CD11c-dependent ablation of the Protein Tyrosine Phosphatase Shp1 improves insulin resistance

学位記番号：医博甲186

The Role of Telomeric Heterochromatin in Regulating Telomere Length Maintenance and Stability

Telomeres are protective structures that preserve genome integrity and stability by preventing chromosome end degradation and misrecognition as DNA damage sites. Dysregulation of telomere structure or length maintenance can have drastic consequences on overall telomere stability, often leading to premature aging diseases or the development of cancer. Though the structural and functional components of telomeres, including the telomere-binding protein complex shelterin,&nbsp; have been well-established, the role of chromatin in maintaining telomere stability remains elusive. Here we investigate the potential role of constitutive heterochromatin using a protein-tethering approach to enrich features of heterochromatin specifically at telomeres. Our results show that telomeric enrichment of the heterochromatin-associated trimethylation of histone 3 on Lysine 9, H3K9me3, does not result in substantial telomere deprotection. Conversely, enrichment of heterochromatin protein 1 (HP1&alpha;),&nbsp; of a different heterochromatin feature, produces significant DNA damage and telomere dysfunction. Using fluorescent microscopy techniques, we measured telomere length, replication stress, and levels of telomeric DNA damage after heterochromatin enrichment at telomeres. We demonstrate that cells with telomeric enrichment of HP1&alpha; exhibit increased DNA damage at telomeres, diminished telomere length, as well as bridging of telomeres between multiple nuclei, indicative of telomere entanglements. These phenotypes suggest that heterochromatin is detrimental, rather than protective, to normal telomere function. Interestingly, a subset of cancer cells, , which maintain their telomeres through a mechanism called Alternative Lengthening of Telomeres (ALT), rely on HP1a for viability and are known to have high levels of heterochromatin, replication stress, recombination, and DNA damage at their telomeres. The observed telomere dysfunction in non-ALT cells upon HP1a enrichment at telomeres may provide insight into the role of HP1&alpha; in the ALT pathway and may thus inform the future development of anti-cancer drug therapies.&nbsp; &nbsp;</p

Demographic profile of patient with acute watery diarrhea during monsoon 2022: Patan Hospital, Nepal

Introduction: Diarrhea is the passage of three or more loose or liquid stools per day or more. Acute watery diarrhea is a major public health problem worldwide.  In Nepal, diarrhea is among the top 10 inpatient morbidity. This study’s objective is to monitor demographic characteristics and laboratory findings of stool specimens of diarrhea. Method: This is a cross-sectional descriptive study done at Patan Hospital. Ethical approval was taken from the Ethical committee. Data for Monsoon 2022 (June to September 2022) were collected from the Patan Hospital record system. Cases from within the Lalitpur district were included. Result: Out of 119 cases, 50(42%) were male and 69(58%) were female. The mean age±SD was 33.28±25.38 (p=0.083) with maximum cases observed during June and a peak observed during the fourth week of June. Out of 119, 4(3.3%) were stool culture positive. Two cases of Vibrio cholera, one case of Shigella sonnei, and one case of Salmonella parathypi B were isolated. In the etiological profile, 14 Entamoeba histolytica were isolated. Conclusion: During the outbreak of diarrhea in Monsoon 2022, adults were affected most. The culture of acute watery diarrhea showed two cases of Vibrio cholera

Ensuring business innovation fundamentals : exploring equity, diversity and inclusion in small and medium sized enterprises (MSMES) of Nepal

Innovation in MSMEs is the key driver of productivity and long-term growth. However, a study done to assess the experience of enterprises in twelve South Asian countries has listed six South Asian countries, including Nepal as poor performer in terms of innovation, production, and export performance. United Nations ESCAP (2011) has highlighted the dominance of SMEs in business communities of Nepal, which make up more than 95% of all enterprises. Given the importance of MSME sector, the government of Nepal has introduced business-support programs to encourage the creation of enterprises, especially with a view of generating employment, import substitution, poverty alleviation, and economic growth. Micro-Enterprise Development for Poverty Alleviation (MEDPA) and Youth and Small Entrepreneur Self-Employment Fund Programme (YSEF) are two flagship innovation support programs (ISPs) in Nepal that provide a wide range of support services to the MSMEs. With the aim of addressing the social and economic aspects, those ISPs have aimed to improve the economic and social condition of low-income and socially backward families through micro-enterprises development, self-employment promotion and entrepreneurship, especially among the youth and women by curbing down the labor migration and promoting domestic production

A Differential Drug Screen for Compounds That Select Against Antibiotic Resistance

Antibiotics increase the frequency of resistant bacteria by providing them a competitive advantage over sensitive strains. Here, we develop a versatile assay for differential chemical inhibition of competing microbial strains, and use it to identify compounds that preferentially inhibit tetracycline-resistant relative to sensitive bacteria, thus “inverting” selection for resistance. Our assay distinguishes compounds selecting directly against specific resistance mechanisms and compounds whose selection against resistance is based on their physiological interaction with tetracycline and is more general with respect to resistance mechanism. A pilot screen indicates that both types of selection-inverting compounds are secreted by soil microbes, suggesting that nature has evolved a repertoire of chemicals that counteracts antibiotic resistance. Finally, we show that our assay can more generally permit simple, direct screening for drugs based on their differential activity against different strains or targets

Survey of CT radiation doses and iodinated contrast medium administration: an international multicentric study

ObjectiveTo assess the relationship between intravenous iodinated contrast media (ICM) administration usage and radiation doses for contrast-enhanced (CE) CT of head, chest, and abdomen-pelvis (AP) in international, multicenter settings. MethodsOur international (n = 16 countries), multicenter (n = 43 sites), and cross-sectional (ConRad) study had two parts. Part 1: Redcap survey with questions on information related to CT and ICM manufacturer/brand and respective protocols. Part 2: Information on 3,258 patients (18-96 years; M:F 1654:1604) who underwent CECT for a routine head (n = 456), chest (n = 528), AP (n = 599), head CT angiography (n = 539), pulmonary embolism (n = 599), and liver CT examinations (n = 537) at 43 sites across five continents. The following information was recorded: hospital name, patient age, gender, body mass index [BMI], clinical indications, scan parameters (number of scan phases, kV), IV-contrast information (concentration, volume, flow rate, and delay), and dose indices (CTDIvol and DLP). ResultsMost routine chest (58.4%) and AP (68.7%) CECT exams were performed with 2-4 scan phases with fixed scan delay (chest 71.4%; AP 79.8%, liver CECT 50.7%) following ICM administration. Most sites did not change kV across different patients and scan phases; most CECT protocols were performed at 120-140 kV (83%, 1979/2685). There were no significant differences between radiation doses for non-contrast (CTDIvol 24 [16-30] mGy; DLP 633 [414-702] mGycm) and post-contrast phases (22 [19-27] mGy; 648 [392-694] mGycm) (p = 0.142). Sites that used bolus tracking for chest and AP CECT had lower CTDIvol than sites with fixed scan delays (p &lt; 0.001). There was no correlation between BMI and CTDIvol (r2 &lt;= - 0.1 to 0.1, p = 0.931). ConclusionOur study demonstrates up to ten-fold variability in ICM injection protocols and radiation doses across different CT protocols. The study emphasizes the need for optimizing CT scanning and contrast protocols to reduce unnecessary contrast and radiation exposure to patients. Clinical relevance statementThe wide variability and lack of standardization of ICM media and radiation doses in CT protocols suggest the need for education and optimization of contrast usage and scan factors for optimizing image quality in CECT

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Un análisis de los programas de asistencia para varones que han ejercido violencia de género en la Área Metropolitana de Buenos Aires (AMBA). An analysis of programs of assistance for men who have committed gender violence in the Metropolitan Area of Buenos Aires.

La violencia de género es una forma de opresión que tiene graves consecuencias para mujeres, niños y niñas y personas LGBTQ+ tanto en Argentina como en el resto del mundo. Históricamente, las iniciativas de prevención en este tema se han centrado en la asistencia destinada a las víctimas de situaciones de violencia, incluyendo apoyo económico y legal. Sin embargo, el hecho de que casi todos los casos de violencia están cometidos por varones ha iniciado una nueva discusión en las últimas décadas sobre los vínculos entre la masculinidad hegemónica y la violencia, junto con estrategías preventivas con el objetivo de acortar el ciclo de violencia a las raíces, principalmente, las socializaciones del patriarcado sobre distintos temáticas de género. Una de esas estrategías es la implementación de los espacios o programas de asistencia para varones que han ejercido violencia. Debido a la novedad relativa de tales iniciativas, no existen muchas investigaciones sobre la efectividad de estos espacios. El presente estudio pretende caracterizar las funciones y los efectos percibidos de varios programas de asistencia en el Área Metropolitana de Buenos Aires desde las perspectivas de cuatro profesionales que están involucrados en estas intervenciones. Se realizaron entrevistas virtuales y los datos recogidos se organizaron en un análisis cualitativo con cinco códigos que abordan los objetivos de investigación. Los resultados de la investigación indican similitudes en las experiencias de los profesionales que trabajan con varones que han ejercido violencia de género, especialmente con respecto a la estructura de los espacios, la coordinación de los grupos y la implementación de estrategias multidisciplinares. Asimismo se reportaron algunas diferencias, especialmente, entre las organizaciones gubernamentales y las organizaciones de la sociedad civil, en los temas de financiamiento y acceso a los recursos. Todos los espacios utilizan un abordaje integral que considera los complejos factores que motivan comportamientos y actitudes violentas en todos los niveles de socialización, desde la cultura y las comunidades hasta las historias de vida de un individuo. A través de una variedad de métodos y actividades, los profesionales facilitan un intercambio entre los participantes para trabajar y sensibilizar temas de género como la identidad masculina, las relaciones interpersonales y la regulación de las emociones en situaciones de conflicto. Aunque ha habido mucho progreso en el fortalecimiento de los espacios que trabajan con varones, todavía los equipos enfrentan desafíos con el acceso a recursos económicos y humanos y la promoción del trabajo para aumentar la visibilización. Podemos concluir que a pesar de esas limitaciones los programas de asistencia son un aspecto muy importante en la prevención de violencia de género, por su capacidad única de abordar las complejidades de violencia de manera transdisciplinaria y multidimensional para reducir los comportamientos y actitudes agresivos en varones y acortar el ciclo de violencia desde la raíz. Gender-based violence is a form of oppression that has profound consequences for women, children, and LGBTQ+ individuals, both in Argentina and around the world. Historically, prevention initiatives in this area have focused on assistance for victims of gender violence, including economic and legal support. However, the fact that almost all cases of violence are committed by men has sparked new discussions in recent decades about the links between hegemonic masculinity and violence, along with preventive strategies aimed at addressing the root causes, particularly the socializations of patriarchy on various gender-related issues. One such strategy is the implementation of assistance programs for men who have perpetrated violence. Due to the relative novelty of such initiatives, there is not much previous research on the effectiveness of these spaces. This study aims to characterize the functions and perceived effects of various assistance programs in the Metropolitan Area of Buenos Aires from the perspectives of four professionals directly involved in the interventions. Virtual interviews were conducted and the collected data was organized into a qualitative analysis with five emerging themes that address the research objectives. The results of this study indicate similarities in the experiences of professionals working with men who have perpetrated gender-based violence, especially regarding the structure of the spaces, group coordination, and the implementation of multidisciplinary strategies. Some differences were also reported, particularly between governmental organizations and civil society organizations, regarding funding and access to resources. All spaces use a comprehensive approach that considers the complex factors that motivate violent behaviors and attitudes at all levels of socialization, from a macro perspective of culture and communities to the micro level of an individual\u27s life experiences. Through a variety of methods and activities, professionals facilitate an exchange among participants to work on and raise awareness of gender-related issues such as male identity, interpersonal relationships, and the regulation of emotions in conflict situations. Although there has been much progress in strengthening spaces working with men, teams still face challenges with access to economic and human resources and promoting work to increase visibility. In conclusion, despite these limitations, assistance programs are a crucial aspect of gender-based violence prevention, given their unique ability to address the complexities of violence in a transdisciplinary and multidimensional manner to reduce aggressive behaviors and attitudes in men and break the cycle of violence from its roots