Miracle-dz/UniFAR-FTUs huggingface dataset:
Harnessing Transcriptomic Signals for Amyotrophic Lateral Sclerosis to Identify Novel Drugs and Enhance Risk Prediction

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics. Methods: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival. Results: SNP-based fine-mapping, TWAS and PWAS identified 117 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified five drugs significantly enriched for interactions with ALS associated genes, with directional analyses highlighting -glucosidase inhibitors may exacerbate ALS pathology. Additionally, drug class enrichment analysis showed calcium channel blockers may reduce ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R2 = 4%; p-value = 2.1x10-21). Conclusions: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.
Transdiagnostic MRI markers of psychopathology following traumatic brain injury: a systematic review and network meta-analysis protocol

Introduction Psychopathology following traumatic brain injury (TBI) is a common and debilitating consequence that is often associated with reduced functional and psychosocial outcomes. There is a lack of evidence regarding the neural underpinnings of psychopathology following TBI, and whether there may be transdiagnostic neural markers that are shared across traditional psychiatric diagnoses. The aim of this systematic review and meta-analysis is to examine the association of MRI-derived markers of brain structure and function with both transdiagnostic and specific psychopathology following moderate–severe TBI. Methods and analysis A systematic literature search of Embase (1974–2022), Ovid MEDLINE (1946–2022) and PsycINFO (1806–2022) will be conducted. Publications in English that investigate MRI correlates of psychopathology characterised by formal diagnoses or symptoms of psychopathology in closed moderate–severe TBI populations over 16 years of age will be included. Publications will be excluded that: (a) evaluate non-MRI neuroimaging techniques (CT, positron emission tomography, magnetoencephalography, electroencephalogram); (b) comprise primarily a paediatric cohort; (c) comprise primarily penetrating TBI. Eligible studies will be assessed against a modified Joanna Briggs Institute Critical Appraisal Instrument and data will be extracted by two independent reviewers. A descriptive analysis of MRI findings will be provided based on qualitative synthesis of data extracted. Quantitative analyses will include a meta-analysis and a network meta-analysis where there are sufficient data available. Ethics and dissemination Ethics approval is not required for the present study as there will be no original data collected. We intend to disseminate the results through publication to a high-quality peer-reviewed journal and conference presentations on completion. PROSPERO registration number CRD42022358358.
Breaking the limitation of polarization multiplexing in optical metasurfaces with engineered noise

Noise is usually undesired yet inevitable in science and engineering. However, by introducing the engineered noise to the precise solution of Jones matrix elements, we break the fundamental limit of polarization multiplexing capacity of metasurfaces that roots from the dimension constraints of the Jones matrix. We experimentally demonstrate up to 11 independent holographic images using a single metasurface illuminated by visible light with different polarizations. To the best of our knowledge, it is the highest capacity reported for polarization multiplexing. Combining the position multiplexing scheme, the metasurface can generate 36 distinct images, forming a holographic keyboard pattern. This discovery implies a new paradigm for high-capacity optical display, information encryption, and data storage. Description For more information, make some noise Holograms can be considered large-capacity memory storage media that are capable of holding information about three-dimensional scenes and compressing it into a two-dimensional pattern (metasurface). Attempting to store more images onto the one hologram pattern tends to result in cross talk and corruption of the stored data. Xiong et al. found that introducing engineered noise into the process enabled an increase in storage capacity. This approach should work for metasurfaces in applications such as high-capacity optical displays, information encryption, and data storage. —ISO Engineered noise can increase the channel capacity for polarization multiplexing with a metasurface hologram.
CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy

Anti–PD-1/PD-L1 therapy, either by anti–PD-1 antibody or anti–PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti–PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti–PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen–specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic. Description The response to anti-PD-1/PD-L1 therapy involves CD200+ T cells, which both predict and mediate the beneficial response. Identifying responders A challenge for the field of cancer immunotherapy is identifying which patients will respond to immune checkpoint blockade treatments such as anti-PD-1 or anti-PD-L1. Here, Wang et al. showed using murine tumor models that CD200+ CD8+ T cells were crucial for the efficacy of anti-PD-1/PD-L1 therapy. These CD200+ cytotoxic T lymphocytes had a unique chromatin landscape and possessed superior anti-tumor effector functions as compared to CD200- CD8+ T cells. Further, the authors showed, using data from multiple patient cohorts, that CD200+ T cells could predict immunotherapy efficacy, suggesting that this cell population could serve as a potential marker in the clinic. —CM
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies. Description A clinical-grade inhibitor of SCD delays tumor growth and increases sensitivity to DNA-damaging agents in GBM preclinical mouse models. SCD-ing into home for GBM Glioblastomas (GBM) are highly enriched with GBM stem-like cells (GSCs), which lead to resistance to standard therapy. GSCs rely on deregulated de novo lipid synthesis (DNLS), which represents a potential target for treatment, however, known inhibitors are not brain-penetrant and susceptibility is unknown. To address this, Eyme et al. evaluated the stearoyl CoA desaturase (SCD) inhibitor YTX-7739, which was able to trigger lipotoxicity in patient-derived GSCs, and showed therapeutic efficacy in GBM mouse models. Mechanistically, aberrant MEK/ERK signaling endowed sensitivity to SCD inhibitors, whereas AMPK activation rendered GSCs resistant. This represents a promising therapy for GBM that requires further study. —DH
Draft Genome Sequence of Lactiplantibacillus plantarum Strain ISO1, a Potential Probiotic Bacterium Isolated from the Milk of South African Saanen Goats

Lactiplantibacillus plantarum strain ISO1, a potential probiotic with wide food and biotechnological applications, was isolated from the raw milk of South African Saanen goats. Here, we report the draft genome sequence of this bacterium. Sequencing yielded a 3.23-Mb genome and 2,967 protein-coding sequences. ABSTRACT Lactiplantibacillus plantarum strain ISO1, a potential probiotic with wide food and biotechnological applications, was isolated from the raw milk of South African Saanen goats. Here, we report the draft genome sequence of this bacterium. Sequencing yielded a 3.23-Mb genome and 2,967 protein-coding sequences.
Mucosal Gene Expression in Response to SARS-CoV-2 Is Associated with Viral Load

Several prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity. ABSTRACT Little is known about the relationships between symptomatic early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and upper airway mucosal gene expression and immune response. To examine the association of symptomatic SARS-CoV-2 early viral load with upper airway mucosal gene expression, we profiled the host mucosal transcriptome from nasopharyngeal swab samples from 68 adults with symptomatic, mild-to-moderate coronavirus disease 19 (COVID-19). We measured SARS-CoV-2 viral load using reverse transcription-quantitative PCR (RT-qPCR). We then examined the association of SARS-CoV-2 viral load with upper airway mucosal immune response. We detected SARS-CoV-2 in all samples and recovered >80% of the genome from 95% of the samples from symptomatic COVID-19 adults. The respiratory virome was dominated by SARS-CoV-2, with limited codetection of other respiratory viruses, with the human Rhinovirus C being identified in 4 (6%) samples. This limited codetection of other respiratory viral pathogens may be due to the implementation of public health measures, like social distancing and masking practices. We observed a significant positive correlation between SARS-CoV-2 viral load and interferon signaling (OAS2, OAS3, IFIT1, UPS18, ISG15, ISG20, IFITM1, and OASL), chemokine signaling (CXCL10 and CXCL11), and adaptive immune system (IFITM1, CD300E, and SIGLEC1) genes in symptomatic, mild-to-moderate COVID-19 adults, when adjusting for age, sex, and race. Interestingly, the expression levels of most of these genes plateaued at a cycle threshold (CT) value of ~25. Overall, our data show that the early nasal mucosal immune response to SARS-CoV-2 infection is viral load dependent, potentially modifying COVID-19 outcomes. IMPORTANCE Several prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity. However, the relationship between SARS-CoV-2 viral load, airway mucosal gene expression, and immune response remains elusive. We profiled the nasal mucosal transcriptome from nasal samples collected from adults infected with SARS-CoV-2 during spring 2020 with mild-to-moderate symptoms using a comprehensive metatranscriptomics method. We observed a positive correlation between SARS-CoV-2 viral load, interferon signaling, chemokine signaling, and adaptive immune system in adults with COVID-19. Our data suggest that early nasal mucosal immune response to SARS-CoV-2 infection was viral load dependent and may modify COVID-19 outcomes.
On the stability of electron–positron pair equilibria and the X-ray variability of active galactic nuclei

A detailed linear stability analysis of pair equilibria in homogeneous, static two-temperature plasma clouds is presented. The case which electrons and positrons are heated in Coulomb interactions with hot protons, and are cooled by bremsstrahlung, annihilation and Compton scattering is considered. The treatment is kept analytical, except for a numerical evaluation of the eigenvalues of the stability matrix. Including energy conservation for both pairs and protons has a stabilizing effect on the equilibria causing the unstable region in parameter space to decrease by a factor of 2. The pair equilibria are unstable only when the compactness of the plasma cloud is in the limited range from 10 to 25, and the proton optical depth is less than 2.
Viruses Regulate Microbial Community Assembly Together with Environmental Factors in Acid Mine Drainage

Viruses as mobile genetic elements play critical roles in the adaptive evolution of their hosts in extreme environments. However, how viruses further influence microbial community structure and assembly is still unclear. ABSTRACT Viruses are widespread in various ecosystems, and they play important roles in regulating the microbial community via host-virus interactions. Recently, metagenomic studies showed that there are extremely diverse viruses in different environments from the ocean to the human gut, but the influences of viral communities on microbial communities are poorly understood, especially in extreme environments. Here, we used metagenomics to characterize microbial communities and viral communities in acid mine drainage (AMD) and evaluated how viruses shape microbial community constrained by the harsh environments. Our results showed that AMD viral communities are significantly associated with the microbial communities, and viral diversity has positive correlations with microbial diversity. Viral community explained more variations of microbial community composition than environmental factors in AMD of a polymetallic mine. Moreover, we found that viruses harboring adaptive genes regulate a relative abundance of hosts under the modulation of environmental factors, such as pH. We also observed that viral diversity has significant correlations with the global properties of microbial cooccurrence networks, such as modularity. In addition, the results of null modeling analyses revealed that viruses significantly affect microbial community phylogeny and play important roles in regulating ecological processes of community assembly, such as dispersal limitation and homogenous dispersal. Together, these results revealed that AMD viruses are critical forces driving microbial network and community assembly via host-virus interactions. IMPORTANCE Viruses as mobile genetic elements play critical roles in the adaptive evolution of their hosts in extreme environments. However, how viruses further influence microbial community structure and assembly is still unclear. A recent metagenomic study observed diverse viruses unexplored in acid mine drainage, revealing the associations between the viral community and environmental factors. Here, we showed that viruses together with environmental factors can constrain the relative abundance of host and microbial community assembly in AMD of copper mines and polymetallic mines. Our results highlight the importance of viruses in shaping the microbial community from the individual host level to the community level.
Factors Influencing the Nitrogen-Source Dependent Flucytosine Resistance in Cryptococcus Species

5-FC is a commonly used antifungal drug for treatment of cryptococcosis caused by Cryptococcus neoformans and C. gattii species complexes. When various amino acids were used as the sole nitrogen source for growth, we found lineage dependent differences in 5-FC susceptibility. ABSTRACT Flucytosine (5-FC) is an antifungal agent commonly used for treatment of cryptococcosis and several other systemic mycoses. In fungi, cytosine permease and cytosine deaminase are known major players in flucytosine resistance by regulating uptake and deamination of 5-FC, respectively. Cryptococcus species have three paralogs each of cytosine permease (FCY2, FCY3, and FCY4) and cytosine deaminase (FCY1, FCY5 and FCY6). As in other fungi, we found FCY1 and FCY2 to be the primary cytosine deaminase and permease gene, respectively, in C. neoformans H99 (VNI), C. gattii R265 (VGIIa) and WM276 (VGI). However, when various amino acids were used as the sole nitrogen source, C. neoformans and C. gattii diverged in the function of FCY3 and FCY6. Though there was some lineage-dependent variability, the two genes functioned as the secondary permease and deaminase, respectively, only in C. gattii when the nitrogen source was arginine, asparagine, or proline. Additionally, the expression of FCY genes, excluding FCY1, was under nitrogen catabolic repression in the presence of NH4. Functional analysis of GAT1 and CIR1 gene deletion constructs demonstrated that these two genes regulate the expression of each permease and deaminase genes individually. Furthermore, the expression levels of FCY3 and FCY6 under different amino acids corroborated the 5-FC susceptibility in fcy2Δ or fcy1Δ background. Thus, the mechanism of 5-FC resistance in C. gattii under diverse nitrogen conditions is orchestrated by two transcription factors of GATA family, cytosine permease and deaminase genes. IMPORTANCE 5-FC is a commonly used antifungal drug for treatment of cryptococcosis caused by Cryptococcus neoformans and C. gattii species complexes. When various amino acids were used as the sole nitrogen source for growth, we found lineage dependent differences in 5-FC susceptibility. Deletion of the classical cytosine permease (FCY2) and deaminase (FCY1) genes caused increased 5-FC resistance in all tested nitrogen sources in C. neoformans but not in C. gattii. Furthermore, we demonstrate that the two GATA family transcription factor genes GAT1 and CIR1 are involved in the nitrogen-source dependent 5-FC resistance by regulating the expression of the paralogs of cytosine permease and deaminase genes. Our study not only identifies the new function of paralogs of the cytosine permease and deaminase and the role of their regulatory transcription factors but also denotes the differences in the mechanism of 5-FC resistance among the two etiologic agents of cryptococcosis under different nitrogen sources.
Photoacoustic elastic bending in thin film—Substrate system

Theoretical model for optically excited two-layer elastic plate, which includes plasmaelastic, thermoelastic, and thermodiffusion mechanisms, is given in order to study the dependence of the photoacoustic (PA) elastic bending signal on the optical, thermal, and elastic properties of thin film—substrate system. Thin film-semiconductor sample (in our case Silicon) is modeled by simultaneous analysis of the plasma, thermal, and elastic wave equations. Multireflection effects in thin film are included in theoretical model and analyzed. Relations for the amplitude and phase of electronic and thermal elastic bending in the optically excited two-layer mechanically-supported circular plate are derived. Theoretical analysis of the thermodiffusion, plasmaelastic, and thermoelastic effects in a sample-gas-microphone photoacoustic detection configuration is given. Two normalization procedures of the photoacoustic elastic bending signal in function of the modulation frequency of the optical excitation are established.
Antibiotics and temperature alter microbiome assembly and host fecundity in spider mites

Abstract The microbial community in arthropods often modulate host fecundity, yet processes driving their assembly remain poorly understood. In this study, we investigated bacterial community assembly and host fecundity in Tetranychus truncatus that were exposed to antibiotics and varying temperatures. Antibiotic exposure dominates over temperature in shaping spider mite bacterial composition and network properties. Specifically, complexity of microbiota networks tend to decrease with antibiotic treatment while increasing along a temperature gradient from 20°C to 35°C. Analysis using neutral and null models revealed that bacterial community assembly in mites was chiefly driven by stochastic processes such as drift, with relative contribution > 85%. Relative contributions of each ecological process was rather weakly correlated with antibiotic and temperature conditions. Finally, fecundity tended to be lower in mites with microbiota variation following antibiotic treatment. This study reveals mechanisms underlying bacterial community assembly in spider mites and establishes microbiota as a potential mediator of host fecundity. Our results provide new insights into immediate adaptive processes between mites and microbiome in the context of environmental change.
Two feather mite species (Alloptidae, Freyanidae) associated with the Laysan Albatross Phoebastria immutabilis (Rothschild, 1893) (Diomedeidae) from Japanese coastal waters

Abstract The Laysan Albatross Phoebastria immutabilis (Rothschild, 1893) is a seabird species included in the Red List of the International Union for Conservation of Nature as Near Threatened (NT). We sampled two feather mite species, Diomedacarus gigas (Dubinin, 1949) and Echinacarus petaliferus (Trouessart, 1898), from the three albatross, and provided their redescriptions. This is the first record of D. gigas from the past half-century in Japan and the first report of E. petaliferus in this country. The haplotype network of partial sequences of cytochrome oxidase subunit for D. gigas showed that six of the seven haplotypes were unique to the mites sampled from each host individual. This mite species may have a very little opportunity for horizontal transmission between host individuals since albatrosses live alone over sea areas, except the breeding period on land.