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The transformation of crystalline silicon to amorphous silicon during ball milling was quantitatively measured by x-ray diffraction and electrochemical methods. Amorphous silicon was found to form rapidly from the very initial stages of ball milling. Simultaneously, the grain size of the crystalline silicon phase decreased. Under extended milling times it was found that a maximum of 86 % of the silicon became amorphous. Similarly, the grain size of the crystalline silicon phase could not be reduced below 6 nm. This transformation followed an Avrami kinetic model, which is consistent with a system which reaches a steady state. These observations suggest a mechanism in which ball milling generates defects, resulting in silicon amorphization and grain size reduction, where the degree of amorphization is limited in extent because there exists a limiting silicon grain size below which defects are no longer formed.
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Variability in drug effectiveness and provider prescribing patterns have been reported in different racial and ethnic populations. We sought to evaluate antihypertensive drug effectiveness and prescribing patterns among self-identified Hispanic/Latino (Hispanic), Non-Hispanic Black (Black), and Non-Hispanic White (White) populations that enrolled in the NIH All of Us Research Program, a US longitudinal cohort. We employed a self-controlled case study method using electronic health record and survey data from 17,718 White, Hispanic, and Black participants who were diagnosed with essential hypertension and prescribed at least one of 19 commonly used antihypertensive medications. Effectiveness was determined by calculating the reduction in systolic blood pressure measurements after 28 or more days of drug exposure. Starting systolic blood pressure and effectiveness for each medication were compared for self-reported Black, Hispanic, and White participants using adjusted linear regressions. Black and Hispanic participants were started on antihypertensive medications at significantly higher SBP than White participants in 13 and 7 out of 19 medications, respectively. More Black participants were prescribed multiple antihypertensive medications (58.46%) than White (52.35%) or Hispanic (49.9%) participants. First-line HTN medications differed by race and ethnicity. Following the 2017 American College of Cardiology and the American Heart Association High Blood Pressure Guideline release, around 64% of Black participants were prescribed a recommended first-line antihypertensive drug compared with 76% of White and 82% of Hispanic participants. Effect sizes suggested that most antihypertensive drugs were less effective in Hispanic and Black, compared with White, participants, and statistical significance was reached in 6 out of 19 drugs. These results indicate that Black and Hispanic populations may benefit from earlier intervention and screening and highlight the potential benefits of personalizing first-line medications.
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We measure the tau-to-light-lepton ratio of inclusive B-meson branching fractions R(X_{τ/â})≡B(BâXτν)/B(BâXâν), where â indicates an electron or muon, and thereby test the universality of charged-current weak interactions. We select events that have one fully reconstructed B meson and a charged lepton candidate from 189 fb^{-1} of electron-positron collision data collected with the Belle II detector. We find R(X_{τ/â})=0.228±0.016(stat)±0.036(syst), in agreement with standard-model expectations. This is the first direct measurement of R(X_{τ/â}).
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Eubacterium species are a group of obligated anaerobic gram-positive bacilli that are recognized as commensals of the gastrointestinal tract flora. Cases of bacteremia mediated by Eubacterium are rare. This report describes a case of bacteremia caused by Eubacterium callanderi in an 82-year-old female with a history of a cecal perforation secondary to an obstructing sigmoid stricture. The results showed the utility of using whole genome sequencing to identify the causative agent and underlined the significance to identify anaerobic organisms in diagnostic microbiology practice and to perform antimicrobial susceptibility testing to guide therapy and enhance patient outcomes.
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Supplementing livestock grazing communal rangelands with leaf-meals from Acacia trees, which are currently considered as problematic invasive alien plants globally, may be a sustainable way of exploiting their desirable nutritional and anthelmintic properties. The current study evaluated worm burdens and growth performance of lambs grazing low-quality communal rangelands supplemented with leaf-meals prepared from the invasive alien plant species; Acacia mearnsii or A. dealbata. Forty, three-month-old ewe lambs weighing an average of 18.9 ± 0.60 kg were randomly allocated to four supplementary diets: (1) rangeland hay only (control), (2) commercial protein supplement plus rangeland hay, (3) A. mearnsii leaf-meal plus rangeland hay and (4) A. dealbata leaf-meal plus rangeland hay. All the supplementary diets were formulated to meet the lambs' minimum maintenance requirements for protein. All the lambs were grazed on communal rangelands daily from 0800 to 1400 after which they were penned to allow them access to their respective supplementary diets until 08:00 the following morning. The respective supplementary diets were offered at the rate of 400 g ewe- 1 day- 1 for 60 days. Lambs fed the commercial protein supplement had the highest dry matter intake followed by those fed the Acacia leaf-meals and the control diet, respectively (P ≤ 0.05). Relative to the other supplementary diets, lambs fed the commercial protein supplement and A. dealbata leaf-meal had higher (P ≤ 0.05) final body weight and average daily gains. Dietary supplementation did not affect lamb faecal worm egg counts over the study period (P > 0.05). There was no association between supplementary diets and lamb FAMACHA© scores (P > 0.05). It was concluded that supplementation of Acacia dealbata versus Acacia mearnsii has the potential to emulate commercial protein in maintaining growth performance of lambs grazing communal rangelands in the dry season.
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Acacia , Alimentación Animal , Dieta , Suplementos Dietéticos , Hojas de la Planta , Animales , Alimentación Animal/análisis , Hojas de la Planta/química , Suplementos Dietéticos/análisis , Femenino , Sudáfrica , Dieta/veterinaria , Oveja Doméstica/crecimiento & desarrollo , Oveja Doméstica/fisiología , Enfermedades de las Ovejas/prevención & control , Enfermedades de las Ovejas/parasitología , Ovinos/crecimiento & desarrollo , Ovinos/fisiología , Heces , Distribución Aleatoria , Recuento de Huevos de Parásitos/veterinaria , Fenómenos Fisiológicos Nutricionales de los AnimalesRESUMEN
The magnitude and duration of vertebrate viremia are critical determinants of arbovirus transmission, geographic spread, and disease severity-yet, mechanisms determining arbovirus viremia levels are poorly defined. Previous studies have drawn associations between in vitro virion-glycosaminoglycan (GAG) interactions and in vivo clearance kinetics of virions from blood circulation. From these observations, it is commonly hypothesized that GAG-binding virions are rapidly removed from circulation due to ubiquitous expression of GAGs by vascular endothelial cells, thereby limiting viremia. Using an in vivo model for viremia, we compared the vascular clearance of low and enhanced GAG-binding viral variants of chikungunya, eastern- (EEEV), and Venezuelan- (VEEV) equine encephalitis viruses. We find GAG-binding virions are more quickly removed from circulation than their non-GAG-binding variant; however individual clearance kinetics vary between GAG-binding viruses, from swift (VEEV) to slow removal from circulation (EEEV). Remarkably, we find phagocytes are required for efficient vascular clearance of some enhanced GAG-binding virions. Moreover, transient depletion of vascular heparan sulfate impedes vascular clearance of only some GAG-binding viral variants and in a phagocyte-dependent manner, implying phagocytes can mediate vascular GAG-virion interactions. Finally, in direct contrast to mice, we find enhanced GAG-binding EEEV is resistant to vascular clearance in avian hosts, suggesting the existence of species-specificity in virion-GAG interactions. In summary, these data support a role for GAG-mediated clearance of some viral particles from the blood circulation, illuminate the potential of blood-contacting phagocytes as a site for GAG-virion binding, and suggest a role for species-specific GAG structures in arbovirus ecology.
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Protein engineering has nearly limitless applications across chemistry, energy and medicine, but creating new proteins with improved or novel functions remains slow, labor-intensive and inefficient. Here we present the Self-driving Autonomous Machines for Protein Landscape Exploration (SAMPLE) platform for fully autonomous protein engineering. SAMPLE is driven by an intelligent agent that learns protein sequence-function relationships, designs new proteins and sends designs to a fully automated robotic system that experimentally tests the designed proteins and provides feedback to improve the agent's understanding of the system. We deploy four SAMPLE agents with the goal of engineering glycoside hydrolase enzymes with enhanced thermal tolerance. Despite showing individual differences in their search behavior, all four agents quickly converge on thermostable enzymes. Self-driving laboratories automate and accelerate the scientific discovery process and hold great potential for the fields of protein engineering and synthetic biology.
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Intracellular Salmonella experiencing oxidative stress downregulates aerobic respiration. To maintain cellular energetics during periods of oxidative stress, intracellular Salmonella must utilize terminal electron acceptors of lower energetic value than molecular oxygen. We show here that intracellular Salmonella undergoes anaerobic respiration during adaptation to the respiratory burst of the phagocyte NADPH oxidase in macrophages and in mice. Reactive oxygen species generated by phagocytes oxidize methionine, generating methionine sulfoxide. Anaerobic Salmonella uses the molybdenum cofactor-containing DmsABC enzymatic complex to reduce methionine sulfoxide. The enzymatic activity of the methionine sulfoxide reductase DmsABC helps Salmonella maintain an alkaline cytoplasm that supports the synthesis of the antioxidant hydrogen sulfide via cysteine desulfuration while providing a source of methionine and fostering redox balancing by associated dehydrogenases. Our investigations demonstrate that nontyphoidal Salmonella responding to oxidative stress exploits the anaerobic metabolism associated with dmsABC gene products, a pathway that has accrued inactivating mutations in human-adapted typhoidal serovars.
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Metionina/análogos & derivados , NADPH Oxidasas , Fagocitos , Animales , Ratones , Humanos , Anaerobiosis , Fagocitos/metabolismo , Metionina/metabolismo , Salmonella typhimurium/metabolismo , RespiraciónRESUMEN
Mobile genetic elements play an important role in the acquisition of antibiotic and biocide resistance, especially through the formation of resistance islands in bacterial chromosomes. We analyzed the contribution of Tn7-like transposons to island formation and diversification in the nosocomial pathogen Acinetobacter baumannii and identified four separate families that recognize different integration sites. One integration site is within the comM gene and coincides with the previously described Tn6022 elements suggested to account for the AbaR resistance island. We established Tn6022 in a heterologous E. coli host and confirmed basic features of transposition into the comM attachment site and the use of a novel transposition protein. By analyzing population features within Tn6022 elements we identified two potential novel transposon-encoded diversification mechanisms with this dynamic genetic island. The activities of these diversification features were confirmed in E. coli. One was a novel natural gain-of-activity allele that could function to broaden transposition targeting. The second was a transposon-encoded hybrid dif-like site that parasitizes the host dimer chromosome resolution system to function with its own tyrosine recombinase. This work establishes a highly active Tn7-like transposon that harnesses novel features allowing the spread and diversification of genetic islands in pathogenic bacteria.
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Acinetobacter baumannii , Elementos Transponibles de ADN , Farmacorresistencia Bacteriana , Variación Genética , Islas Genómicas , Acinetobacter baumannii/genética , Elementos Transponibles de ADN/genética , Farmacorresistencia Bacteriana/genética , Escherichia coli/genética , Variación Genética/genética , Genoma Bacteriano/genética , Islas Genómicas/genéticaRESUMEN
BACKGROUND: Women have been under-represented in trials of antipsychotic medications. AIM: Our primary objective was to evaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to men through an analysis of the FDA Adverse Event Reporting System (FAERS). METHOD: We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men. RESULTS: A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71-0.87) for NMS, 0.83 (0.68-1.01) for TD, 1.21 (0.94-1.53) for TdP, 0.71 (0.51-0.98) for AG, and 0.91 (0.68-1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29-2.94) and death associated with reports of AG (ROR = 2.46, 1.15-5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26-2.21) for women relative to men for TdP. CONCLUSION: The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.
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Antipsicóticos , Torsades de Pointes , Masculino , Humanos , Femenino , Estados Unidos/epidemiología , Antipsicóticos/efectos adversos , Haloperidol/efectos adversos , Farmacovigilancia , Estudios Retrospectivos , Proteínas de Unión al ADN , Sistemas de Registro de Reacción Adversa a Medicamentos , United States Food and Drug AdministrationRESUMEN
Infection with chikungunya virus (CHIKV) causes disruption of draining lymph node (dLN) organization, including paracortical relocalization of B cells, loss of the B cell-T cell border, and lymphocyte depletion that is associated with infiltration of the LN with inflammatory myeloid cells. Here, we found that, during the first 24 hours of infection, CHIKV RNA accumulated in MARCO-expressing lymphatic endothelial cells (LECs) in both the floor and medullary LN sinuses. The accumulation of viral RNA in the LN was associated with a switch to an antiviral and inflammatory gene expression program across LN stromal cells, and this inflammatory response - including recruitment of myeloid cells to the LN - was accelerated by CHIKV-MARCO interactions. As CHIKV infection progressed, both floor and medullary LECs diminished in number, suggesting further functional impairment of the LN by infection. Consistent with this idea, antigen acquisition by LECs, a key function of LN LECs during infection and immunization, was reduced during pathogenic CHIKV infection.
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Fiebre Chikungunya , Virus Chikungunya , Células Endoteliales/metabolismo , Inmunización , Ganglios Linfáticos , AnimalesRESUMEN
Via molecular and morphological analyses, we describe adult specimens of a new species of Versteria (Cestoda: Taeniidae) infecting mink and river otter (Carnivora: Mustelidae) in Western Canada, as well as larval forms from muskrat and mink. These sequences closely matched those reported from adult specimens from Colorado and Oregon, as well as larval infections in humans and a captive orangutan. We describe here a new species from British Columbia and Alberta (Canada), Versteria rafei n. sp., based upon morphological diagnostic characteristics and genetic distance and phylogeny. Versteria rafei n. sp. differs from the three other described species of the genus in the smaller scolex and cirrus sac. It also differs from V. mustelae (Eurasia) and V. cuja (South America) by having an armed cirrus, which is covered in hair-like bristles, and in the shape of its hooks, with a long thorn-like blade, and short or long handle (vs. a short sharply curved blade and no difference in handle size in previously described species). The poorly known V. brachyacantha (Central Africa) also has an armed cirrus and similarly shaped hooks. However, it differs from the new species in the number and size of hooks. Phylogenetic analysis of the cox1 and nad1 mitochondrial regions showed that our specimens clustered with isolates from undescribed adults and larval infections in North America, and separate from V. cuja, confirming them to be a distinct species from the American Clade.
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Cestodos , Infecciones por Cestodos , Nutrias , Humanos , Animales , Visón , Filogenia , AlbertaRESUMEN
Importance: Reported coronavirus disease 2019 (COVID-19) pandemic effects on pediatric trauma have been variable. Objective: We investigated the characteristics of pediatric trauma including alcohol use during the pandemic at our urban trauma center. Methods: The trauma database of our adult level 1 trauma center was queried for all pediatric (age ≤ 18 years) patients presenting between March 1, 2020, and October 30, 2020. Data from 2017 to 2019 served as a control. Variables analyzed included demographics, mechanisms, injury severity, hospitalization characteristics, and positive blood alcohol. Results: Pandemic pediatric trauma volumes increased by 67.5% (330/year vs. 197/year). Pandemic patients were younger (median age 13 vs. 14 years, P = 0.011), but similar in gender, ethnicity, severity, hospital length of stay, mortality, and rates of penetrating injury. Falls doubled (79/year vs. 34/year) and shifted away from high falls >6â¯meters (0% vs. 7.9%) to moderate falls 1-6â¯meters (58.2% vs. 51.5%) (P = 0.028). Transportation injury rates were similar however mechanisms shifted from motor vehicle crashes (-13.5%) towards recreational vehicles including motorcycles (+2.1%), all-terrain vehicles (+8.6%), and bicycles (+3.8%) (P = 0.018). Pediatric-positive blood alcohol was significantly higher (11.2% vs. 5.1%, P < 0.001), especially for ages 14-18 years (21.7% vs. 9.5%, P < 0.001). Interpretation: Pediatric trauma volumes during the COVID-19 pandemic increased. Pandemic patients had more recreational vehicle injuries and higher rates of positive blood alcohol. This suggests an increased need for alcohol assessment and targeted interventions in the pediatric population during pandemics or periods of school closures.
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The first simultaneous determination of the absolute value of the Cabibbo-Kobayashi-Maskawa matrix element V_{ub} using inclusive and exclusive decays is performed with the full Belle data set at the Ï(4S) resonance, corresponding to an integrated luminosity of 711 fb^{-1}. We analyze collision events in which one B meson is fully reconstructed in hadronic modes. This allows for the reconstruction of the hadronic X_{u} system of the semileptonic bâuâν[over ¯]_{â} decay. We separate exclusive Bâπâν[over ¯]_{â} decays from other inclusive BâX_{u}âν[over ¯]_{â} and backgrounds with a two-dimensional fit that utilizes the number of charged pions in the X_{u} system and the four-momentum transfer q^{2} between the B and X_{u} systems. Combining our measurement with information from lattice QCD and QCD calculations of the inclusive partial rate as well as external experimental information on the shape of the Bâπâν[over ¯]_{â} form factor, we determine |V_{ub}^{excl}|=(3.78±0.23±0.16±0.14)×10^{-3} and |V_{ub}^{incl}|=(3.88±0.20±0.31±0.09)×10^{-3}, respectively, with the uncertainties being the statistical error, systematic errors, and theory errors. The ratio of |V_{ub}^{excl}|/|V_{ub}^{incl}|=0.97±0.12 is compatible with unity.
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We report on a search for a heavy Majorana neutrino in the decays τ^{-}âπ^{-}ν_{h}, ν_{h}âπ^{±}â^{∓}, â=e, µ. The results are obtained using the full data sample of 988 fb^{-1} collected with the Belle detector at the KEKB asymmetric energy e^{+}e^{-} collider, which contains 912×10^{6} ττ pairs. We observe no significant signal and set 95% CL upper limits on the couplings of the heavy right-handed neutrinos to the conventional standard model left-handed neutrinos in the mass range 0.2-1.6 GeV/c^{2}. This is the first study of a mixed couplings of heavy neutrinos to τ leptons and light-flavor leptons.
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We measure the lifetime of the D_{s}^{+} meson using a data sample of 207 fb^{-1} collected by the Belle II experiment running at the SuperKEKB asymmetric-energy e^{+}e^{-} collider. The lifetime is determined by fitting the decay-time distribution of a sample of 116×10^{3} D_{s}^{+}âÏπ^{+} decays. Our result is τ_{D_{s}^{+}}=(499.5±1.7±0.9) fs, where the first uncertainty is statistical and the second is systematic. This result is significantly more precise than previous measurements.
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We present the first comprehensive tests of the universality of the light leptons in the angular distributions of semileptonic B^{0}-meson decays to charged spin-1 charmed mesons. We measure five angular-asymmetry observables as functions of the decay recoil that are sensitive to lepton-universality-violating contributions. We use events where one neutral B is fully reconstructed in Ï(4S)âBB[over ¯] decays in data corresponding to 189 fb^{-1} integrated luminosity from electron-positron collisions collected with the Belle II detector. We find no significant deviation from the standard model expectations.
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OBJECTIVES: The Royal College of Surgeons (RCS) Diversity Review 2021 found that premedical school students from ethnic minority backgrounds were dissuaded from pursuing a surgical career. Gloucestershire is in the bottom 20% of disadvantaged counties; there is no widening participation (WP) scheme in the county. We implemented a fully inclusive WP scheme in Gloucester, with means of accessing virtual and face-to-face work experience, to enhance the equity of work experience. METHODS: A three-stage project was conducted. Stage 1; two separate virtual Q and A sessions, to allow students to ask questions about life as a doctor. Stage 2; conversation between student and patient held virtually, to gain insight into working as a doctor to help determine whether medicine is the career for them. Stage 3; face-to-face work experience. Distribution sent to all 58 schools (state and private) in the county, targeted at secondary school children. RESULTS: One hundred twenty-nine people attended the Q and A; 70 feedback responses received. Of the total, 86% female and 56% of ethnic minority background. 26% did not have an immediate family member that attended university, 10% had care-giving responsibilities. Eighty-one percent rated the session >8/10 for usefulness. Twenty-seven undertook the virtual conversation, feedback from 11; 91% female, 45% of ethnic minority background, and 27% did not have an immediate family member that attended university. All rated the session 10/10 for usefulness. 10 attended the face-to-face experience, 50% from an ethnic minority background. CONCLUSION: The RCS Report identified barriers to aspiring students from less-privileged backgrounds pursuing a medical career. More needs to be done with WP schemes to promote equity. Targeted distribution of WP schemes to all schools, utilization of a variety of means of offering work experience, and accessibility to any school-aged student were aspects of our WP to improve exposure to the medical profession.
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INTRODUCTION: The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy. BACKGROUND: Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction. METHODS: Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9. RESULTS: We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise. CONCLUSIONS: Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy.
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Técnicas de Transferencia de Gen , Músculo Esquelético , Humanos , Ratones , Animales , Transgenes , Terapia Genética/métodos , Corazón , Dependovirus/genética , Vectores GenéticosRESUMEN
Infection with chikungunya virus (CHIKV) causes disruption of draining lymph node (dLN) organization, including paracortical relocalization of B cells, loss of the B cell-T cell border, and lymphocyte depletion that is associated with infiltration of the LN with inflammatory myeloid cells. Here, we find that during the first 24 h of infection, CHIKV RNA accumulates in MARCO-expressing lymphatic endothelial cells (LECs) in both the floor and medullary LN sinuses. The accumulation of viral RNA in the LN was associated with a switch to an antiviral and inflammatory gene expression program across LN stromal cells, and this inflammatory response, including recruitment of myeloid cells to the LN, was accelerated by CHIKV-MARCO interactions. As CHIKV infection progressed, both floor and medullary LECs diminished in number, suggesting further functional impairment of the LN by infection. Consistent with this idea, we find that antigen acquisition by LECs, a key function of LN LECs during infection and immunization, was reduced during pathogenic CHIKV infection.