Miracle-dz/UniFAR-FTUs huggingface dataset:
SARS-CoV-2 nucleocapsid protein inhibits the stress 5 response through RNA-binding domain N2b

The nucleocapsid protein N of severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) enwraps and condenses the viral genome for packaging but is also an antagonist of the 21 innate antiviral defense. It suppresses the integrated stress response (ISR), purportedly by 22 interacting with stress granule (SG) assembly factors G3BP1 and 2, and inhibits type I 23 interferon responses. To elucidate its mode of action, we systematically deleted and over- 24 expressed distinct regions and domains. We show that N via domain N2b blocks PKR- 25 mediated ISR activation, as measured by suppression of ISR-induced translational arrest and 26 SG formation. N2b mutations that prevent dsRNA binding abrogate these activities also 27 when introduced in the intact N protein. Substitutions reported to block post-translation 28 modifications of N or its interaction with G3BP1/2 did not have a detectable additive effect. 29 In an encephalomyocarditis virus-based infection model, N2b - but not a derivative defective 30 in RNA binding - prevented PKR activation, inhibited β -interferon expression and promoted 31 virus replication. Apparently, SARS-CoV-2 N inhibits innate immunity by sequestering dsRNA 32 to prevent activation of PKR and RIG-I-like receptors. Observations made for the N protein of 33 human coronavirus 229E suggests that this may be a general trait conserved among 34 members of other orthocoronavirus (sub)genera. modifications elsewhere in the N protein that are known to regulate RNA binding nor dependent on physical interaction with G3BP1 and G2BP2. Using the encephalomyocarditis virus as a surrogate infection system we show that N2b domain prevents PKR-mediated activation of the ISR and suppresses IFNβ expression also in virus-infected cells. Our findings suggest that in addition to a function in replication and genome packaging, SARS-CoV-2 N functions as a classical antagonist of dsRNA-induced host defense. β recombinant EMCVs at MOI 10, were lysed at 6 or 8 hpi. Images are representative of three independent experiments.
In vitro efficacy of humanized regimen of flomoxef against extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae

ABSTRACT This study compared the efficacy of flomoxef with other β-lactam antibiotics against extended-spectrum β-lactamases (ESBL)-producing bacteria of clinical relevance. First, the prevalence and β-lactamase genotypes of ESBL-producing strains among Escherichia coli and Klebsiella pneumoniae isolates collected in Japan from 2004 to 2018 were investigated. High MIC90 values (>64 µg/mL) of ceftriaxone, cefepime, and ceftazidime and low MIC90 values (≤0.06–2 µg/mL) of flomoxef, cefmetazole, and meropenem against both species were observed. Second, a chemostat model was used to analyze the efficacy of humanized regimens of three oxacephem/cephamycin antibiotics (flomoxef, cefmetazole, cefoxitin) and two other antibiotics (meropenem and piperacillin/tazobactam) in suppressing the growth of five ESBL-producing E. coli and two K. pneumoniae strains. Flomoxef, piperacillin/tazobactam, and meropenem showed good bactericidal effects with >4 log10 CFU/mL reduction without bacterial regrowth at 24 h even when the MIC of test isolates was >MIC90. Cefmetazole and cefoxitin resulted in regrowth of test isolates with MIC ≥MIC90 at 24 h. Cefmetazole, cefoxitin, flomoxef, and meropenem showed increased MICs for regrown samples. A clear relationship between the proportion of time that the free drug concentration exceeded the MIC (%fT>MIC) and antibiotic efficacy was found for flomoxef, cefoxitin, and cefmetazole, and flomoxef had the highest %fT>MIC, whereas discrepancies between Clinical and Laboratory Standards Institute breakpoint and bactericidal activity were observed for cefmetazole. Flomoxef was effective in preventing the growth of all ESBL-producing strains, even those with an MIC eight times the MIC90. Thus, flomoxef may be a good alternative to meropenem in context of carbapenems sparing stewardship.
Spatial distribution of hand‐grasp motor task activity in spinal cord functional magnetic resonance imaging

Upper extremity motor paradigms during spinal cord functional magnetic resonance imaging (fMRI) can provide insight into the functional organization of the cord. Hand-grasping is an important daily function with clinical significance, but previous studies of similar squeezing movements have not reported consistent areas of activity and are limited by sample size and simplistic analysis methods. Here, we study spinal cord fMRI activation using a unimanual isometric hand-grasping task that is calibrated to participant maximum voluntary contraction (MVC). Two task modeling methods were considered: (1) a task regressor derived from an idealized block design (Ideal) and (2) a task regressor based on the recorded force trace normalized to individual MVC (%MVC). Across these two methods, group motor activity was highly lateralized to the hemicord ipsilateral to the side of the task. Activation spanned C5-C8 and was primarily localized to the C7 spinal cord segment. Specific differences in spatial distribution are also observed, such as an increase in C8 and dorsal cord activity when using the %MVC regressor. Furthermore, we explored the impact of data quantity and spatial smoothing on sensitivity to hand-grasp motor task activation. This analysis shows a large increase in number of active voxels associated with the number of fMRI runs, sample size, and spatial smoothing, demonstrating the impact of experimental design choices on motor activation.
A selection and targeting framework of cortical locations for line‐scanning fMRI

Depth‐resolved functional magnetic resonance imaging (fMRI) is an emerging field growing in popularity given the potential of separating signals from different computational processes in cerebral cortex. Conventional acquisition schemes suffer from low spatial and temporal resolutions. Line‐scanning methods allow depth‐resolved fMRI by sacrificing spatial coverage to sample blood oxygenated level‐dependent (BOLD) responses at ultra‐high temporal and spatial resolution. For neuroscience applications, it is critical to be able to place the line accurately to (1) sample the right neural population and (2) target that neural population with tailored stimuli or tasks. To this end, we devised a multi‐session framework where a target cortical location is selected based on anatomical and functional properties. The line is then positioned according to this information in a separate second session, and we tailor the experiment to focus on the target location. Anatomically, the precision of the line placement was confirmed by projecting a nominal representation of the acquired line back onto the surface. Functional estimates of neural selectivities in the line, as quantified by a visual population‐receptive field model, resembled the target selectivities well for most subjects. This functional precision was quantified in detail by estimating the distance between the visual field location of the targeted vertex and the location in visual cortex (V1) that most closely resembled the line‐scanning estimates; this distance was on average ~5.5 mm. Given the dimensions of the line, differences in acquisition, session, and stimulus design, this validates that line‐scanning can be used to probe local neural sensitivities across sessions. In summary, we present an accurate framework for line‐scanning MRI; we believe such a framework is required to harness the full potential of line‐scanning and maximize its utility. Furthermore, this approach bridges canonical fMRI experiments with electrophysiological experiments, which in turn allows novel avenues for studying human physiology non‐invasively.
Association between perimenopausal age and greater posttraumatic stress disorder and depression symptoms in trauma-exposed women

Posttraumatic stress disorder and depression symptoms in trauma-exposed women are impacted by reproductive age, such that perimenopausal women show higher symptom severity than premenopausal and postmenopausal women. Abstract Objective This study aimed to determine the relationship between stages of the menopause transition (premenopausal, perimenopausal, and postmenopausal) on symptoms of posttraumatic stress disorder (PTSD) and depression in trauma-exposed women. Methods A cross-sectional study conducted between 2005 and 2017 recruited and enrolled an urban community sample (n = 6,093) from nonpsychiatric medical clinic waiting rooms of Grady Memorial Hospital, a public safety net hospital in Atlanta, Georgia. Participants were female, 18 to 65 years old, and predominantly Black/African American. Results Of the 6,093 participants, 93.8% were Black/African American, 2.5% were White, and 3.8% were of all other races (Hispanic/Latino, Asian, multiracial). Participants younger than 40 years were categorized as premenopausal (n = 3,166), between 40 and 55 years of age were categorized as perimenopausal (n = 2,127), and older than 55 years were categorized as postmenopausal (n = 790). Menopause status was associated with total PTSD symptom severity (F2,5416 = 9.61, P < 0.001), symptom severity within all three PTSD symptom clusters (avoidance/numbing symptoms: F2,5416 = 7.10, P < 0.001; intrusive symptoms: F2,5416 = 7.04, P < 0.001; hyperarousal symptoms: F2,5409 = 8.31, P < 0.001), and depression symptom severity (F2,5148 = 11.4, P < 0.001). Compared with both premenopausal and postmenopausal women, perimenopausal women reported significantly worse total PTSD symptoms, symptoms in the hyperarousal cluster, and depressive symptoms. Conclusions The current cross-sectional data show that symptoms of PTSD and depression in women are associated with reproductive age, such that perimenopausal women show higher symptom severity than premenopausal and postmenopausal women. Future longitudinal studies can reveal how changes in hormones over the course of the menopause transition impact the symptoms, neurobiology, and psychophysiology of PTSD.
Predicting sport fish mercury contamination in heavily managed reservoirs: Implications for human and ecological health

Mercury (Hg) is a concerning contaminant due to its widespread distribution and tendency to accumulate to harmful concentrations in biota. We used a machine learning approach called random forest (RF) to test for different predictors of Hg concentrations in three species of Colorado reservoir sport fish. The RF approach indicated that the best predictors of 864 mm northern pike (Esox lucius) Hg concentrations were covariates related to salmonid stocking in each study system, while system-specific metrics related to productivity and forage base were the best predictors of Hg concentrations of 381 mm smallmouth bass (Micropterus dolomieu), and walleye (Sander vitreus). Protecting human and ecological health from Hg contamination requires an understanding of fish Hg concentrations and variability across the landscape and through time. The RF approach could be applied to identify potential areas/systems of concern, and predict whether sport fish Hg concentrations may change as a result of a variety of factors to help prioritize, focus, and streamline monitoring efforts to effectively and efficiently inform human and ecological health.
Clinical and Safety Outcomes of Endovascular Therapy 6 to 24 Hours After Large Vessel Occlusion Ischemic Stroke With Tandem Lesions

Background and Purpose Effect of endovascular therapy (EVT) in acute large vessel occlusion (LVO) patients with tandem lesions (TLs) within 6–24 hours after last known well (LKW) remains unclear. We evaluated the clinical and safety outcomes among TL-LVO patients treated within 6–24 hours. Methods This multicenter cohort was divided into two groups, based on LKW to puncture time: early window (<6 hours), and late window (6–24 hours). Primary clinical and safety outcomes were 90-day functional independence measured by the modified Rankin Scale (mRS: 0–2) and symptomatic intracranial hemorrhage (sICH). Secondary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction score ≥2b), first-pass effect, early neurological improvement, ordinal mRS, and in-hospital and 90-day mortality. Results Of 579 patients (median age 68, 32.1% females), 268 (46.3%) were treated in the late window and 311 (53.7%) in the early window. Late window group had lower median National Institutes of Health Stroke Scale score at admission, Alberta Stroke Program Early Computed Tomography Score, rates of intravenous thrombolysis, and higher rates for perfusion imaging. After adjusting for confounders, the odds of 90-day mRS 0–2 (47.7% vs. 45.0%, adjusted odds ratio [aOR] 0.71, 95% confidence interval [CI] 0.49–1.02), favorable shift in mRS (aOR 0.88, 95% CI 0.44–1.76), and sICH (3.7% vs. 5.2%, aOR 0.56, 95% CI 0.20–1.56) were similar in both groups. There was no difference in secondary outcomes. Increased time from LKW to puncture did not predicted the probability of 90-day mRS 0–2 (aOR 0.99, 95% CI 0.96–1.01, for each hour delay) among patients presenting <24 hours. Conclusion EVT for acute TL-LVO treated within 6–24 hours after LKW was associated with similar rates of clinical and safety outcomes, compared to patients treated within 6 hours.
Diaschisis in the human brain reveals specificity of cerebrocerebellar connections

Anatomical studies in animals and imaging studies in humans show that cerebral sensorimotor areas map onto corresponding cerebellar sensorimotor areas and that cerebral association areas map onto cerebellar posterior lobe regions designated as the representation of the association (cognitive and limbic) cerebellum. We report a patient with unilateral left hemispheric status epilepticus, whose brain MRI revealed diffuse unihemispheric cerebral cortical FLAIR and diffusion signal hyperintensity but spared primary motor, somatosensory, visual, and to lesser extent auditory cerebral cortices. Crossed cerebellar diaschisis (dysfunction at a site remote from, but connected to, the location of the primary lesion) showed signal hyperintensity in the right cerebellar posterior lobe and lobule IX, with sparing of the anterior lobe, and lobule VIII. This unique topographic pattern of involvement and sparing of cerebral and cerebellar cortical areas matches the anatomical and functional connectivity specialization in the cerebrocerebellar circuit. This first demonstration of within‐hemispheric specificity in the areas affected and spared by cerebrocerebellar diaschisis provides further confirmation in the human brain for topographic organization of connections between the cerebral hemispheres and the cerebellum.
Salt‐inducible kinases are required for glucose uptake and insulin signaling in human adipocytes

Salt‐inducible kinase 2 (SIK2) is abundantly expressed in adipocytes and downregulated in adipose tissue from individuals with obesity or insulin resistance. The main aims of this work were to investigate the involvement of SIKs in the regulation of glucose uptake in primary mature human adipocytes and to identify mechanisms underlying this regulation.
Predicting Insulin Resistance in a Pediatric Population With Obesity

Objectives: Insulin resistance (IR) affects children and adolescents with obesity and early diagnosis is crucial to prevent long-term consequences. Our aim was to identify predictors of IR and develop a multivariate model to accurately predict IR. Methods: We conducted a cross-sectional analysis of demographical, clinical, and biochemical data from a cohort of patients attending a specialized Paediatric Nutrition Unit in Portugal over a 20-year period. We developed multivariate regression models to predict IR. The participants were randomly divided into 2 groups: a model group for developing the predictive models and a validation group for cross-validation of the study. Results: Our study included 1423 participants, aged 3–17 years old, randomly divided in the model (n = 879) and validation groups (n = 544). The predictive models, including uniquely demographic and clinical variables, demonstrated good discriminative ability [area under the curve (AUC): 0.834–0.868; sensitivity: 77.0%–83.7%; specificity: 77.0%–78.7%] and high negative predictive values (88.9%–91.6%). While the diagnostic ability of adding fasting glucose or triglycerides/high density lipoprotein cholesterol index to the models based on clinical parameters did not show significant improvement, fasting insulin appeared to enhance the discriminative power of the model (AUC: 0.996). During the validation, the model considering demographic and clinical variables along with insulin showed excellent IR discrimination (AUC: 0.978) and maintained high negative predictive values (90%–96.3%) for all models. Conclusion: Models based on demographic and clinical variables can be advantageously used to identify children and adolescents at moderate/high risk of IR, who would benefit from fasting insulin evaluation.
Molecular targets for anti-oxidative protection of açaí berry against diabetes myocardial ischemia/reperfusion injury

Abstract Myocardial ischemia/reperfusion injury (MIRI) is the principal cause of death and occurs after prolonged blockage of the coronary arteries. Diabetes represents one of the main factors aggravating myocardial injury. Restoring blood flow is the first intervention against a heart attack, although reperfusion process could cause additional damage, such as the overproduction of reacting oxygen species (ROS). In recent years, açaí berry has gained international attention as a functional food due to its antioxidant and anti-inflammatory properties; not only that but this fruit has shown glucose-lowering effects. Therefore, this study was designed to evaluate the cardioprotective effects of açaí berry on the inflammatory and oxidative responses associated with diabetic MIRI. Diabetes was induced in rats by a single intravenous inoculation of streptozotocin (60 mg/kg) and allowed to develop for 60 days. MIRI was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. Açaí (200 mg/kg) was administered 5 min before the end of ischemia and 1 h after reperfusion. In this study, we clearly demonstrated that açaí treatment was able to reduce biomarkers of myocardial damage, infarct size, and apoptotic process. Moreover, açaí administrations reduced inflammatory and oxidative response, modulating Nf-kB and Nrf2 pathways. These results suggest that açai berry supplementation could represent a useful strategy for pathological events associated to MIRI.
Spatial heterogeneity-based Voronoi matching method for GlobeLand30 data inconsistency detection: a case study of Linqu County, Shandong, China

Abstract. Remotely sensed data have become a valuable source of data for mapping regional or global land cover. Referable to the spectral complexity and the quality of remotely sensed data selected, classification errors usually occurred in land cover mapping, where the errors occurred can result in an issue in which the spatial heterogeneity in remotely sensed data is inconsistent with that in land cover data. To ensure data quality, land cover data checking mainly depends on manual labor, which is time-consuming and labor-intensive. To tackle this issue, a spatial heterogeneity-based Voronoi matching method for automated detection of land cover data inconsistency is proposed. First, Harris corner-based Voronoi diagrams (HCVDs) are constructed utilizing the image noise filter and Harris corner detector. Second, the regional statistics of range on land cover data using HCVDs is calculated. Ultimately, by matching the heterogeneity in HCVDs and using HCVDs-based first-order neighbor filter, where inconsistent spatial heterogeneity occurs in land cover data can be found. A GlobeLand30 case study from Linqu County, Shandong, for the year 2010 in China is carried out. After detection and validation, this method is shown to be workable for detecting spatial regions where inconsistent spatial heterogeneity occurs in land cover data, and the data quality is improved by 6.3% in this study area after manual verification.
Metformin rescues migratory deficits of cells derived from patients with periventricular heterotopia

Periventricular neuronal heterotopia (PH) is one of the most common forms of cortical malformation in the human cortex. We show that human neuronal progenitor cells (hNPCs) derived from PH patients with a DCHS1 or FAT4 mutation as well as isogenic lines had altered migratory dynamics when grafted in the mouse brain. The affected migration was linked to altered autophagy as observed in vivo with an electron microscopic analysis of grafted hNPCs, a Western blot analysis of cortical organoids, and time‐lapse imaging of hNPCs in the presence of bafilomycin A1. We further show that deficits in autophagy resulted in the accumulation of paxillin, a focal adhesion protein involved in cell migration. Strikingly, a single‐cell RNA‐seq analysis of hNPCs revealed similar expression levels of autophagy‐related genes. Bolstering AMPK‐dependent autophagy by metformin, an FDA‐approved drug, promoted migration of PH patients‐derived hNPCs. Our data indicate that transcription‐independent homeostatic modifications in autophagy contributed to the defective migratory behavior of hNPCs in vivo and suggest that modulating autophagy in hNPCs might rescue neuronal migration deficits in some forms of PH.
Sequence specificity defines the effectiveness of PPMOs targeting Pseudomonas aeruginosa

ABSTRACT Development of new therapeutics against antibiotic resistant pathogenic bacteria is recognized as a priority across the globe. We have reported using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) as species-specific antibiotics. The oligo sequences, 11 bases are designed to be complementary to specific essential genes near the Shine-Dalgarno site and inhibit translation. Here, we analyzed target specificity and the impact of genetic mutations on lead PPMOs targeting the rpsJ or acpP gene of Pseudomonas aeruginosa. Mutants in P. aeruginosa PAO1 were generated with four, two, or one base-pair mutations within the 11-base target sequence of the rpsJ gene. All mutants exhibited increased MICs compared to wild-type PAO1 when treated with the RpsJ PPMO, and the increase in the MICs was proportional to the number of base-pair mutations. Among single base-pair mutants, mutations in the middle of the sequence were more impactful than mutations in 5′ or 3′ end of the sequence. The increased MICs shown by the rpsJ mutants could be reversed by PPMOs designed to target the mutated rpsJ sequence. BALB/c mice infected intratracheally with mutants demonstrated increased lung burden when treated with RpsJ PPMO compared to wild-type PAO1-infected mice treated with RpsJ PPMO. Treating mice with a PPMOs designed to specifically target the mutant sequence was more effective against these mutant strains. These experiments confirm target specificity of two lead P. aeruginosa PPMOs and illustrate one potential mechanism of resistance that could emerge from an antisense approach.