bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological Inhibition of BTK reduces neuroinflammation and stress induced anxietyin vivo
Authors: Ghosh Simantini , Mohammed Zaidan , Singh Itender 
Published: January 2021

AbstractStress related disorders lead to serious psychiatric disabilities and are comorbid with anxiety and depression. Current therapies targeting several neurotransmitter systems are only able to mitigate symptoms partially. It is well recognized that stress and trauma related disorders lead to a prominent inflammatory response in humans, and in several animal models a robust neuroinflammatory response has been observed. However, the therapeutic potential of targeting specific components of the inflammatory response has not been adequately studied in this context. The current study investigated the NLRP3 - Caspase1-IL-1β pathway, which recent research has identified as a major contributor to exacerbated inflammatory response in several peripheral and central nervous system pathological conditions. Using two different models of stress, first - single prolonged restraint stress followed by brief underwater submersion and second - predator odor exposure in mice, we demonstrate heightened anxious behavior in mice one-week after stress. Females in both models display an exacerbated anxiety response than males within the stressed group. Consistent with this data stressed animals demonstrate upregulation of IL-1β, IL-6, Caspase1 activity and NLRP3 inflammasome activation in brain, with female animals showing a stronger neuroinflammatory phenotype. Pharmacological inhibition of NLRP3 inflammasome activation led to a rescue in terms of anxious behavior as well as attenuated neuroinflammatory response, both of which were significantly more prominent in female animals. Further, we observed induction of activated Bruton’s Tyrosine Kinase (BTK), an upstream positive regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with Ibrutinib, a drug that is already FDA approved for use in certain types of lymphomas and leukemias, as well as a second inhibitor of BTK, LFM-A13. In both sets of experiments, we found inhibition of BTK significantly reduced the anxious behavior in stressed mice and attenuated the induction of NLRP3 inflammasome, Caspase 1 and IL1β. Our results suggest that BTK inhibition can be further investigated in context of human stress and trauma related disorders as a therapeutic strategy.
Natural variation inGmRAVconfers ecological adaptation through photoperiod control of flowering time and maturity in soybean
Authors: Wang Yuhe , Xu Chongjing , Sun Jiafan , Dong Lidong , Li Minmin , Liu Ying , Wang Jianhui , Zhang Xiaoming , Li Dongmei , Sun Jingzhe , Zhang Yuntong , Shan Jinming , Li Wenbin , Zhao Lin 
Published: January 2021

ABSTRACTPhotoperiod strictly controlled vegetative and reproductive growth stages in soybean. A soybeanGmRAVtranscription factor containing both AP2 and B3 domains was shown to be a key component of this process. We identified six polymorphisms inGmRAVpromoter that showed significant association with flowering time and maturity of soybean in one or multiple environments. Soybean varieties with minor polymorphism exhibited longer growth period contributing to soybean adaptation to lower latitudes. The cis-acting element GT1CONSENSUS motif ofGmRAVpromoter controlled the growth period and shortened R5-R7 by reducing the expression level ofGmRAVin soybean. ThreeGmRAV-overexpressing (GmRAV-ox)transgenic lines displayed later flowering time and maturity, shorter height and fewer numbers of leaves compared with control plants, and transgenic inhibition ofGmRAV (GmRAV-i)soybean displayed earlier flowering time and maturity, and increased plant heights. 163 GmRAV-target genes were determined to be putatively directly bound and transcriptionally regulated by GmRAV by combining the results from the DAP-seq and RNA-seq analyses. Two GmRAV binding motifs [C(A/G/T)A(C)ACAA(G/T)A(C/T)A(G/T)] and [C(T/A)A(C/T) C(T/G)CTG] were identified.GmRAVacting downstream ofE3E4delayed soybean growth period by repressingGmFT5atranscriptional activity to guaranteed both vegetative and reproductive phase long enough to allow necessary energy reserved to be accumulated.
Antifungal activities of artesunate, chloramphenicol, and cotrimoxazole againstBasidiobolusspecies, the causal agents of gastrointestinal basidiobolomycosis
Authors: Al-Qahtani Saleh , Joseph Martin R.P. , Al Hakami Ahmed M. , Asseri Ali A. , Mathew Anjali , Al Bshabshe Ali , Alhumayed Suliman , Hamid Mohamed E. 
Published: January 2021

AbstractBasidiobolusspecies (n =13) isolated from human gastrointestinal basidiobolomycosis and lizards were tested against artesunate, chloramphenicol, and cotrimoxazole. The three agents exhibited inhibitory actions againstBasidiobolusspecies comparable to the known antifungals. The combined effects of artesunate + voriconazole and cotrimoxazole + voriconazole have significant synergic effects, p = 0.003 and p = 0.021, respectively. These are promising results that enhance accelerated combined treatment of GIB in humans particularly the combination of artesunate and voriconazole.
Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-low Induction of Therapy Resistance
Authors: Cotter Kellie A. , Gallon John , Uebersax Nadine , Rubin Philip , Meyer Kate D. , Piscuoglio Salvatore , Jaffrey Samie R. , Rubin Mark A. 
Published: January 2021

ABSTRACTRecent evidence has highlighted the role ofN6-methyladenosine (m6A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post-transcriptional regulation mediated by m6A in cancer. Here we explore prostate cancer as an exemplar and demonstrate that low levels ofN6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To explore this relationship, we generated the first prostate m6A maps, and further examined howMETTL3regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding extracellular matrix proteins are consistently upregulated withMETTL3knockdown. We also examined the relationship betweenMETTL3and androgen signaling and discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly,METTL3knockdown rendered the cells resistant to androgen receptor antagonists, implicating changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.
Inhibitor Binding Modulates Protonation States in the Active Site of SARS-CoV-2 Main Protease
Authors: Kneller Daniel W. , Phillips Gwyndalyn , Weiss Kevin L. , Zhang Qiu , Coates Leighton , Kovalevsky Andrey 
Published: January 2021

ABSTRACTThe main protease (3CL Mpro) from SARS-CoV-2, the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mproand to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the α-ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other α-ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation changes induced by inhibitors we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.
Acute inflammation, mediated by lung neutrophils, confers enhanced protection againstMycobacterium tuberculosisinfection in mice
Authors: Piergallini Tucker J. , Scordo Julia M. , Pino Paula A. , Torrelles Jordi B. , Turner Joanne 
Published: January 2021

AbstractInflammation plays a crucial role in the control ofMycobacterium tuberculosis(M.tb) infection. In this study, we demonstrate that an inflammatory pulmonary environment at the time of infection mediated by liposaccharide (LPS) treatment in mice confers enhanced protection againstM.tbfor up to 6 months post infection. This transient protective inflammatory environment was associated with a neutrophil and monocyte/macrophage influx as well as increased inflammatory cytokines.In vitroinfection of neutrophils from LPS treated mice demonstrated that LPS neutrophils exhibited increased recognition ofM.tb, and had a greater innate capacity for killingM.tb. Finally, partial depletion of neutrophils in LPS treated mice showed an increase inM.tbburden, suggesting neutrophils conferred the enhanced protection observed in LPS treated mice. These results indicate a positive role of an inflammatory environment during initialM.tbinfection, and suggests that acute inflammation at the time ofM.tbinfection can positively alter disease outcome.
Δ9-Tetrahydrocannabinolic acid A, the precursor to Δ9-tetrahydrocannabinol (THC)
Authors: Skell Jeffrey M. , Kahn Michael , Foxman Bruce M. 
Published: January 2021

While Δ9-tetrahydrocannabinolic acid A (THCA-A) has been reported to be difficult to crystallize and/or amorphous, we have obtained THCA-A in a pure crystalline form by extraction of marijuana and selective fractionation with liquid CO2. THCA-A (systematic name: 1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]isochromene-2-carboxylic acid, C22H30O4) crystallizes in the orthorhombic space group P212121, with Z = 8 and Z′ = 2. The two independent molecules are related by a pseudo-twofold axis centered between the two –CO2H groups, but the conformations of the two –C5H11 chains are quite different (tgt and ttg; t is trans and g is gauche). The carboxylate groups form an intermolecular R
2
2(8) hydrogen-bonded ring; the two C2O2 carboxylate planes are twisted out of the planes of the attached arene rings in opposite directions by 13.59 (8) and 18.92 (8)°, respectively, with a resultant interplanar angle of 28.89 (8)°. Each molecule also has an intramolecular S(6) hydrogen-bond motif between the ortho –OH group and the dihydropyran-ring O atom. Other conformational aspects of the two independent molecules are quite similar to those found in the previously determined structure of THCA-B. THCA-A has shown promise in a number of medical applications. Demonstration of the crystallinity and details of the crystal structure are expected to provide a standard point of departure for chemical and medical experiments.
Money Moves the Mare: The Response of Community‐Based Organizations to Health Care's Embrace of Social Determinants
Authors: TAYLOR LAUREN A. , BYHOFF ELENA 
Published: January 2021

Policy Points
Health policies that encourage health and social integration can induce community‐based organizations (CBOs) to adopt new ways of working from health care organizations, including their language, staffing patterns, and metrics. These changes can be explained by CBOs’ perceptions that health care organizations may provide new sources of revenue.
While the welfare implications of these changes are not yet known, policymakers should consider balancing the benefits of professionalizing CBOs against the risks of medicalizing them.
ContextRecent health policies incentivize health care providers to collaborate with community‐based organizations (CBOs), such as food pantries and homeless shelters, to address patients’ social determinants of health (SDOH). The perspectives of health care leaders on these policy changes have been studied, but the perspectives of CBO managers have not.MethodsOur research question was: How are CBOs in Massachusetts perceiving and responding to new Medicaid policies that encourage collaboration between health care organizations and CBOs? We interviewed 46 people in leadership positions at CBOs in Massachusetts for approximately an hour each. We analyzed these data abductively, meaning that we iterated between inductively coding transcripts and consulting existing theories and frameworks.FindingsWe found evidence of a knowing‐doing gap among CBOs. Even though CBOs value their distinctiveness and autonomy from health care, they have undertaken a series of organizational changes in response to the new Medicaid policy that make their organizations appear more like health care organizations. These changes include adopting new performance metrics, hiring clinical staff to the board and senior management positions, and using medical language to describe nonmedical work. Drawing on institutional theory, we suggest that the nonprofits undertake such changes in an effort to demonstrate legitimacy to health care organizations, who may be able to provide new sources of critically needed revenue.ConclusionsMassachusetts CBOs perceive health systems as potential sources of revenue, due in part to an ongoing Medicaid redesign that encourages the integration of health and social services. This perception is driving CBOs to appear more like health care organizations, but the impacts of these changes on welfare remain unknown.
Sociodemographic and health‐related determinants of seasonal influenza vaccination in pregnancy: A systematic review and meta‐analysis of the evidence since 2000
Authors: Okoli George N. , Reddy Viraj K. , Al‐Yousif Yahya , Neilson Christine J. , Mahmud Salaheddin M. , Abou‐Setta Ahmed M. 
Published: January 2021

AbstractIntroductionVaccination is considered to be the most practical and effective preventative measure against influenza. It is highly recommended for population subgroups most at risk of developing complications, including pregnant women. However, seasonal influenza vaccine uptake remains suboptimal among pregnant women, even in jurisdictions with universal vaccination. We summarized the evidence on the determinants of seasonal influenza vaccine uptake during pregnancy to better understand factors that influence vaccine uptake among pregnant women.Material and methodsWe systematically searched MEDLINE, Embase and CINAHL from January 2000 to February 2020 for publications in English reporting on sociodemographic and/or health‐related determinants of seasonal influenza vaccine uptake during pregnancy. Two reviewers independently included studies. One reviewer extracted data and assessed study quality, and another reviewer checked extracted data and study quality assessments for errors. Disagreements were resolved through consensus, or a third reviewer. We meta‐analyzed using the inverse variance, random‐effects method, and reported the odds ratios (OR) and 95% confidence intervals (CI).ResultsFrom 1663 retrieved citations, we included 36 studies. The following factors were associated with increased seasonal influenza vaccine uptake: Older age (20 studies: OR 1.13, 95% CI 1.07‐1.20), being nulliparous (13 studies: OR 1.26, 95% CI 1.15‐1.38), married (8 studies: OR 1.11, 95% CI 1.07‐1.15), employed (4 studies: OR 1.13, 95% CI 1.02‐1.24), a non‐smoker (8 studies: OR 1.25, 95% CI 1.04‐1.51) and having prenatal care (3 studies: OR 3.36, 95% CI 2.25‐5.02), a chronic condition (6 studies: OR 1.30, 95% CI 1.17‐1.44), been previously vaccinated (9 studies: OR 4.88, 95% CI 3.14‐7.57) and living in a rural area (9 studies: OR 1.09, 95% CI 1.05‐1.14). Compared with being black, being white was also associated with increased seasonal influenza vaccine uptake (11 studies: OR 1.30, 95% CI 1.20‐1.41).ConclusionsThe evidence suggests that several sociodemographic and health‐related factors may determine seasonal influenza vaccination in pregnancy, and that parity, history of influenza vaccination, prenatal care and comorbidity status may be influential.
Family socio‐economic status and children’s executive function: The moderating effects of parental subjective socio‐economic status and children’s subjective social mobility
Authors: Ming Hua , Zhang Feng , Jiang Ying , Ren Yi , Huang Silin 
Published: January 2021

Family socio‐economic status (SES) is significantly related to disparities in children’s executive function. Children from economically disadvantaged backgrounds perform worse on executive function tasks than their peers from high‐SES families. The protective factors in the relationship between SES and executive function have not been sufficiently investigated, especially from the perspective of parents’ and children’s perceptions and expectations regarding SES. Therefore, this study aimed to examine whether parental subjective SES and children’s subjective social mobility separately moderated the relationship between family SES and children’s executive function among 885 participants aged 9–13 years. The results showed that family SES was positively related to the three components of executive function (cognitive flexibility, inhibitory control, and working memory). Moreover, the relationship between SES and cognitive flexibility was weak among the children with a high level of subjective social mobility or those whose parents had high levels of subjective SES. Among children from families with economic hardship, subjective social mobility is a potential protective factor mitigating the negative effects of low family SES on their cognitive flexibility.
Non‐vitamin K antagonist oral anticoagulants versus warfarin in AF patients ≥ 85 years
Authors: Tsai Chuan‐Tsai , Liao Jo‐Nan , Chen Su‐Jung , Jiang Yu‐Ru , Chen Tzeng‐Ji , Chao Tze‐Fan 
Published: January 2021

AbstractBackgroundAtrial fibrillation (AF) prevalence and its risk of stroke rise with ageing. We aimed to investigate the outcomes of NOAC and warfarin in AF patients aged ≥ 85 years.MethodsThis is a retrospective study using Taiwan National Health Insurance Research Database. A total of 15,361 patients aged ≥ 85 years with AF on oral anticoagulants were identified. The end points included ischaemic stroke, intracranial haemorrhage (ICH), major bleeding, all‐cause mortality and composite adverse events (ICH or major bleeding or all‐cause mortality). Clinical outcomes were compared between each NOAC and warfarin after propensity matching.ResultsBefore propensity matching, patients taking warfarin were older, more female with more comorbidities than NOACs users. After propensity matching, baseline characteristics did not differ significantly between matched subjects receiving warfarin and each NOAC. Compared to warfarin, dabigatran was associated with a lower risk of ICH (hazard ratio [HR] 0.496), mortality (HR 0.558) and adverse events (HR 0.628), while rivaroxaban was associated with a lower risk of ischaemic stroke (HR 0.781), ICH (HR 0.453), mortality (HR 0.558) and adverse events (HR 0.636). Apixaban was associated with a lower risk of mortality (HR 0.488) and adverse events (HR 0.557) compared to warfarin. (all P < .05).ConclusionFor the efficacy, NOACs were associated with a comparable or lower risk of ischaemic stroke compared to warfarin. For adverse events, NOACs were associated with a lower risk of all‐cause mortality and composite adverse events. In the elderly AF population, NOACs could be a more favourable choice for stroke prevention.
Structure, content, unsafe abbreviations, and completeness of discharge summaries: A retrospective analysis in a University Hospital in Austria
Authors: Schwarz Christine Maria , Hoffmann Magdalena , Smolle Christian , Eiber Michael , Stoiser Bianca , Pregartner Gudrun , Kamolz Lars‐Peter , Sendlhofer Gerald 
Published: January 2021

AbstractRationale and objectiveThe discharge summary (DS) is one of the most important instruments to transmit information to the treating general physician (GP). The objective of this study was to analyse important components of DS, structural characteristics as well as medical and general abbreviations.MethodOne hundred randomly selected DS from five different clinics were evaluated by five independent reviewers regarding content, structure, abbreviations and conformity to the Austrian Electronic Health Records (ELGA) using a structured case report form. Abbreviations of all 100 DS were extracted. All items were scored on a 4‐point Likert‐type scale ranging from “strongly agree” to “strongly disagree” (or “not relevant”). Subsequently, the results were discussed among reviewers to achieve a consensus decision.ResultsThe mandatory fields, reason for admission and diagnosis at discharge were present in 80% and 98% of DS. The last medication was fully scored in 48% and the recommended medication in 94% of 100 DS. There were significant overall differences among clinics for nine mandatory items. In total, 750 unexplained abbreviations were found in 100 DS.ConclusionsIn conclusion, DS are often lacking important items. Particularly important are a detailed medication history and recommendations for further medication that should always be listed in each DS. It is thus necessary to design and implement changes that improve the completeness of DS. An important quality improvement can be achieved by avoiding the use of ambiguous abbreviations.
Neutropenia in dogs receiving vincristine for treatment of presumptive immune‐mediated thrombocytopenia
Authors: LaQuaglia Kathryn A. , Robertson James B. , Lunn Katharine F. 
Published: January 2021

AbstractBackgroundNeutropenia is an adverse effect of vincristine when used in multidrug chemotherapy protocols.ObjectiveTo determine the incidence of neutropenia, identify potential risk factors for neutropenia, and determine the effect of neutropenia on outcome, in dogs receiving vincristine for treatment of immune‐mediated thrombocytopenia (ITP).AnimalsOne hundred twenty‐seven client‐owned dogs presumptively diagnosed with ITP.MethodsIn this retrospective cohort study, medical records were reviewed to identify dogs presumptively diagnosed with ITP, and treated with vincristine, over a 15‐year period. Logistic regression was used to identify risk factors for the development of neutropenia in dogs receiving vincristine. Time to platelet count ≥40 000 platelets/μL, survival, and duration of hospitalization were compared between neutropenic and non‐neutropenic dogs.ResultsVincristine was administered to 127 dogs with presumptive ITP; 19 became neutropenic. Administration of cyclosporine was significantly (P < .001) associated with the development of neutropenia (odds ratio: 12.97, 95% confidence interval: 4.17, 40.35). There was no difference in median time to ≥40 000 platelets/μL between neutropenic dogs (4 days; range, 1‐14 days) and non‐neutropenic dogs (3 days; range, 0‐48 days). Percentage survival to discharge was 95% in both groups, but median duration of hospitalization was significantly longer in neutropenic dogs (6 days; range, 3‐22 days) compared to non‐neutropenic dogs (4 days; range, 2‐15 days).Conclusions and Clinical ImportanceCyclosporine administration was associated with the development of neutropenia in dogs receiving vincristine, which might be related to effects on metabolism of vincristine. Neutrophil counts should be monitored in dogs receiving vincristine treatment for ITP, particularly if administered in conjunction with cyclosporine.