Miracle-dz/UniFAR-FTUs huggingface dataset:
Extracellular Vesicle–Derived miR-124 Resolves Radiation-Induced Brain Injury

Radiation-induced neurocognitive decrements in immuno-competent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124. Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector–mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124. Significance: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124.
A Longitudinal Person-Centered Perspective on Positive and Negative Affect at Work

Abstract This research examines how the direction and intensity of employee’s positive and negative affect at work combine within different profiles, and the relations between these profiles and theoretically-relevant predictors (psychological need satisfaction and supervisor autonomy support) and outcomes (work-family conflict, absenteeism, and turnover intentions). A total sample of 491 firefighters completed our measures initially, and 139 of those completed the same measures again four months later, allowing us to examine the stability of these affect profiles over time. Latent profile analyses and latent transition analyses revealed five identical profiles across the two measurements occasions: (1) Low Negative Affect Facilitators; (2) Moderately Low Positive Affect Incapacitators; (3) High Positive Affect Facilitators; (4) Very Low Positive Affect Incapacitators; and (5) Normative. Membership into Profiles 3, 4, and 5 was very stable over time. In contrast, Profiles 1 and 2 were associated with a highly unstable membership over time. The highest levels of work-family conflict, absenteeism, and turnover intentions were associated with the Very Low Positive Affect Incapacitators. In contrast, the lowest levels of turnover intentions were associated with the Low Negative Affect Facilitators and High Positive Affect Facilitators.
Drought-Induced Xylem Embolism Limits the Recovery of Leaf Gas Exchange in Scots Pine1[OPEN]

Severe drought causes persistent damage to the water transport system of Scots pine seedlings and reduces carbon dioxide uptake of needles for at least 1 month after stress release. Climate change increases the occurrence of prolonged drought periods with large implications for forest functioning. Scots pine (Pinus sylvestris) is one of the most abundant conifers worldwide, and evidence is rising that its resilience to severe drought is limited. However, we know little about its ability to recover from drought-induced embolism. To analyze postdrought hydraulic recovery, we investigated stress and recovery dynamics of leaf gas exchange, nonstructural carbohydrates, and hydraulic properties in 2.5-year-old Scots pine seedlings. We quantified the degree of xylem embolism by combining in vivo x-ray microtomography with intrusive techniques including measurements of hydraulic conductivity and dye staining during drought progression and short-term (2 d) and long-term (4 weeks) recovery. Seedlings were grown under controlled conditions, and irrigation was withheld until stomata closed and xylem water potential declined to −3.2 MPa on average, causing a 46% loss of stem hydraulic conductivity. Following drought release, we found a gradual recovery of leaf gas exchange to 50% to 60% of control values. This partial recovery indicates hydraulic limitations due to drought-induced damage. Whereas xylem water potential recovered close to control values within 2 d, both x-ray microtomography and intrusive measurements revealed no recovery of stem hydraulic conductivity. Moreover, we did not find indications for nonstructural carbohydrate reserves limiting hydraulic recovery. Our findings demonstrate that Scots pine is able to survive severe drought and to partially recover, although we assume that xylem development during the next growing season might compensate for some of the hydraulic impairment. Such drought-induced legacy effects are important when considering vegetation responses to extreme events.
Motor memories in manipulation tasks are linked to contact goals between objects.

Skillful manipulation requires forming memories of object dynamics, linking applied force to motion. Although it has been assumed that such memories are linked to objects, a recent study showed that people can form separate memories when these are linked to different controlled points on an object (Heald et al. 2018). In that study, participants controlled the handle of a robotic device to move a virtual bar with circles (control points) on the left and right sides. Participants were instructed to move either the left or right control point to a target on the left or right, respectively, such that the required movement was constant. When these control points were paired with opposing force fields, adaptation was observed. In this previous study, both the controlled point and the target changed between contexts. To assess which of these factors is critical for learning, here we used a similar paradigm but with a bar that automatically rotated as it was moved. In the first experiment, the bar rotated such that the left and right control points moved to a common target. In the second experiment, the bar rotated such that a single control point moved to a target located on either the left or right. In both experiments, participants were able to learn opposing force fields applied in the two contexts. We conclude that separate memories of dynamics can be formed for different 'contact goals' involving a unique combination of the controlled point on an object and the target location this point 'contacts'.
PGE2 accounts for bidirectional changes in alveolar macrophage self-renewal with aging and smoking

Dysregulation of self-renewal contributes to alterations in alveolar macrophages (AMs). In this study, Penke et al identify PGE2 as a suppressor of AM proliferation, whose divergent bioavailability in aged and cigarette smoke-exposed mice could explain opposite effects on AM numbers. Alveolar macrophages (AMs) are resident immune cells of the lung that are critical for host defense. AMs are capable of proliferative renewal, yet their numbers are known to decrease with aging and increase with cigarette smoking. The mechanism by which AM proliferation is physiologically restrained, and whether dysregulation of this brake contributes to altered AM numbers in pathologic circumstances, however, remains unknown. Mice of advanced age exhibited diminished basal AM numbers and contained elevated PGE2 levels in their bronchoalveolar lavage fluid (BALF) as compared with young mice. Exogenous PGE2 inhibited AM proliferation in an E prostanoid receptor 2 (EP2)-cyclic AMP-dependent manner. Furthermore, EP2 knockout (EP2 KO) mice exhibited elevated basal AM numbers, and their AMs resisted the ability of PGE2 and aged BALF to inhibit proliferation. In contrast, increased numbers of AMs in mice exposed to cigarette smoking were associated with reduced PGE2 levels in BALF and were further exaggerated in EP2 KO mice. Collectively, our findings demonstrate that PGE2 functions as a tunable brake on AM numbers under physiologic and pathophysiological conditions.
Initial clinical experience treating patients with palliative radiotherapy for malignant pleural mesothelioma on the HalcyonTM linear accelerator.

BACKGROUND Radiation therapy (RT) can provide effective symptomatic palliation in patients with malignant pleural mesothelioma (MPM). Advances in RT technology, including intensity-modulated RT (IMRT) and volumetric-modulated arc therapy (VMAT), have improved treatment conformality, potentially improving the therapeutic ratio of RT. A novel 6-MV flattening-filter-free O-ring linear accelerator, HalcyonTM (Varian Medical Systems, Palo Alto, CA, USA), was built to provide such advanced therapies, while possibly reducing treatment time. Here, we report the initial clinical experience using HalcyonTM to deliver palliative RT for patients with MPM. METHODS We retrospectively assessed consecutive patients with MPM who received thoracic RT on HalcyonTM. Their electronic medical records were reviewed for clinical, RT planning, treatment timing, and image-guidance RT (IGRT) data. RESULTS Four patients with metastatic MPM received palliative RT on HalcyonTM between 1/2017-1/2020 for severe pain (50%), dysphagia (25%), or dyspnea (25%). Targets included a combination of pleura, chest wall, lung, hilum, and mediastinum, with patient-specific dose and fractionation regimens ranging from 20-45 Gy in 5-15 fractions, and 75% of patients receiving concurrent systemic therapy. Pre-specified target and organ-at-risk constraints were met for nearly all plans. At a median follow-up of 2.2 months (range, 1.6-7.1 months), all patients experienced either improved (75%) or stable (25%) tumor-related symptoms following palliative RT. The mean 3D vector couch correction was 0.67±0.15 cm. The mean beam-on, treatment (beam-on plus cone-beam computed tomography times), and approximated total room usage times were 1.6±0.2, 1.8±0.2, and 9.8±0.2 min, respectively. Grade 2 fatigue and cough occurred in 25% and 25% of patients, and no patients experienced Grade ≥3 toxicity. CONCLUSIONS In this initial clinical experience treating patients with palliative RT for MPM on HalcyonTM, treatment provided symptom palliation and local control across multiple palliative scenarios, with minimal toxicity, acceptable dosimetry, and setup corrections and treatment times that compared favorably with other published experiences of MPM RT. Palliative RT on HalcyonTM can provide patients with MPM quick and safe tumor-related symptom relief, even in a frail, elderly population.
Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission

Abstract The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses – the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other β-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.
Coffee Consumption and Invasive Breast Cancer Incidence among Postmenopausal Women in the Cancer Prevention Study-II Nutrition Cohort

Background: There is limited evidence of a potential inverse association between coffee, particularly caffeinated coffee, consumption and postmenopausal breast cancer risk, and few studies have examined this association by tumor hormone receptor status. To provide further evidence, we examined total, caffeinated, and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence overall, and by tumor estrogen receptor (ER) and/or progesterone receptor (PR) subtype. Methods: Among 57,075 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort who were cancer free and reported coffee intake in 1999, we identified 2,980 women diagnosed with invasive breast cancer during follow-up through June 2015. Multivariable-adjusted Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Neither total, caffeinated, nor decaffeinated coffee consumption was associated with invasive breast cancer risk; HRs (95% CIs) comparing consumption of ≥2 cups per day with <1 cup per month were 0.99 (0.89–1.11), 0.96 (0.87–1.06), and 1.06 (0.95–1.19), respectively. Similarly, coffee consumption was not associated with risk of hormone receptor–positive (ER+ or PR+) or hormone receptor–negative (ER− and PR−) breast tumors. Conclusions: These findings do not support an association between coffee consumption and invasive breast cancer risk among postmenopausal women. Impact: This large prospective study contributes to the limited evidence on coffee consumption and breast cancer risk, finding no association overall or by tumor receptor subtype.
Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd-stranded, i.e. 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel. Here, using the human voltage-dependent anion channel as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V216, V217, V218) and larger (V220, V221) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid-dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage-gated channel regulation, efficient mitochondrial targeting, and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.
Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa

Background Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP. Methods Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role. Results Exome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments. Conclusion This study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.
Interleukin-6 (IL-6) response to a simulated night-shift schedule is modulated by brain-derived neurotrophic factor (BDNF) genotype

ABSTRACT The BDNF gene contains a polymorphism (Val66Met) that influences sleep and may be associated with more flexible adaptation to circadian misalignment. Fifteen adult men (10 Val/Val homozygotes, 5 Val/Met heterozygotes) participated in a laboratory study involving two 5 d cycles of simulated night shifts. Circulating interleukin-6 (IL-6) was measured from plasma, sleep was recorded polysomnographically, and performance was measured using a psychomotor vigilance test. Compared to Val/Val homozygotes, heterozygotes exhibited a blunted IL-6 temporal (diurnal) pattern, less daytime sleep restriction, and less nighttime performance impairment after the first simulated night-shift cycle. These observations suggest that heterozygotes experienced more flexible circadian adaptation.
Urban upbringing and psychiatric disorders in the United States: A racial comparison

Background: Studies that link urbanicity to mental health are mixed depending on outcome and context. More research is needed to examine whether the urban upbringing effect holds true across racial populations in a large and diverse country like the United States. Methods: We analyzed two large datasets that were administered contemporaneously with similar methods: The National Comorbidity Survey-Replication (NCS-R, Whites) and the National Survey of American Life (NSAL, Blacks). We ran multivariable logistic regression models to examine the associations between area of upbringing (urban/large city, other, rural) and six psychiatric disorders, controlling for sex, age, years of education and income-to-poverty ratio (and ethnicity in the NSAL). We performed these analyses in both the NCS-R and the NSAL separately. Results: The majority (58.97%) of the White sample grew up in the ‘other’ category (i.e. small town, small city, or suburb of a large city), whereas a much larger percentage (39.89%) of the Black sample grew up in a large city. In the White sample, urban upbringing was not associated with any of the psychiatric disorders at a conventional level of statistical significance. In the Black sample, urban upbringing was associated with greater odds of having mood disorder, alcohol use disorder and drug use disorder, but was not significantly associated with anxiety disorders, PTSD, or eating disorders. Conclusions: Urban upbringing was not associated with psychiatric disorders among Whites, but was associated with greater odds of mood disorders, alcohol us disorder and drug use disorder among Blacks. Future research can elucidate how differences in urban upbringing between Whites and Blacks are linked to differences in risk for psychiatric disorders.
Prediction of COVID-19 Outbreaks Using Google Trends in India: A Retrospective Analysis

Objectives Considering the rising menace of coronavirus disease 2019 (COVID-19), it is essential to explore the methods and resources that might predict the case numbers expected and identify the locations of outbreaks. Hence, we have done the following study to explore the potential use of Google Trends (GT) in predicting the COVID-19 outbreak in India. Methods The Google search terms used for the analysis were “coronavirus”, “COVID”, “COVID 19”, “corona”, and “virus”. GTs for these terms in Google Web, News, and YouTube, and the data on COVID-19 case numbers were obtained. Spearman correlation and lag correlation were used to determine the correlation between COVID-19 cases and the Google search terms. Results “Coronavirus” and “corona” were the terms most commonly used by Internet surfers in India. Correlation for the GTs of the search terms “coronavirus” and “corona” was high (r > 0.7) with the daily cumulative and new COVID-19 cases for a lag period ranging from 9 to 21 days. The maximum lag period for predicting COVID-19 cases was found to be with the News search for the term “coronavirus”, with 21 days, i.e., the search volume for “coronavirus” peaked 21 days before the peak number of cases reported by the disease surveillance system. Conclusions Our study revealed that GTs may predict outbreaks of COVID-19, 2 to 3 weeks earlier than the routine disease surveillance, in India. Google search data may be considered as a supplementary tool in COVID-19 monitoring and planning in India.
When Beliefs Face Reality: An Integrative Review of Belief Updating in Mental Health and Illness

Belief updating is a relatively nascent field of research that examines how people adjust their beliefs in light of new evidence. So far, belief updating has been investigated in partly unrelated lines of research from different psychological disciplines. In this article, we aim to integrate these disparate lines of research. After presenting some prominent theoretical frameworks and experimental designs that have been used for the study of belief updating, we review how healthy people and people with mental disorders update their beliefs after receiving new information that supports or challenges their views. Available evidence suggests that both healthy people and people with particular mental disorders are prone to certain biases when updating their beliefs, although the nature of the respective biases varies considerably and depends on several factors. Anomalies in belief updating are discussed in terms of both new insights into the psychopathology of various mental disorders and societal implications, such as irreconcilable political and societal controversies due to the failure to take information into account that disconfirms one’s own view. We conclude by proposing a novel integrative model of belief updating and derive directions for future research.