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Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator ( CFTR ) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction. Roughly 10% of Cystic Fibrosis (CF) patients still have no effective medicine to take. Lung Selective Organ Targeting (SORT) Lipid Nanoparticles can efficiently deliver Cas9 mRNA, sgRNA, and donor ssDNA templates for precise homology-directed repair-mediated gene correction in ex vivo and in vivo CF models.

This paper aims to review the current state of brain-to-brain interface (B2BI) technology and its potential. B2BIs function via a brain-computer interface (BCI) to read a sender's brain activity and a computer-brain interface (CBI) to write a pattern to a receiving brain, transmitting information. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to systematically review current literature related to B2BI, resulting in 15 relevant publications. Experimental papers primarily used transcranial magnetic stimulation (tMS) for the CBI portion of their B2BI. Most targeted the visual cortex to produce phosphenes. In terms of study design, 73.3% (11) are unidirectional and 86.7% (13) use only a 1:1 collaboration model (subject to subject). Limitations are apparent, as the CBI method varied greatly between studies indicating no agreed upon neurostimulatory method for transmitting information. Furthermore, only 12.4% (2) studies are more complicated than a 1:1 model and few researchers studied direct bidirectional B2BI. These studies show B2BI can offer advances in human communication and collaboration, but more design and experiments are needed to prove potential. B2BIs may allow rehabilitation therapists to pass information mentally, activating a patient's brain to aid in stroke recovery and adding more complex bidirectionality may allow for increased behavioral synchronization between users. The field is very young, but applications of B2BI technology to neuroergonomics and human factors engineering clearly warrant more research.

Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock and humans. To determine the exposure factors and range of symptoms associated with human RVF, we performed a population-based cross-sectional survey in six villages across a 40 km transect in northeastern Kenya. A systematic survey of the total populations of six Northeastern Kenyan villages was performed. Among 1082 residents tested via anti-RVFV IgG ELISA, seroprevalence was 15% (CI95%, 13-17%). Prevalence did not vary significantly among villages. Subject age was a significant factor, with 31% (154/498) of adults seropositive vs. only 2% of children ≤15 years (12/583). Seroprevalence was higher among men (18%) than women (13%). Factors associated with seropositivity included a history of animal exposure, non-focal fever symptoms, symptoms related to meningoencephalitis, and eye symptoms. Using cluster analysis in RVFV positive participants, a more severe symptom phenotype was empirically defined as having somatic symptoms of acute fever plus eye symptoms, and possibly one or more meningoencephalitic or hemorrhagic symptoms. Associated with this more severe disease phenotype were older age, village, recent illness, and loss of a family member during the last outbreak. In multivariate analysis, sheltering livestock (aOR = 3.5 CI95% 0.93-13.61, P = 0.065), disposing of livestock abortus (aOR = 4.11, CI95% 0.63-26.79, P = 0.14), and village location (P = 0.009) were independently associated with the severe disease phenotype. Our results demonstrate that a significant proportion of the population in northeastern Kenya has been infected with RVFV. Village and certain animal husbandry activities were associated with more severe disease. Older age, male gender, herder occupation, killing and butchering livestock, and poor visual acuity were useful markers for increased RVFV infection. Formal vision testing may therefore prove to be a helpful, low-technology tool for RVF screening during epidemics in high-risk rural settings.

The present study examined the roles of shame- and guilt-proneness as mediators of associations between general causality orientations and depressive symptoms. We expected autonomy would be associated with less depressive symptoms based on higher guilt-proneness and lower shame-proneness, whereas control would be associated with more depressive symptoms based on lower guilt-proneness and higher shame-proneness. Undergraduates ( = 354) completed assessments of general causality orientations, shame- and guilt-proneness, and depressive symptoms in exchange for extra credit. Results of mediation analyses were generally supportive of the framework indicating that shame- and guilt-proneness mediate associations between self-determination and depressive symptoms. Autonomy was indirectly associated with less depressive symptoms through positive associations with guilt-proneness, in spite of unexpected positive associations with shame-proneness. Control and impersonal orientation were indirectly associated with more depressive symptoms through positive associations with shame-proneness. Results extend previous research relating self-determination to mental health in providing preliminary support suggesting that individual differences in self-determination facilitate differential tendencies in experiencing guilt and shame.

Abstract Rationale Pulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown. Objectives To determine effects of IAV infection on AFC, and to identify intercellular signaling mechanisms underlying influenza-mediated inhibition of AFC. Methods BALB/c mice were infected intranasally with influenza A/WSN/33 (10,000 or 2,500 focus-forming units per mouse). AFC was measured in anesthetized, ventilated mice by instilling 5% bovine serum albumin into the dependent lung. Measurements and Main Results Infection with high-dose IAV resulted in a steady decline in arterial oxygen saturation and increased lung water content. AFC was significantly inhibited starting 1 hour after infection, and remained suppressed through Day 6. AFC inhibition at early time points (1–4 h after infection) did not require viral replication, whereas AFC inhibition later in infection was replication-dependent. Low-dose IAV infection impaired AFC for 10 days, but induced only mild hypoxemia. High-dose IAV infection increased bronchoalveolar lavage fluid ATP and UTP levels. Impaired AFC at Day 2 resulted primarily from reduced amiloride-sensitive AFC, mediated by increased activation of the pyrimidine-P2Y purinergic receptor axis. However, an additional component of AFC impairment was due to activation of A1 adenosine receptors and stimulation of increased cystic fibrosis transmembrane regulator–mediated anion secretion. Finally, IAV-mediated inhibition of AFC at Day 2 could be reversed by addition of β-adrenergic agonists to the AFC instillate. Conclusions AFC inhibition may be an important feature of early IAV infection. Its blockade may reduce the severity of pulmonary edema and hypoxemia associated with influenza pneumonia.

Multiple recent outbreaks of Rift Valley Fever (RVF) in Africa, Madagascar, and the Arabian Peninsula have resulted in significant morbidity, mortality, and financial loss due to related livestock epizootics. Presentation of human RVF varies from mild febrile illness to meningoencephalitis, hemorrhagic diathesis, and/or ophthalmitis with residual retinal scarring, but the determinants for severe disease are not understood. The aim of the present study was to identify human genes associated with RVF clinical disease in a high-risk population in Northeastern Province, Kenya. We conducted a cross-sectional survey among residents (N = 1,080; 1-85 yrs) in 6 villages in the Sangailu Division of Ijara District. Participants completed questionnaires on past symptoms and exposures, physical exam, vision testing, and blood collection. Single nucleotide polymorphism (SNP) genotyping was performed on a subset of individuals who reported past clinical symptoms consistent with RVF and unrelated subjects. Four symptom clusters were defined: meningoencephalitis, hemorrhagic fever, eye disease, and RVF-not otherwise specified. SNPs in 46 viral sensing and response genes were investigated. Association was analyzed between SNP genotype, serology and RVF symptom clusters. The meningoencephalitis symptom phenotype cluster among seropositive patients was associated with polymorphisms in DDX58/RIG-I and TLR8. Having three or more RVF-related symptoms was significantly associated with polymorphisms in TICAM1/TRIF, MAVS, IFNAR1 and DDX58/RIG-I. SNPs significantly associated with eye disease included three different polymorphisms TLR8 and hemorrhagic fever symptoms associated with TLR3, TLR7, TLR8 and MyD88. Of the 46 SNPs tested, TLR3, TLR7, TLR8, MyD88, TRIF, MAVS, and RIG-I were repeatedly associated with severe symptomatology, suggesting that these genes may have a robust association with RVFV-associated clinical outcomes. Studies of these and related genetic polymorphisms are warranted to advance understanding of RVF pathogenesis.

Major Depression Disorder (MDD) is a common mental disorder that negatively affects many people’s lives worldwide. Developing an automated method to find useful diagnostic biomarkers from brain imaging data would help clinicians to detect MDD in its early stages. Depression is known to be a brain connectivity disorder problem. In this paper, we present a brain connectivity-based machine learning (ML) workflow that utilizes similarity/dissimilarity of spatial cubes in brain MRI images as features for depression detection. The proposed workflow provides a unified framework applicable to both structural MRI images and resting-state functional MRI images. Several cube similarity measures have been explored, including Pearson or Spearman correlations, Minimum Distance Covariance, or inverse of Minimum Distance Covariance. Discriminative features from the cube similarity matrix are chosen with the Wilcoxon rank-sum test. The extracted features are fed into machine learning classifiers to train MDD prediction models. To address the challenge of data imbalance in MDD detection, oversampling is performed to balance the training data. The proposed workflow is evaluated through experiments on three independent public datasets, all imbalanced, of structural MRI and resting-state fMRI images with depression labels. Experimental results show good performance on all three datasets in terms of prediction accuracy, specificity, sensitivity, and area under the Receiver Operating Characteristic (ROC) curve. The use of features from both structured MRI and resting state functional MRI is also investigated.

Women have a higher incidence of pain-related conditions, reports of pain, and are generally considered by medical professionals to have less tolerance for pain. These beliefs have pervaded society as well, with many believing women to be weaker, or sometimes stronger, than men. The effect on clinical research has also been profound, with many clinical trials and models failing to account for differences between the sexes in dangerous ways. Actual consensus in research on the subject of this difference has become a debate, with most researchers supporting the difference, some denying it, some explaining that it’s complicated, and others still failing to report on it in their results.This study seeks to provide a neuroscientific approach to this problem via analyzing eventrelated EEG components indicative of pain, paired with a traditional behavioral analysis of pain perception. Previous research has largely neglected the ability of neuroscience to shed further light on differences in pain processing between men and women. By leveraging the well-studied painevoked potential, we demonstrate that the difference between men and women regarding pain perception may not be as reliable as literature suggests.A public dataset of 51 subjects was used (25 female) containing physiological and behavioral data, and a repeated-measures ANCOVA was conducted to determine the impact of sex (male or female) on pain thresholds, verbal pain ratings, N1 amplitude, N2 amplitude, P2 amplitude, and Gamma band power while controlling for between-subject differences and stimulus intensity. Results indicate no significant differences between men and women in any of the measured dependent variables. We propose potential alternative sources for the well-studied paingap between sexes, including psych-sociocultural sources and the need for more nuanced models, as our results do not support the existence of this pain gap between men and women in response to laser-evoked pain. In total, this study presents a novel application of statistics and event-related EEG analysis to question the extent of the difference between men and women’s pain perception.