Miracle-dz/UniFAR-FTUs huggingface dataset:
Measuring brain integrity using MRI: a novel biomarker for Alzheimers disease using T2 relaxometry

Early Alzheimer's disease diagnosis is vital for development of disease-modifying therapies. Prior to significant loss of brain tissue, several microstructural changes take place as a result of Alzheimer's pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. The different factors that affect T2 may cause it to increase, as in the case of free water, or decrease, as in the case of iron, amyloid and tau. Thus, tissue affected by early Alzheimer's disease could become more heterogeneous yet show no change in average T2. We hypothesise that T2 heterogeneity in regions affected early in Alzheimer's disease (hippocampus and thalamus) may present a sensitive early marker of microstructural changes in Alzheimer's disease. In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a diagnosis of Alzheimer's disease. All participants underwent structural MRI including multi-echo sequence for assessing quantitative T2. Cognitive change over one year was assessed in participants with MCI. Hippocampus and thalamus were automatically masked using ASHS and Freesurfer, respectively. T2 distributions were modelled using log-logistic distribution giving measures of log-median value (midpoint; T2) and distribution width (heterogeneity; T2{sigma}). We show an increase in heterogeneity (T2{sigma}; p<.0001) in MCI compared to healthy controls, which was not seen with midpoint (T2; p=.149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over one year in MCI participants (p=.018), but midpoint (p=.132) and volume (p=.315) did not. Age affects T2, but the effects described here are significant even after correcting for age. We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in prodromal Alzheimer's disease. We describe a new model that takes into account the competing effects of factors that both increase and decrease T2. These two opposing forces act in opposition and mean that previous human literature focusing on midpoint T2 has obscured the true potential of T2 as an early marker of Alzheimer's disease. In fact, T2 heterogeneity outperforms midpoint and volumetry in predicting cognitive decline in those with MCI. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of Alzheimer's disease.
Antibiotic Resistance Profile of Gram Negative Bacteria Isolated from Surgical Wounds in Minna, Bida, Kontagora and Suleja Areas of Niger State

Antibiotics resistance profiles of bacteria from surgical wounds were investigated in four (4) General Hospitals (Bida, Kontagora, Minna and Suleja) in Niger State. Five hundred (500) samples (i.e. Two hundred (200) samples in Minna, One hundred (100) samples each Suleja, Kontagora and Bida) of wound exudates from these general hospitals, were analysed. The results showed the presence of Klebsiella Pneumoniae , Escherichia coli , Pseudomonas aeruginosa , and Proteus vulgaris in the samples from the wounds. From the five hundred (500) samples collected from all locations, forty two (42) samples had Kl. p neumoniae , sixty four (64) samples had Ps. aeruginosa , fifty two (52) samples had P . vulgaris and one hundred and nine (109) samples had E. coli. E. coli was the most frequently isolated bacteria from wounds in all the locations, while Kl. pneumoniae was the least isolated from wounds in all the locations. All the bacteria were tested for sensitivity against tarivid, pefloxacin, ciprofloxacin, augmentin, gentamycin, streptomycin, ceporex, nalidixic acid, septrin, ampicillin, ampiclox, zinacef, amoxacillin, rocephin, erythromycin. Most of all the isolates were sensitive to ciprofloxacin, pefloxacin and Tarivid while others were resistant to remaining antibiotics. E. coli, Strept. pyogenes and S. aureus showed highest resistance profile and P. vulgaris, Kl. pneumoniae and Ps. aeruginosa showed least resistance profile to most antibiotics used.
FLEXIQuant-LF: Robust Regression to Quantify Protein Modification Extent in Label-Free Proteomics Data

Improvements in LC-MS/MS methods and technology have enabled the identification of thousands of modified peptides in a single experiment. However, protein regulation by post-translational modifications (PTMs) is not binary, making methods to quantify the modification extent crucial to understanding the role of PTMs. Here, we introduce FLEXIQuant-LF, a software tool for large-scale identification of differentially modified peptides and quantification of their modification extent without prior knowledge of the type of modification. We developed FLEXIQuant-LF using label-free quantification of unmodified peptides and robust linear regression to quantify the modification extent of peptides. As proof of concept, we applied FLEXIQuant-LF to data-independent-acquisition (DIA) data of the anaphase promoting complex/cyclosome (APC/C) during mitosis. The unbiased FLEXIQuant-LF approach to assess the modification extent in quantitative proteomics data provides a better understanding of the function and regulation of PTMs. The software is available at https://github.com/SteenOmicsLab/FLEXIQuantLF.
Ppd-1 Remodels Spike Architecture by Regulating Floral Development in wheat

The determination of spike architecture is critical to grain yield in wheat (Triticum aestivum), yet the underlying mechanisms remain largely unknown. Here, we measured 51 traits associated with spike architecture and floral development in 197 wheat accessions with photoperiod sensitive and insensitive alleles. We included five distinct allele combinations at the Photoperiod-1 (Ppd-1) loci. A systematic dissection of all recorded phenotypes revealed connections between floral development, spike architecture and grain yield. Modifying the durations of spikelet primordia initiation did not necessarily affect spikelet number. In addition, Ppd-1 loci clearly influenced rachis dry weight, pointing to the rachis vascular system as a potential target for higher yield. Ppd-1 displayed opposite effects on the durations of pre and post-anthesis phases. Ppd-1 controlled carpel size, but not anther size. Finally, the photoperiod-insensitive alleles of Ppd-1 triggered floral degeneration. In parallel, we profiled the spike transcriptome at six stages and four positions in three Ppd-1 genotypes which consists of 234 samples. Integrating phenotypic and expression data suggested that loss of function in Ppd-1 loci delayed floral degeneration by regulating autophagy and extended floret development by regulating genes in different families. Therefore, we concluded that Ppd-1 remodels spike architecture by regulating floral development in wheat.
Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

NatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and α-synuclein (αSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in Parkinson’s disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-αSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis reveals functionally important differences with human NatA and Candida albicans NatB, resolves key hNatB protein determinants for αSyn N-terminal acetylation, and identifies important residues for substrate-specific recognition and acetylation by NatB enzymes. These studies have implications for developing small molecule NatB probes and for understanding the mode of substrate selection by NAT enzymes.
Arp2/3 complex-mediated actin assembly drives microtubule-independent motility and phagocytosis in the evolutionarily divergent amoeba Naegleria

Much of our current understanding of actin-driven phenotypes in eukaryotes has come from the “yeast to human” opisthokont lineage, as well as the related amoebozoa. Outside of these groups lies the genus Naegleria, which shared a common ancestor with humans over a billion years ago, and includes the deadly “brain-eating amoeba. ” Unlike nearly every other known eukaryotic cell type, Naegleria amoebae are thought to lack cytoplasmic microtubules. The absence of microtubules suggests that these amoebae rapidly crawl and phagocytose bacteria using actin alone. Although this makes Naegleria a powerful system to probe actin-driven functions in the absence of microtubules, surprisingly little is known about Naegleria’s actin cytoskeleton. Here, we use microscopy and genomic analysis to show that Naegleria amoebae have an extensive actin cytoskeletal repertoire, complete with nucleators and nucleation promoting factors. Naegleria use this cytoskeletal machinery to generate Arp2/3-dependent lamellar protrusions, which correlate with the capacity to migrate and phagocytose bacteria. Because human cells also use Arp2/3-dependent lamellar protrusions for motility and phagocytosis, this work supports an evolutionarily ancient origin for these actin-driven processes and establishes Naegleria as a natural model system for studying microtubule-independent cytoskeletal phenotypes.
Performance trade-offs for single- and dual-objective light-sheet microscope designs

Light-sheet microscopy (LSM) has emerged as a powerful tool for high-speed volumetric imaging of live model organisms and large optically cleared specimens. When designing cleared-tissue LSM systems with certain desired imaging specifications (e.g. resolution, contrast, and working distance), various design parameters must be taken into consideration. In order to elucidate some of the key design trade-offs for LSM systems, we present a diffraction-based analysis of single- and dual-objective LSM configurations where Gaussian illumination is utilized. Specifically, we analyze the effects of the illumination and collection numerical aperture (NA), as well as their crossing angle, on spatial resolution and contrast. Assuming an open-top light-sheet (OTLS) architecture, we constrain these parameters based on fundamental geometric considerations as well as those imposed by currently available microscope objectives. In addition to revealing the performance tradeoffs of various single- and dual-objective LSM configurations, our analysis showcases the potential advantages of a novel, non-orthogonal dual-objective (NODO) architecture, especially for moderate-resolution imaging applications (collection NA of 0.5 to 0.8).
Anti-GPR56 monoclonal antibody potentiates GPR56-mediated Src-Fak signaling to modulate cell adhesion

GPR56, also known as ADGRG1, is a member of the adhesion G protein-coupled receptor (aGPCR) family shown to play important roles in cell adhesion, brain development, immune system function, and tumorigenesis. GPR56 is upregulated in colorectal cancer and high expression correlates with poor prognosis. Several studies have shown that GPR56 couples to the Gα12/13 class of heterotrimeric G-proteins to promote RhoA activation. However, due to its structural complexity and lack of a high affinity receptor-specific ligand, the complete GPR56 signaling mechanism still remains largely unknown. To delineate the activation mechanism and intracellular signaling functions of GPR56, we generated a monoclonal antibody (mAb) which binds GPR56 with high affinity and specificity to the extracellular domain (ECD). We show that overexpression of GPR56 in 293T cells lead to increased phosphorylation of Src, Fak, and paxillin adhesion proteins and activation of the Gα12/13-RhoA-mediated serum response factor (SRF) pathway. Treatment of cells with anti-GPR56 mAb potentiated Src-Fak phosphorylation, RhoA-SRF signaling, and cell adhesion. Consistently, knockdown of GPR56 in colorectal cancer cells decreased Src-Fak pathway phosphorylation and cell adhesion. Interestingly, GPR56-mediated activation of Src-Fak phosphorylation occurred independent of RhoA, yet mAb-induced potentiation of RhoA-SRF signaling was Src-dependent. Furthermore, we show that the Serine–Threonine–Proline-rich (STP) region of the ECD of GPR56 was not essential for mAb binding, yet was required for activation of Src-Fak signaling. These data support a new ECD-dependent mechanism by which GPR56 functions to regulate cell adhesion through activation of Src-Fak signaling.
In-silico screening of drug candidates for thermoresponsive liposome formulations

Liposomal formulations can be advantageous in a number of scenarios such as targeted delivery to reduce the systemic toxicity of highly potent Active Pharmaceutical Ingredients (APIs), to increase drug bioavailability by prolonging systemic circulation, to protect labile APIs from degradation in the gastrointestinal tract, or to improve skin permeation in dermal delivery. However, not all APIs are suitable for encapsulation in liposomes. Some of the issues are too high permeability of the API across the lipid bilayer, which may lead to premature leakage, too low permeability, which may hinder the drug release process, or too strong membrane affinity, which may reduce the overall efficacy of drug release from liposomes. Since the most reliable way to test API encapsulation and release from liposomes so far has been experimental, an in silico model capable of predicting API transport across the lipid bilayer might accelerate formulation development. In this work, we demonstrate a new in silico approach to compute the temperature dependent permeability of a set of compounds across the bilayer of virtual liposomes constructed by molecular dynamics simulation. To validate this approach, we have conducted a series of experiments confirming the model predictions using a homologous series of fluorescent dyes. Based on the performance of individual molecules, we have defined a set of selection criteria for identifying compatible APIs for stable encapsulation and thermally controlled release from liposomes. To further demonstrate the in silico-based methodology, we have screened the DrugBank database, identified potent drugs suitable for liposome encapsulation and successfully carried out the loading and thermal release of one of them - an antimicrobial compound cycloserine.
An integrated in silico immuno-genetic analytical platform provides insights into COVID-19 serological and vaccine targets

During COVID-19, diagnostic serological tools and vaccines have been developed. To inform control activities in a post-vaccine surveillance setting, we have developed an online “immuno-analytics” resource that combines epitope, sequence, protein and SARS-CoV-2 mutation analysis. SARS-CoV-2 spike and nucleocapsid proteins are both vaccine and serological diagnostic targets. Using the tool, the nucleocapsid protein appears to be a sub-optimal target for use in serological platforms. Spike D614G (and nsp12 L314P) mutations were most frequent (> 86%), whilst spike A222V/L18F have recently increased. Also, Orf3a proteins may be a suitable target for serology. The tool can accessed from: http://genomics.lshtm. ac.uk/immuno (online); https://github.com/dan-ward-bio/COVID-immunoanalytics (source code).
A comparative analysis of statistical methods to estimate the reproduction number in emerging epidemics with implications for the current COVID-19 pandemic

As the SARS-CoV-2 pandemic continues its rapid global spread, quantification of local transmission patterns has been, and will continue to be, critical for guiding pandemic response. Understanding the accuracy and limitations of statistical methods to estimate the reproduction number, R0, in the context of emerging epidemics is therefore vital to ensure appropriate interpretation of results and the subsequent implications for control efforts. Using simulated epidemic data we assess the performance of 6 commonly-used statistical methods to estimate R0 as they would be applied in a real-time outbreak analysis scenario - fitting to an increasing number of data points over time and with varying levels of random noise in the data. Method comparison was also conducted on empirical outbreak data, using Zika surveillance data from the 2015-2016 epidemic in Latin America and the Caribbean. We find that all methods considered here frequently over-estimate R0 in the early stages of epidemic growth on simulated data, the magnitude of which decreases when fitted to an increasing number of time points. This trend of decreasing bias over time can easily lead to incorrect conclusions about the course of the epidemic or the need for control efforts. We show that true changes in pathogen transmissibility can be difficult to disentangle from changes in methodological accuracy and precision, particularly for data with significant over-dispersion. As localised epidemics of SARS-CoV-2 take hold around the globe, awareness of this trend will be important for appropriately cautious interpretation of results and subsequent guidance for control efforts.
Distribution and Diversity of Bacteria and Archaea in Marine Sediments Affected by Gas Hydrates at Mississippi Canyon in the Gulf of Mexico

The microbial community structures of gas hydrate-bearing (Core 9) and non-hydrate-bearing (Core 1) marine sediments were investigated at Mississippi Canyon (MC) 118 in the Gulf of Mexico. Quantification by quantitative competitive (QC)-PCR showed that bacterial abundance was 2–3 orders of magnitude higher than archaeal abundance in these cores. Sulfate-reducing bacteria (SRB) were present at 103–104 dsrAB gene copies/g in both cores; methanogens or anaerobic methanotrophs were only present in Core 9 (102–105 mcrA gene copies/g). Denaturing gradient gel electrophoresis (DGGE) showed distinct patterns of bacterial community structure between Core 9 and Core 1 with ϵ-Proteobacteria predominating in the former and γ-Proteobacteria in the latter. Clone libraries were successfully constructed for both Archaea and Bacteria using functional genes (mcrA and dsrAB, respectively). The mcrA gene was present in Core 9, suggesting enhanced abundance or activity of methanogens or methane-oxidizing archaea in the hydrate-impacted sediment. The mcrA gene sequences were dominated by group c-d and group e. The majority (80%) of the dsrAB gene sequences fell into Syntrophobacteraceae-related group. This study indicates that microbial community structures are considerably different between the hydrate-bearing and non-hydrate-bearing sediment at MC 118. Our study is among the initial steps toward a comprehensive and long-term monitoring of microbial dynamics associated with gas hydrates in the Gulf of Mexico.
Reimplementing Unirep in JAX

UniRep is a recurrent neural network model trained on 24 million protein sequences, and has shown utility in protein engineering. The original model, however, has rough spots in its implementation, and a convenient API is not available for certain tasks. To rectify this, we reimplemented the model in JAX/NumPy, achieving near-100X speedups in forward pass performance, and implemented a convenient API for specialized tasks. In this article, we wish to document our model reimplementation process with the goal of educating others interested in learning how to dissect a deep learning model, and engineer it for robustness and ease of use.
Human follicular CD4 T cell function is defined by specific molecular, positional and TCR dynamic signatures

The orchestrated interaction between follicular helper CD4 T cells (TFH) and germinal center (GC) B cells is crucial for optimal humoral immunity. However, the regulatory mechanisms behind spatial distribution and function of TFH is not well understood. Here, we studied human TFH cells and found that transitioning to a CD57hi TFH status was associated with distinct positioning in the GC, phenotype, transcriptional signatures, function and downregulation of their T-cell receptor (TCR). Single cell TCR clonotype analysis indicated a unidirectional transition towards the CD57hi TFH status, which was marked with drastic changes in the nature of immunological synapse formation where peripheral microclusters become dominant. Lack of central supra molecular activation cluster (cSMAC) formation in TFH synapse was associated with enhanced ubiquitination/proteasome activity in these cells. Our data reveal significant aspects of the tissue organization and heterogeneity of follicular adaptive immunity and suggest that CD57hi TFH cells are endowed with distinctive programming and spatial positioning for optimal GC B cell help. One Sentence Summary human TFH cell heterogeneity
Exotic Hobos: Release, escape, and potential secondary dispersal of African red-headed agamas (Agama picticauda PETERS, 1877) through the Florida railway systems

Context Invasive reptile species are introduced and established through a variety of distribution channels (e.g. accidental/intentional release by pet owners, hitchhiking on imported goods), and can be detrimental to native ecosystems. Understanding the origins and spread of non-native species can help land managers to make informed decisions when attempting to prevent future introductions and remove established populations. Aims The objectives of this study were to employ modelling techniques with open-source observational data to confirm putative local origins of African red-headed agamas in Florida and to locate potential distribution channels in which they are spreading throughout the state. Methods Geographic profiling, a technique commonly used for criminal investigations, was used along with suspected origin locations of introduced African red-headed agamas (Agama picticauda) from the literature and observations from the Early Detection and Distribution Mapping System (EDDMapS). Anchor points and their immediate surroundings were investigated for potential patterns of origination and dispersal. Key results The results of this study provide evidence that African red-headed agamas likely established themselves through both intentional releases and unintentional escapes from the pet owners and breeders, while also potentially hitchhiking on plant exports, and dispersing throughout Florida via the railway systems. Conclusions Given the potential for railways as a method of assisted dispersal, and given the potential exports they may be hitchhiking on, the results of this study suggest that railcars and railway export facilities should be included in future management of non-native African red-headed agamas in Florida. Implications The implications of this study builds on prior evidence that geographic profiling is an effective modelling tool in regards to biological invasions, which can accurately confirm suspected origins while also effectively mapping previously unknown epicenters of population clusters to be investigated by managers.