization, a single microgamete nucleus was associated with the endoplasmic reticulum in the macrogamete, followed by fusion of the nuclear envelopes of the gametes. Sporogony involved peripheral budding of sporozoite anlagen and subsequent development to form approximately 32 sporozoites in mature oocysts.
Comparative photosynthesis of sun and shade plants.

INTRODUCTION 355 SUN AND SHADE SPECIES . 356 Light Saturation Characteristics 356 Pigment Content and Leaf Anatomy . 357 Chloroplast Structure 358 Parameters Influencing Photosynthetic Rates 359 CO2 Diff usion and the Carboxylation of Ribulose Diphosphate 360 Photosynthetic Electron Transport 361 Electron Transport Components . 361
MORONET: Multi-omics Integration via Graph Convolutional Networks for Biomedical Data Classification

To fully utilize the advances in omics technologies and achieve a more comprehensive understanding of human diseases, novel computational methods are required for integrative analysis for multiple types of omics data. We present a novel multi-omics integrative method named Multi-Omics gRaph cOnvolutional NETworks (MORONET) for biomedical classification. MORONET jointly explores omics-specific learning and cross-omics correlation learning for effective multi-omics data classification. We demonstrate that MORONET outperforms other state-of-the-art supervised multi-omics integrative analysis approaches from a wide range of biomedical classification applications using mRNA expression data, DNA methylation data, and miRNA expression data. Furthermore, MORONET is able to identify important biomarkers from different omics data types that are related with the investigated diseases.
Zinc Determines Dynamical Properties and Aggregation Kinetics of Human Insulin

Protein aggregation is a widespread process leading to deleterious consequences in the organism, with amyloid aggregates being important not only in biology but also for drug design and biomaterial production. Insulin is a protein largely used in diabetes treatment and its amyloid aggregation is at the basis of the so-called insulin-derived amyloidosis. Here we uncover the major role of zinc in both insulin dynamics and aggregation kinetics at low pH, where the formation of different amyloid superstructures (fibrils and spherulites) can be thermally induced. Amyloid aggregation is accompanied by zinc release and the suppression of water-sustained insulin dynamics, as shown by particle-induced X-ray emission and X-ray absorption spectroscopy and by neutron spectroscopy, respectively. Our study shows that zinc binding stabilizes the native form of insulin by facilitating hydration of this hydrophobic protein and suggests that introducing new binding sites for zinc can improve insulin stability and tune its aggregation propensity. Statement of Significance Localized amyloidosis occurs at insulin injection sites for diabetes treatment, leading to deleterious inflammations known as insulin-derived amyloidosis. Amyloid superstructures are also promising candidates in the field of biomaterials. Here we revealed that zinc, coordinated to insulin in the native form, is released upon amyloid aggregation, when insulin forms superstructures known as fibrils and spherulites. Zinc release leads to a full suppression of functionally essential protein dynamics through a modification of the protein’s hydration properties and completely modifies insulin amyloid kinetics. The results suggest that changes in protein hydration upon zinc binding/release modifies both stability and dynamics of insulin and might then be a general strategy to control protein stability and tune protein aggregation into amorphous and ordered superstructures.
Fine-scale Population Structure and Demographic History of Han Chinese Inferred from Haplotype Network of 111,000 Genomes

Han Chinese is the most populated ethnic group across the globe with a comprehensive substructure that resembles its cultural diversification. Studies have constructed the genetic polymorphism spectrum of Han Chinese, whereas high-resolution investigations are still missing to unveil its fine-scale substructure and trace the genetic imprints for its demographic history. Here we construct a haplotype network consisted of 111,000 genome-wide genotyped Han Chinese individuals from direct-to-consumer genetic testing and over 1.3 billion identity-by-descent (IBD) links. We observed a clear separation of the northern and southern Han Chinese and captured 5 subclusters and 17 sub-subclusters in haplotype network hierarchical clustering, corresponding to geography (especially mountain ranges), immigration waves, and clans with cultural-linguistic segregation. We inferred differentiated split histories and founder effects for population clans Cantonese, Hakka, and Minnan-Chaoshanese in southern China, and also unveiled more recent demographic events within the past few centuries, such as Zou Xikou and Chuang Guandong. The composition shifts of the native and current residents of four major metropolitans (Beijing, Shanghai, Guangzhou, and Shenzhen) imply a rapidly vanished genetic barrier between subpopulations. Our study yields a fine-scale population structure of Han Chinese and provides profound insights into the nation’s genetic and cultural-linguistic multiformity.
Linking the dynamics of chromatin occupancy and transcription with predictive models

Though the sequence of the genome within each eukaryotic cell is essentially fixed, it exists in a complex and changing chromatin state. This state is determined, in part, by the dynamic binding of proteins to the DNA. These proteins—including histones, transcription factors (TFs), and polymerases—interact with one another, the genome, and other molecules to allow the chromatin to adopt one of exceedingly many possible configurations. Understanding how changing chromatin configurations associate with transcription remains a fundamental research problem. We sought to characterize at high spatiotemporal resolution the dynamic interplay between transcription and chromatin in response to cadmium stress. While gene regulatory responses to environmental stress in yeast have been studied, how the chromatin state is modified and how those modifications connect to gene regulation remain unexplored. By combining MNase-seq and RNA-seq data, we found chromatin signatures of transcriptional activation and repression involving both nucleosomal and TF-sized DNA binding factors. Using these signatures, we identified associations between chromatin dynamics and transcriptional regulation, not only for known cadmium response genes, but across the entire genome, including antisense transcripts. Those associations allowed us to develop generalizable models that can predict dynamic transcriptional responses on the basis of dynamic chromatin signatures.
Defining endogenous TACC3–chTOG–clathrin–GTSE1 interactions at the mitotic spindle using induced relocalization

A multiprotein complex containing TACC3, clathrin, and other proteins has been implicated in mitotic spindle stability. To disrupt this complex in an anti-cancer context, we need to understand the composition of the complex and the interactions between complex members and with microtubules. Induced relocalization of proteins in cells is a powerful way to analyze protein-protein interactions and additionally monitoring where and when these interactions occur. We used CRISPR/Cas9 gene-editing to add tandem FKBP-GFP tags to each complex member. The relocalization of endogenous tagged protein from the mitotic spindle to mitochondria and assessment of the effect on other proteins allowed us to establish that TACC3 and clathrin are core complex members and that chTOG and GTSE1 are ancillary to the complex, respectively binding to TACC3 and clathrin, but not each other. PIK3C2A, a membrane trafficking protein that binds clathrin, was previously proposed to also bind TACC3 and stabilize the TACC3–chTOG–clathrin–GTSE1 complex during mitosis. We show that PIK3C2A is not on the mitotic spindle and that knockout of this gene had no effect on the localization of the complex. We therefore conclude that PIK3C2A is not a member of the TACC3–chTOG–clathrin–GTSE1 complex. This work establishes that targeting the TACC3–clathrin interface or their microtubule-binding sites are the two strategies most likely to disrupt spindle stability mediated by this multiprotein complex.
Frecuencia de serotipos de Cryptococcus neoformans/C. gattii en México

La criptococosis es causada principalmente por Cryptococcus neoformans o C. gattii. Pocos estudios acerca de la subtipifi cacion de los agentes causales han sido desarrollados en paises latinoamericanos. Para conocer la presencia de los serotipos en nuestro pais, se hizo un estudio descriptivo en el cual fueron estudiados 150 cultivos de Cryptococcus sp, provenientes de pacientes y proporcionados por dos hospitales de concentracion en el Distrito Federal. Se obtuvieron los datos clinico-demografi cos de los pacientes a partir de los cuales se efectuaron los aislamientos de las levaduras. La subtipifi cacion de las levaduras se elaboro mediante pruebas bioquimicas y serologicas; los datos obtenidos fueron correlacionados. Todas las levaduras identifi cadas como C. neoformans fueron aisladas de pacientes con SIDA, mientras que los casos C. gattii se asociaron a pacientes aparentemente inmunocompetentes. Se encontro la siguiente distribucion: serotipo A 83% (Crytococcus neoformans var. grubii); serotipo B 5% (C. gattii); serotipo D 5% (C. neoformans var. neoformans); serotipo AD 4% (C. neoformans hibrido) y serotipo C 3% (C. gattii). Los resultados corroboran al serotipo A como el agente etiologico de la criptococosis mayormente identifi cado y, a diferencia de otros paises, en Mexico el complejo C. neoformans/C. gattii muestra una evidente diversidad en serotipos. ABSTRACT
Leaf Trichome Distribution Pattern in Arabidopsis Reveals Gene Expression Variation Associated with Environmental Adaptation

Gene expression varies stochastically even in both heterogenous and homogeneous cell populations. This variation is not simply useless noise; rather, it is important for many biological processes. Unicellular organisms or cultured cell lines are useful for analyzing the variation in gene expression between cells; however, owing to technical challenges, the biological relevance of this variation in multicellular organisms such as higher plants remains unclear. Here, we addressed the biological relevance of this variation between cells by examining the genetic basis of trichome distribution patterns in Arabidopsis thaliana. The distribution pattern of a trichome on a leaf is stochastic and can be mathematically represented using Turing’s reaction-diffusion (RD) model. We analyzed simulations based on the RD model and found that the variability in the trichome distribution pattern increased with the increase in stochastic variation in a particular gene expression. Moreover, differences in heat-dependent variability of the trichome distribution pattern between the accessions showed a strong correlation with environmental factors to which each accession was adapted. Taken together, we successfully visualized variations in gene expression by quantifying the variability in the Arabidopsis trichome distribution pattern. Thus, our data provide evidence for the biological importance of variations in gene expression for environmental adaptation.
Cryo-EM structure of enteric adenovirus HAdV-F41 highlights structural divergence among human adenoviruses

Enteric adenoviruses are one of the main causes of viral gastroenteritis in the world. To carry out a successful infection, the virions must withstand the harsh conditions found in the gut. This requirement suggests that capsid stability must be different from that of other adenoviruses. We have determined the structure of a human enteric adenovirus, HAdV-F41, at 4.0 Å resolution by single particle averaging cryo-electron microscopy, and compared it with that of other adenoviruses with respiratory (HAdV-C5) and ocular (HAdV-D26) tropisms. While the overall structures of hexon, penton base and internal minor coat proteins IIIa and VIII are conserved, we observe partially ordered elements reinforcing the vertex region, which suggests their role in enhancing the physicochemical capsid stability of HAdV-F41. Unexpectedly, we find an organization of the external minor coat protein IX different from all previously characterized human and non-human mastadenoviruses. Knowledge of the structure of enteric adenoviruses can provide a starting point for the design of vectors suitable for oral delivery or intestinal targeting.
Hemispheric specialization within the inferior parietal lobe across cognitive domains

The inferior parietal lobe (IPL) is a key neural substrate underlying diverse mental processes, from basic attention to language and social cognition that define human interactions. Its putative domain-global role appears to tie into poorly understood functional differences between both hemispheres. Across attentional, semantic, and social cognitive experiments, our study explored hemispheric specialization within the IPL. The task specificity of IPL subregion activity was substantiated by distinct predictive signatures identified by multivariate pattern-learning algorithms. Moreover, the left and right IPL exerted domain-specific modulation of effective connectivity among their subregions. Task-evoked functional interactions of the anterior and posterior IPL subregions involved recruitment of distributed cortical partners. While each anterior IPL subregion was engaged in strongly lateralized coupling links, both posterior subregions showed more symmetric coupling patterns across hemispheres. Our collective results shed light on how under-appreciated lateralization effects within the IPL support some of the most distinctive human mental capacities.
Connectivity patterns of task-specific brain networks allow individual prediction of cognitive symptom dimension of schizophrenia and link to molecular architecture

Background Despite the marked inter-individual variability in the clinical presentation of schizophrenia, it remains unclear the extent to which individual dimensions of psychopathology may be reflected in variability across the collective set of functional brain connections. Here, we address this question using network-based predictive modeling of individual psychopathology along four data-driven symptom dimensions. Follow-up analyses assess the molecular underpinnings of predictive networks by relating them to neurotransmitter-receptor distribution patterns. Methods We investigated resting-state fMRI data from 147 schizophrenia patients recruited at seven sites. Individual expression along negative, positive, affective, and cognitive symptom dimensions was predicted using relevance vector machine based on functional connectivity within 17 meta-analytic task-networks following a repeated 10-fold cross-validation and leave-one-site-out analyses. Results were validated in an independent sample. Networks robustly predicting individual symptom dimensions were spatially correlated with density maps of nine receptors/transporters from prior molecular imaging in healthy populations. Results Ten-fold and leave-one-site-out analyses revealed five predictive network-symptom associations. Connectivity within theory-of-mind, cognitive reappraisal, and mirror neuron networks predicted negative, positive, and affective symptom dimensions, respectively. Cognitive dimension was predicted by theory-of-mind and socio-affective-default networks. Importantly, these predictions generalized to the independent sample. Intriguingly, these two networks were positively associated with D1 dopamine receptor and serotonin reuptake transporter densities as well as dopamine-synthesis-capacity. Conclusions We revealed a robust association between intrinsic functional connectivity within networks for socio-affective processes and the cognitive dimension of psychopathology. By investigating the molecular architecture, the present work links dopaminergic and serotonergic systems with the functional topography of brain networks underlying cognitive symptoms in schizophrenia.
A community-driven resource for genomic surveillance of Neisseria gonorrhoeae at Pathogenwatch

Background Antimicrobial resistant (AMR) Neisseria gonorrhoeae is an urgent threat to public health, as strains resistant to at least one of the two last line antibiotics used in empiric therapy of gonorrhoea, ceftriaxone and azithromycin, have spread internationally. With new treatment options not yet available, this has prompted a call for collaborative action on global surveillance for this sexually transmitted pathogen. Whole genome sequencing (WGS) data can be used to identify new AMR clones, outbreaks, transmission networks and inform the development of point-of-care tests for antimicrobial susceptibility, novel antimicrobials and vaccines. Community driven tools that provide an easy access to and analysis of genomic and epidemiological data is the way forward for public health surveillance. Methods Here we present a public health focussed scheme for genomic epidemiology of N. gonorrhoeae using Pathogenwatch (https://pathogen.watch/ngonorrhoeae), which enables the processing of raw or assembled genomic data. We implement backwards compatibility with MLST, NG-MAST and NG-STAR typing schemes as well as an exhaustive library of genetic AMR determinants associated with resistance to eight antibiotics. A collection of over 12,000 N. gonorrhoeae genome sequences from public archives has been quality-checked, assembled and made public together with available metadata for contextualization. Results An international advisory group of experts in epidemiology, public health, genetics and genomics of N. gonorrhoeae was convened to identify public health needs in the field and inform on the utility of current and future analytics in the platform, including a customised library of genetic AMR determinants. After uploading genome data, this platform automatically provides typing information, detects genetic determinants of AMR for eight antibiotics including azithromycin and the extended-spectrum cephalosporins ceftriaxone and cefixime, and infers resistance based on the specific combination of mechanisms. Furthermore, genomes are contextualised with globally available genomic data to aid epidemiological investigation. Conclusions The N. gonorrhoeae scheme in Pathogenwatch provides customized bioinformatic pipelines guided by expert opinion that can be adapted to public health agencies and departments with little expertise in bioinformatics and lower resourced settings with internet connection but limited computational infrastructure. This advisory group will assess and identify ongoing public health needs in the field of gonococcal AMR in order to further enhance utility with modified or new analytic methods.