bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae
Authors: Swank Zoe , Senussi Yasmeen , Alter Galit , Walt David R. 
Published: June 2022

AbstractThe diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC.
Conformational rearrangements in 2nd voltage sensor domain switch PIP2- and voltage-gating modes in two-pore channels
Authors: Shimomura Takushi , Hirazawa Kiichi , Kubo Yoshihiro 
Published: June 2022

AbstractTwo-pore channels (TPCs) are activated by PIP2 binding to domain I and/or by voltage-sensing in domain II (DII). Little is known about how these two stimuli are integrated and how each TPC subtype achieves its unique preference. Here, we show that the distinct conformations of DII-S4 in the voltage-sensor domain determine the two gating modes. DII-S4 takes an intermediate conformation, and forced stabilization in this conformation was found to give or maintain a high PIP2-dependence in primarily voltage- dependent TPC3 or in PIP2-gated and non-voltage-dependent TPC2, respectively. We also found in TPC2 that a tricyclic antidepressant desipramine induces the DII-S4 based voltage-dependence and that a flavonoid naringenin biases the mode preference from PIP2-gating to desipramine-induced voltage-gating. Taken together, our study on TPCs revealed an unprecedented mode-switching mechanism involving conformational changes in DII-S4. This will pave the way for drug development by targeting specific gating modes of TPCs.Significance statementMembrane voltage and PIP2 are different types of signals on endosomal and lysosomal membranes. The two signals are integrated into two-pore channels (TPCs) whose two repeating domains, DI and DII, play roles in PIP2 binding and voltage sensing, respectively. We showed that the conformation of the S4 helix in DII determines the voltage-dependent or PIP2-dependent gating mode, which explains the different preferences of the two signals between TPC subtypes. The preference for these two gating modes can be changed by a flavonoid, naringenin. Our findings on the molecular mechanism of the two gating modes in TPCs provide a clue to the understanding and pharmacological manipulation of the signaling by PIP2 and voltage in intracellular organelles.
Epidemiological Mapping of Onchocerciasis Hypoendemic Area of North Achefer District, Amhara Regional State, Ethiopia
Authors: Mekonnin Wuletaw Tadesse , Kebede Tadesse , Mekasha Sindew 
Published: June 2022

AbstractBackgroundOnchocerciasis (river blindness) is caused by a filarial nematode worm called Onchocerca volvulus encapsulated in nodules under skin. The adult worm logged itself in nodules of cutaneous skin producing thousands of microfilariae per-day those migrating under the dermis of the skin causing cutaneous and eye disease. Ethiopia is one of countries with a high disease burden of onchocerciasis in Africa. Epidemiological mapping of onchocerciasis in hypoendemic area is a first step in elimination programme and to identify intervention eligible areas. Many districts are uncertain about onchocerciasis transmission; in identifying intervention eligible areas especially North Achefer is located adjacent to onchocerciasis endemic district (Alefa) which receiving semi-annual MDA, and its transmission status of the district is not well studied.ObjectiveThe purpose of this study was to assess the epidemiological status of onchocerciasis in the hypoendemic area of the North Achefer district of the Amhara Regional State.Methodologycommunity-based cross-sectional study design conducted from July to August 2021. Parasitological, immunological and serological (ELISA and RDT) data were collected from the field and for central laboratory. Statistical analysis was conducted using Epi-info software version 7, transported to SPSS software version 26. Descriptive analysis was conducted and presented with frequencies and percentages. The association between dependent and independent variables was analyzed using bivariate logistic regression and variables those with a P-value <0.05% was considered statistically significant.Resulta total of 264 participants enrolled in the study out of which 56.4% were male, with mean age of 28 years. The microscopic examination of skin snip was no microfilariae positive cases, whereas, 3% and 9.1% positive were recorded for Ov16 RDT and Ov16 ELISA test, respectively. Onchocerciasis morbidity indicators were 6 (2.3%), 12 (4.5%), and 9 (3.4%) palpable nodule, skin discoloration, and skin depigmentation respectively. Age, gender, village type, and distance from the river were independent variables that had a significant association with positivity for Ov16 ELISA test.Conclusiona high prevalence of onchocerciasis exposure which is above the WHO recommended threshold (5%) by Ov16 ELISA assay was observed. Distance from the river, village type, age, and gender had significantly associated with Ov16 ELISA test. Therefore, onchocerciasis elimination intervention in North Achefer is recommended to be implemented. Increasing the sample size and including molecular (i.e. PCR) and entomological technique best recommended to maximize the positivity of the disease and to insure the exact status of the disease in the district respectively.
Efficacy and Safety of Nebulized Ethanol Inhalation in COVID-19 Treatment. A Randomized, Clinical Trial
Authors: Amoushahi Ali , Moazam Elham , Reza Tabatabaei Amin , Ghasimi Golnaz , Salvatori Pietro , Grant-Whyte Ian , Ragab Ezz Ahmed 
Published: June 2022

AbstractBackgroundConsidering anti coronavirus effects of ethanol, the efficacy of its administration was evaluated in this research. Because of respiratory tract entrance of virus in COVID-19, this study was done by inhalation of nebulized ethanol.MethodsNinety-nine positive SARS-CoV-2-PCR patients who had been admitted at a respiratory clinic were included in this study. Patients were randomly assigned to the control (distilled water spray) and intervention (35% ethanol spray) group. Both groups were instructed to inhale 3 puffs of spray and inhale it, every six hours for a week. Global symptomatic score (GSS), clinical status scale,0020Blood Oxygenation, and C-Reactive Protein (CRP) at the first visit and days 3, 7, 14 were measured and compared between groups.ResultsThe GSS decreased more and faster in the intervention group (ethanol) (1.4+1.4 vs 2.3+1.7, P=0.035) two weeks after starting intervention. On day 14, the odds of intervention group to have better clinical status was 5.715 times (95% CI, 2.47 to 13.19) than of control group a statistically significant effect, Wald χ2 (1) =16.67, P =0.001. Blood oxygen saturation also improved earlier in the ethanol group but without statistical significance difference. The readmission rate was lower in the intervention group (zero vs 10.9%, P=0.02).ConclusionInhaled ethanol seems to be effective in improvement, mitigating clinical symptoms and reducing the need to repeat treatment. Considering the low cost, availability and no significant adverse events of ethanol, research and additional efforts are recommended to evaluate its curative effects in the early stages of COVID-19.
Accuracy of a Risk Alert Threshold for ICU Hypoglycemia: Retrospective Analysis of Alert Performance and Association with Clinical Deterioration Events
Authors: Horton William B. , Hannah Elaine E. , Morales Frances L. , Chaney Cherie R. , Krahn Katy N. , Chernyavskiy Pavel , Clark Matthew T. , Moorman J. Randall 
Published: June 2022

AbstractObjectiveTo quantify the accuracy of and clinical events associated with a risk alert threshold for impending hypoglycemia during ICU admissions.DesignRetrospective electronic health record review of clinical events occurring ≥1 and ≤12 hours after the hypoglycemia risk alert threshold was met.SettingAdult ICU admissions from June 2020 through April 2021 at the University of Virginia Medical Center.Patients342 critically-ill adults that were 63.5% male with median age 60.8 years, median weight 79.1 kg, and median body mass index of 27.5 kg/m2.InterventionsReal-world testing of our validated predictive model as a clinical decision support tool for ICU hypoglycemia.Measurements and Main ResultsWe retrospectively reviewed 350 hypothetical alerts that met inclusion criteria for analysis. The alerts correctly predicted 48 cases of Level 1 hypoglycemia that occurred ≥1 and ≤12 hours after the alert threshold was met (positive predictive value= 13.7%). Twenty-one of these 48 cases (43.8%) involved Level 2 hypoglycemia. Notably, three myocardial infarctions, one medical emergency team call, two initiations of cardiopulmonary resuscitation, 6 unplanned surgeries, 19 deaths, 20 arrhythmias, and 38 blood or urine cultures were identified or obtained ≥1 and ≤12 hours after an alert threshold was met. Alerts identified 102 total events of hypoglycemia and/or clinical deterioration, yielding a positive predictive value for any event of 29.1%.ConclusionsAlerts generated by a validated ICU hypoglycemia prediction model had positive predictive value of 29.1% for hypoglycemia and other associated adverse clinical events.Key PointsQuestionWhat are the accuracy of and clinical events associated with a risk alert threshold for ICU hypoglycemia?FindingsWe retrospectively reviewed 350 hypothetical alerts that correctly predicted 48 cases of Level 1 hypoglycemia occurring ≥1 and ≤12 hours after the alert threshold was met (positive predictive value= 13.7%). Notably, three myocardial infarctions, one medical emergency team call, two initiations of cardiopulmonary resuscitation, 6 unplanned surgeries, 19 deaths, 20 arrhythmias, and 38 blood or urine cultures were identified or obtained ≥1 and ≤12 hours after an alert threshold was met.MeaningAlerts generated by a validated ICU hypoglycemia prediction model had positive predictive value of 29.1% for hypoglycemia and other associated adverse clinical events.
Global estimates of the fitness advantage of SARS-CoV-2 variant Omicron
Authors: van Dorp Christiaan , Goldberg Emma , Ke Ruian , Hengartner Nick , Romero-Severson Ethan 
Published: June 2022

AbstractNew variants of SARS-CoV-2 show remarkable heterogeneity in their relative fitness both over time and space. In this paper we extend a previously published model for estimating the selection strength for new SARS-CoV-2 variants to a hierarchical, mixed-effects, renewal equation model. This formulation allows us to globally estimate selection effects at different spatial levels while controlling for complex patterns of transmission and jointly inferring the effects of unit-level covariates in the spatial heterogeneity of SARS-CoV-2 selection effects. Applying this model to the spread of Omicron in 40 counties finding evidence for very strong (64%) but very heterogeneous selection effects at the country level. We further considered different measures of vaccination levels and measures of recent population-level infection as possible explanations. However, none of those variables were found to explain a significant proportion of the heterogeneity in country-level selection effects. We did find a significant positive correlation between the selection advantage of Delta and Omicron at the country level, suggesting that region-specific explanatory variables of fitness differences do exist. Our method is implemented in the Stan programming language, can be run on standard commercial-grade computing resources, and should be straightforward to apply to future variants.
Effectiveness of mRNA COVID-19 vaccine boosters against infection, hospitalization and death: a target trial emulation in the omicron (B.1.1.529) variant era
Authors: Ioannou George N. , Bohnert Amy SB , O’Hare Ann M. , Boyko Edward J. , Maciejewski Matthew L. , Smith Valerie A. , Bowling C. Barrett , Viglianti Elizabeth , Iwashyna Theodore J. , Hynes Denise M. , Berry Kristin ,   the COVID-19 Observational Research Collaboratory (CORC)
Published: June 2022

AbstractBackgroundThe effectiveness of a 3rd mRNA COVID-19 vaccine (“booster”) dose against the omicron (B.1.1.529) variant is uncertain especially in older, high-risk populations.ObjectiveTo determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization and death in the omicron era by type of booster, type of primary vaccine, time since primary vaccine, age and comorbidity burden.DesignTarget trial emulation study comparing booster vaccination versus no booster.SettingU.S. Department of Veterans Affairs (VA) healthcare systemParticipants and InterventionAmong persons who had received two mRNA COVID-19 vaccine doses at least 5 months earlier, we designed this retrospective matched cohort study to emulate a target trial of booster mRNA vaccination (BNT162b2 or mRNA-1273) versus no booster, conducted from 12/01/2021 to 03/31/2022.MeasurementsBooster VE.ResultsEach group included 490,838 well-matched persons, predominantly male (88%), mean age 63.0±14.0 years, followed for up to 121 days (mean 79.8 days). Booster VE >10 days after booster was 42.3% (95% CI 40.6-43.9) against SARS-CoV-2 infection, 53.3% (48.1-58.0) against SARS-CoV-2-related hospitalization and 79.1% (71.2-84.9) against SARS-CoV-2-related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups or primary vaccination regimens, but was significantly higher with longer time since primary vaccination and with higher comorbidity burden.LimitationsPredominantly male population.ConclusionsBooster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden.Primary Funding Source: Department of Veterans Affairs
Insights for disease modeling from single cell transcriptomics of iPSC-derived Ngn2-induced neurons and astrocytes across differentiation time and co-culture
Authors: Das D , Sonthalia S , Stein-O’Brien G , Wahbeh MH , Feuer K , Goff L , Colantuoni C , Mahairaki V , Avramopoulos D 
Published: June 2022

ABSTRACTTrans-differentiation of human induced pluripotent stem cells into neurons via Ngn2-induction (hiPSC-N) has become an efficient system to quickly generate neurons for disease modeling andin vitroassay development, a significant advance from previously used neoplastic and other cell lines. Recent single-cell interrogation of Ngn2-induced neurons however, has revealed some similarities to unexpected neuronal lineages. Similarly, a straightforward method to generate hiPSC derived astrocytes (hiPSC-A) for the study of neuropsychiatric disorders has also been described. Here we examine the homogeneity and similarity of hiPSC-N and hiPSC-A to theirin vivocounterparts, the impact of different lengths of time post Ngn2 induction on hiPSC-N (15 or 21 days) and of hiPSC-N / hiPSC-A co-culture. Leveraging the wealth of existing public single-cell RNA-seq (scRNA-seq) data in Ngn2-induced neurons andin vivodata from the developing brain, we provide perspectives on the lineage origins and maturation of hiPSC-N and hiPSC-A. While induction protocols in different labs produce consistent cell type profiles, both hiPSC-N and hiPSC-A show significant heterogeneity and similarity to multiplein vivocell fates, and both more precisely approximate theirin vivocounterparts when co-cultured. Gene expression data from the hiPSC-N show enrichment of genes linked to schizophrenia (SZ) and autism spectrum disorders (ASD) as has been previously shown for neural stem cells and neurons. These overrepresentations of disease genes are strongest in our system at early times (day 15) in Ngn2-induction/maturation of neurons, when we also observe the greatest similarity to earlyin vivoexcitatory neurons. We have assembled this new scRNA-seq data along with the public data explored here as an integrated biologist-friendly web-resource for researchers seeking to understand this system more deeply: nemoanalytics.org/p?l=DasEtAlNGN2&g=PRPH.
DHCR7 as a novel regulator of ferroptosis in hepatocytes
Authors: Yamada Naoya , Karasawa Tadayoshi , Komada Takanori , Matsumura Takayoshi , Baatarjav Chintogtokh , Ito Junya , Nakagawa Kiyotaka , Yamamuro Daisuke , Ishibashi Shun , Miura Kouichi , Sata Naohiro , Takahashi Masafumi 
Published: June 2022

AbstractRecent evidence indicates that ferroptosis is implicated in the pathophysiology of various liver diseases; however, the mechanism of ferroptosis regulation in the liver is poorly understood. Here, using the whole-genome screening approach, we identified 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a novel regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppressed lipid peroxidation and ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increased its substrate, 7-dehydrocholesterol (7-DHC), and extrinsic 7-DHC supplementation in turn suppressed ferroptosis. On the other hand, cholesterol deprivation had no effect on ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), was increased by a ferroptosis inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition was driven by intracellular 7-DHC as a radical scavenger. While extrinsic 7-DHC supplementation suppressed ferroptosis in various cancer cells, pharmacological DHCR7 inhibition by AY9944 showed cell-type specific effects, which could be explained by high DHCR7 expression in Huh-7 cells. We further showed that AY9944 suppressed ferroptosis in murine primary hepatocytes in vitro and systemic administration of AY9944 inhibited hepatic ischemia-reperfusion injury in vivo. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest that DHCR7 inhibition is a potential therapeutic option for ferroptosis-related liver diseases.
The essential role of disulfide bonds for the hierarchical self-assembly and wet-adhesion of CP20-derived peptides
Authors: Li Baoshan , Song Junyi , Mao Ting , Zeng Ling , Ye Zonghuang , Hu Biru 
Published: June 2022

AbstractBarnacles are typical fouling organisms which strongly adhere to immersed solid substrates by secreting proteinaceous adhesives called cement proteins (CPs). The self-assembly of the cement proteins forms a permanently bounded layer that binds barnacle to foreign surfaces. However, due to the abundance of cysteines in whole-length CP20, it is difficult to determine its natural structure and to properly describe its self-assembly properties. In this study, a putative functional motif of Balanus albicostatus CP20 (BalCP20) is identified and found to present distinctive self-assembly and wet-adhesion characteristics. The atomic force microscopy (AFM) and transmission electron microscope (TEM) investigations show that wildtype BalCP20-P3 forms grain-like spindles, which further assembly into fractal-like structures looks like ears of wheat. SDS-PAGE, AFM and LSCM show that DTT treatment opens up disulfide bonds between cysteines and disrupts the fractal-like structures (eras of wheat). Additionally, these morphologies are abolished when one of the BalCP20-P3 four cysteines is mutated by alanine. Circular dichroism (CD) results further suggest that the morphological diversity among BalCP20-P3 and its mutations lays on the proportion of α-helix. The above results demonstrate that cysteines and disulfide bonds play a crucial role in the self-assembly of BalCP20-P3. This study provides new insights into BalCP20 underwater adhesion, and brings in new inspirations for the development of novel bionic underwater adhesive.
An engineered xCas12i with high activity, high specificity and broad PAM range
Authors: Zhang Hainan , Kong Xiangfeng , Xue Mingxing , Wang Zikang , Wei Yinghui , Wang Haoqiang , Zhou Jingxing , Zhang Weihong , Xu Mengqiu , Shen Xiaowen , Li Jinhui , Hu Jing , Zhong Na , Zhou Yingsi , Yang Hui 
Published: June 2022

AbstractThe type-V CRISPR effector Cas12i, with its smaller size, short crRNA guiding, and self-processing features, is a potentially versatile genome editing tool. By screening Cas12i proteins from a metagenomic database, we identified a natural variant with high activity in mammalian cells, named as xCas12i. We further engineered the PAM-interacting, REC, and RuvC domains for enhanced cleavage activity and specificity. This variant, named as high-fidelity Cas12Max, exhibited robust genome editing activity and minimal off-target activity with a broad 5’-TN recognition profile. With the fusion of deaminase TadA8e and further optimization of xCas12i, the base editor dCas12i-Tad8e also showed the high editing efficiency. This study provides highly efficient and specific tools for gene therapy.
Phenotypic selection analysis and confounding environmental variables
Authors: Morrissey Michael B. , Henshaw Jonathan M. 
Published: June 2022

AbstractWhen environmental variation contributes to relationships between traits and fitness, it can confound analyses of phenotypic selection and, ultimately, bias predictions of adaptive evolution. To date, discussions of how to combat this problem emphasise complex statistical analyses aimed at estimating the genetic basis of the relationship between traits and fitness (e.g., the secondary theorem of selection). This article presents a path analysisbased description of the environmental confounding problem, which clarifies the issue and motivates simpler analyses as potential solutions. We show how standard selection analyses can be expanded to explicitly include environmental variables that may confound trait-fitness relationships, potentially leading to dramatically improved predictions of the evolutionary response to selection relative to classical phenotype-based estimates. We provide both univariate and multivariate treatments of the decomposition of the selection differential into components that may cause evolution via direct and indirect selection and components representing evolutionarily inert, environmentally-induced covariance. The multivariate treatment also yields expressions for the decomposition of the selection differential based on extended selection gradients, which may be of wide general interest beyond the environmental problem. Our approach to the environmental confounding problem makes more plausible demands on data than previous, more involved, quantitative genetic approaches, and addresses the issue of environmental confounding in a more biologically informative way.