Adenosine A2A Receptor Regulates microRNA-181b Expression in Aorta: Therapeutic Implications for Large-Artery Stiffness.

Background The identification of large-artery stiffness as a major, independent risk factor for cardiovascular disease-associated morbidity and death has focused attention on identifying therapeutic strategies to combat this disorder. Genetic manipulations that delete or inactivate the translin/trax microRNA-degrading enzyme confer protection against aortic stiffness induced by chronic ingestion of high-salt water (4%NaCl in drinking water for 3 weeks) or associated with aging. Therefore, there is heightened interest in identifying interventions capable of inhibiting translin/trax RNase activity, as these may have therapeutic efficacy in large-artery stiffness. Methods and Results Activation of neuronal adenosine A2A receptors (A2ARs) triggers dissociation of trax from its C-terminus. As A2ARs are expressed by vascular smooth muscle cells (VSMCs), we investigated whether stimulation of A2AR on vascular smooth muscle cells promotes the association of translin with trax and, thereby increases translin/trax complex activity. We found that treatment of A7r5 cells with the A2AR agonist CGS21680 leads to increased association of trax with translin. Furthermore, this treatment decreases levels of pre-microRNA-181b, a target of translin/trax, and those of its downstream product, mature microRNA-181b. To check whether A2AR activation might contribute to high-salt water-induced aortic stiffening, we assessed the impact of daily treatment with the selective A2AR antagonist SCH58261 in this paradigm. We found that this treatment blocked aortic stiffening induced by high-salt water. Further, we confirmed that the age-associated decline in aortic pre-microRNA-181b/microRNA-181b levels observed in mice also occurs in humans. Conclusions These findings suggest that further studies are warranted to evaluate whether blockade of A2ARs may have therapeutic potential in treating large-artery stiffness.

What does the demographic profile of convicts tell us about social equity in India?

Social equity is a critical component of social justice and is measured in multiple ways. Conventionally, researchers use literacy levels, workforce participation, political participation and representation, corporate presence, and demographic parity as indicators of social and economic equity. We add law enforcement outcomes to this literature by examining the demographic profiles of convicts in prisons in India for each state and compare it with that of the population of the respective state. To test whether entrenched social inequities have permeated into the law enforcement system, we use three indicators of social identity-religion, caste, and domicile-to create a social equity index (SEI). This is a composite index combining caste, religion and domicile similar in method to the Human Development Index which combines income, education and health. Our indicators are not considered in other popular development indices and is a conceptual innovation. Our paper innovates by combining prison data and census data at the state level over the two latest census rounds (2001 and 2011). We use a spatial panel analysis as well as a distributional dynamics approach to test for bias and transitions over time at the state level. We find that entrenched social hierarchies are mirrored in conviction outcomes and that social identities influence law enforcement. In contrast to earlier studies, we find that states that are conventionally considered to perform poorly in terms of economic and human development have done better in terms of social equity than economically advanced states.

Retrospective cohort comparison between fluoroscopic and radiograph-only exams for evaluation of gastrostomy and gastrojejunostomy tubes.

BACKGROUND: Gastrostomy (G) tube or gastrojejunostomy (GJ) tube checks are radiographic procedures that are frequently ordered to confirm tube positioning. OBJECTIVE: To characterize the sensitivity and specificity of radiograph-only examinations and traditional radiologist-performed fluoroscopy exams for G-tube or GJ-tube malposition and other adverse events detectable by imaging. MATERIALS AND METHODS: We performed a retrospective cohort study at a single tertiary pediatric center that included all subjects who underwent G-tube or GJ-tube checks using fluoroscopy or radiograph-only exams between January 1, 2008, and January 1, 2019. Radiograph-only examinations were defined as checks that consist of frontal and lateral abdominal radiographs after injection of contrast through the G-tube or GJ-tube. Fluoroscopy exams were defined as exams performed by a radiologist in the fluoroscopy suite. Radiology reports were evaluated for reported tube malposition and for other adverse events that are detectable by imaging. Clinical notes from the day of the procedure and longer-term clinical follow-up notes were used as a reference standard for adverse events. The sensitivity and specificity of the two procedures were calculated. RESULTS: A total of 212 exams, including 86 (41%) fluoroscopy exams and 126 (59%) radiograph-only exams, were evaluated. The most common correctly identified adverse event was tube malposition (9 true positives). The most commonly missed adverse event was leakage around the tube (8 false negatives). Fluoroscopy exams had a sensitivity of 100% (6/6; 95% CI: 100%, 100%) and a specificity of 100% (80/80; 95% CI: 100%, 100%) for tube malposition, while radiograph-only exams had 75% sensitivity (3/4; 95% CI: 33%,100%) and 100% specificity (112/112; 95% CI: 100%, 100%). CONCLUSIONS: Fluoroscopy and radiograph-only exams have similar sensitivity and specificity for detecting G-tube or GJ-tube malposition.

Microorganisms in Organic Food-Issues to Be Addressed.

The review aimed to analyse the latest data on microorganisms present in organic food, both beneficial and unwanted. In conclusion, organic food's microbial quality is generally similar to that of conventionally produced food. However, some studies suggest that organic food may contain fewer pathogens, such as antibiotic-resistant strains, due to the absence of antibiotic use in organic farming practices. However, there is little discussion and data regarding the importance of some methods used in organic farming and the risk of food pathogens presence. Concerning data gaps, it is necessary to plan and perform detailed studies of the microbiological safety of organic food, including foodborne viruses and parasites and factors related to this method of cultivation and specific processing requirements. Such knowledge is essential for more effective management of the safety of this food. The use of beneficial bacteria in organic food production has not yet been widely addressed in the scientific literature. This is particularly desirable due to the properties of the separately researched probiotics and the organic food matrix. The microbiological quality of organic food and its potential impact on human health is worth further research to confirm its safety and to assess the beneficial properties resulting from the addition of probiotics.

Retinoic acid signaling is critical for generation of pancreatic progenitors from human embryonic stem cells.

Retinoic acid (RA) is essential for gut endoderm development and has been extensively used for in vitro pancreatic differentiation from human pluripotent stem cells. However, the gene regulatory network triggered by RA signaling remains poorly addressed. Also, whether RA signals control histone modifiers such as the Polycomb group proteins during pancreatic specification remains to be explored. Here, we assess the role of RA on pancreas-specific genes during the differentiation of human embryonic stem cells (hESCs). We demonstrate that RA helps cells exit the definitive endoderm stage and proceed toward a pancreatic fate. Inhibition of the RA pathway using the pharmacological inhibitor LE135 impairs the induction of pancreatic endoderm (PE) markers FOXA2, HNF4α, HNF1ß, HHEX, and PDX1. We further determine that RA signals alter the expression of epigenetic-associated genes BMI1 and RING1B in the hESC-derived pancreatic progenitors. These findings broaden our understanding of the mechanisms that drive early PE specification.

Ulcerative Colitis: Rapid Evidence Review.

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients.

Crimes Against Women in India: A District-Level Analysis (1991-2011).

Crimes against women (CAW) in India have been rising despite faster economic growth, higher education attainment, and increasing numbers of women in the economic sphere. This article explores the reasons for the incidence of reported CAW in India. We study five CAW (rape, kidnapping, cruelty, dowry deaths, and molestation), across 35 states and union territories, 594 districts, over three decades (1991-2011). We use panel fixed-effects regression models to explain crime. Our results confirm the importance of female literacy rates, female paid workforce participation, and female-male ratio in understanding crime. We find that these commonly-used socioeconomic variables have nonlinear effects on CAW. Our findings improve upon earlier results that have not explored either spatial distribution or nonlinearity in India. These findings could have significant implications for the policies aiming to reduce CAW.

Writing an effective and supportive recommendation letter.

Writing recommendation letters on behalf of students and other early-career researchers is an important mentoring task within academia. An effective recommendation letter describes key candidate qualities such as academic achievements, extracurricular activities, outstanding personality traits, participation in and dedication to a particular discipline, and the mentor's confidence in the candidate's abilities. In this Words of Advice, we provide guidance to researchers on composing constructive and supportive recommendation letters, including tips for structuring and providing specific and effective examples, while maintaining a balance in language and avoiding potential biases.

Building and sustaining mentor interactions as a mentee.

Mentorship is experience and/or knowledge-based guidance. Mentors support, sponsor and advocate for mentees. Having one or more mentors when you seek advice can significantly influence and improve your research endeavours, well-being and career development. Positive mentee-mentor relationships are vital for maintaining work-life balance and success in careers. Early-career researchers (ECRs), in particular, can benefit from mentorship to navigate challenges in academic and nonacademic life and careers. Yet, strategies for selecting mentors and maintaining interactions with them are often underdiscussed within research environments. In this Words of Advice, we provide recommendations for ECRs to seek and manage mentorship interactions. Our article draws from our experiences as ECRs and published work, to provide suggestions for mentees to proactively promote beneficial mentorship interactions. The recommended practices highlight the importance of identifying mentorship needs, planning and selecting multiple and diverse mentors, setting goals, and maintaining constructive, and mutually beneficial working relationships with mentors.

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity.

Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.

Degradation of Premature-miR-181b by the Translin/Trax RNase Increases Vascular Smooth Muscle Cell Stiffness.

[Figure: see text].

Outcomes of patients hospitalized for acute pulmonary embolism by obstructive sleep apnea status.

Pulmonary embolism (PE) is a major cause of cardiovascular morbidity and mortality. Obstructive sleep apnea (OSA) is increasingly recognized in the aging population, especially with the rising obesity epidemic. The impact of OSA on inpatient mortality in PE is not well understood. We used the Nationwide Inpatient Sample databases from 2005 to 2016 to identify 755,532 acute PE patients (age≥18 years). Among these, 61,050 (8.1%) were OSA+. Temporal trends in length of stay, inpatient mortality, and its association with OSA in PE patients were analyzed. The proportion of PE patients who were OSA+ increased from 2005 to 2016. OSA+ PE patients were younger and predominantly men. Despite a higher prevalence of traditional risk factors for inpatient mortality in OSA+ patients, OSA was associated with a lower risk of mortality in PE patients (odds ratio, 95% confidence interval; p: unadjusted 0.56, 0.53-0.58; p < 0.0001 and adjusted 0.55, 0.52-0.58; p < 0.0001). Overall mortality and length of stay in PE patients decreased over time. Relative to OSA- patients, there was a slight increase in mortality among OSA+ PE patients over time, although the length of stay remained unchanged between the two groups. In conclusion, OSA+ PE patients had a lower inpatient mortality compared to OSA- patients despite a higher prevalence of traditional mortality risk factors. Secondary pulmonary hypertension related to OSA with preconditioning of the right ventricle to elevated afterload may potentially explain the protective effect of OSA on mortality in PE. However, mechanistic studies need to further elucidate the links behind this association.

Sonic hedgehog signals hinder the transcriptional network necessary for pancreatic endoderm formation from human embryonic stem cells.

Hedgehog morphogens govern multiple aspects of pancreas organogenesis and functioning with diverse outcomes across species. Although most current differentiation protocols repress Sonic hedgehog (SHH) signals during in vitro endocrine specification, the role and mechanisms through which the SHH pathway antagonizes pancreas development during in vitro human embryonic stem (hES) cell differentiation remain unclear. We modulated SHH signaling at transitory stages of hES cell-derived pancreatic progenitors and analyzed the effect on cellular fate decisions. We identify the Hedgehog pathway as a negative regulator of pancreatic endoderm formation through up-regulation of a set of pancreatobiliary markers required for ductal specification, including SOX17, FOXA2, HNF1ß, HNF6, PDX1, and SOX9. Surprisingly, active Hedgehog signals impeded a group of pancreatic epithelium markers, including HNF4α, HHEX, PAX6, and PTF1α. To understand how SHH signals repress the transcription of these specific markers, we analyzed Polycomb group proteins. We found differential expression of Polycomb Repressive Complex 1 subunit, BMI1 upon Shh pathway modulation in the pancreatic progenitors. Ectopic activation of Sonic hedgehog results in over-expression of BMI1 and its associated repressive histone mark, H2AK119Ub1, in the multipotent progenitors. Our data suggest that Sonic hedgehog restricts the pancreatic differentiation program by limiting progenitor cells acquiring pancreatic epithelial fates and instead promotes pancreatobiliary differentiation. We further provide mechanistic cues of an association between Hedgehog signaling and epigenetic silencers during pancreatic lineage decisions.

Nephrocalcinosis-A gateway to the Diagnosis.

Nephrocalcinosis (NC) is the augmented calcium content within the renal parenchyma. Its pathogenesis mainly involves hypercalciuria. The presence of medullary NC provides a window to the clinician for the diagnosis of many important diseases. In this case series, we highlight three diseases that could be diagnosed with a high index of suspicion and detailed evaluation after their presentation as medullary NC.

A solitary extraventricular subependymal giant cell astrocytoma in the absence of tuberous sclerosis.

Subependymal giant cell astrocytomas (SEGAs) are the most common intracranial tumors in Tuberous Sclerosis Complex (TSC). Very few cases of solitary SEGA without a diagnosis of TSC have been described. Most of these previously reported solitary SEGAs were located near the caudothalamic groove or in close proximity to the lateral ventricles. Here, we describe a unique case of solitary extraventricular SEGA in a 17-year-old boy who presented with new-onset seizures in the absence of the clinical and genetic diagnosis of TSC. This extraventricular SEGA was involving white matter and cortex of the occipital lobe and was predominantly hypointense on T1 and T2-weighted images with a markedly hypointense signal on susceptibility-weighted images likely secondary to dense internal calcifications. Solitary SEGA can occur in the extraventricular location in patients without TSC and should be included in the differential diagnosis of a densely calcified supratentorial intra-axial tumor in children, especially during the second decade of life.

Salt intake among women in an Urban resettlement colony of Delhi.

BACKGROUND: Monitoring of population salt intake is essential for compliance with the WHO target of a 30% relative reduction in mean population salt intake. OBJECTIVE: This study was conducted to estimate the daily salt intake and find the associated variables among adult women in an urban resettlement colony of Delhi. METHODS: In this community-based cross-sectional study, 426 women aged 20-59 years from an urban resettlement colony were randomly selected. Sociodemographic details, anthropometric measurements, blood pressure, and morning spot urine samples were obtained. INTERSALT equation was used to estimate the 24-h salt intake from spot urine sodium. Association of salt intake with related variables was studied using t-test/analysis of variance, and P < 0.05 was considered to be significant. RESULTS: A total of 426 women participated in the study, and 381 participants' urine samples could be collected. The study participants' mean age (standard deviation [SD]) was 34.5 (9.4) years. The mean salt intake (SD, 95% confidence interval) of the participants calculated using the INTERSALT equation was 7.6 (1.7, 7.5-7.8) g/day. The salt intake was significantly associated with educational status, occupation, marital status, socioeconomic status, blood pressure, and waist circumference. Waist circumference was found to have a significant positive linear relationship with daily salt intake. CONCLUSION: The daily salt intake of this population was well above the recommendation and had a positive linear relationship with waist circumference. Reduction in daily salt intake is a must to control the epidemic of hypertension.

"Understanding growth convergence in India (1981-2010): Looking beyond the usual suspects".

The literature on growth convergence has focused to a great extent on the role of initial incomes as a primary determinant of long-term growth outcomes. Expanded versions of growth models have used other explanators to unpack the growth process. In this paper we add to the literature in two significant ways: (a) we use socioeconomic variables that are sometimes overlooked in explaining growth (such as, political stability and political alliance, social heterogeneity, and demographic distribution), and (b) we demonstrate that earlier analyses may be overlooking the problem of normality and endogeneity in regression models (and we provide alternate methods like instrumental variable and distribution dynamics to control for these). In this paper we analyze the per capita income growth at the subnational level in India for the period 1981-82 to 2010-11 using an expanded growth framework. We find that initial incomes, the ratio of working age group to total population, political stability and alliance, and the extent of development expenditure play a positive and significant role in predicting growth. We also find that, contrary to popular belief, the presence of marginalized groups-namely Scheduled Castes and Scheduled Tribes-have not been a hindrance to growth of per capita incomes in states. Our findings on the influence of social institutions may have significant implications for a public policy of affirmative action in India. The results on the impact of development expenditure on growth is also important for states seeking to increase their growth rates through policy intervention.

Genetic inactivation of the translin/trax microRNA-degrading enzyme phenocopies the robust adiposity induced by Translin (Tsn) deletion.

OBJECTIVE: Deletion of Translin (Tsn) from mice induces an unusual metabolic profile characterized by robust adiposity, normal body weight and glucose tolerance. Translin (TN) protein and its partner, trax (TX), form the TN/TX microRNA-degrading enzyme. Since the microRNA system plays a prominent role in regulating metabolism, we reasoned that the metabolic profile displayed by Tsn KO mice might reflect dysregulation of microRNA signaling. METHODS: To test this hypothesis, we inserted a mutation, E126A, in Tsnax, the gene encoding TX, that abolishes the microRNA-degrading enzymatic activity of the TN/TX complex. In addition, to help define the cell types that drive the adiposity phenotype, we have also generated mice with floxed alleles of Tsn or Tsnax. RESULTS: Introduction of the E126A mutation in Tsnax does not impair expression of TN or TX proteins or their co-precipitation. Furthermore, these mice display selective increases in microRNAs that match those induced by Tsn deletion, confirming that this mutation in Tsnax inactivates the microRNA-degrading activity of the TN/TX complex. Mice homozygous for the Tsnax (E126A) mutation display a metabolic profile that closely mimics that of Tsn KO mice. Selective deletion of Tsn or Tsnax from either adipocytes or hepatocytes, two candidate cell types, does not phenocopy the elevated adiposity displayed by mice with constitutive Tsn deletion or the Tsnax (E126A) mutation. Furthermore, global, conditional deletion of Tsn in adulthood does not elicit increased adiposity. CONCLUSION: Taken together, these findings indicate that inactivation of the TN/TX microRNA-degrading enzyme during development is necessary to drive the robust adiposity displayed by Tsn KO mice.

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance.

OBJECTIVE: Translin knockout (KO) mice display robust adiposity. Recent studies indicate that translin and its partner protein, trax, regulate the microRNA and ATM kinase signaling pathways, both of which have been implicated in regulating metabolism. In the course of characterizing the metabolic profile of these mice, we found that they display normal glucose tolerance despite their elevated adiposity. Accordingly, we investigated why translin KO mice display this paradoxical phenotype. METHODS: To help distinguish between the metabolic effects of increased adiposity and those of translin deletion per se, we compared three groups: (1) wild-type (WT), (2) translin KO mice on a standard chow diet, and (3) adiposity-matched WT mice that were placed on a high-fat diet until they matched translin KO adiposity levels. All groups were scanned to determine their body composition and tested to evaluate their glucose and insulin tolerance. Plasma, hepatic, and adipose tissue samples were collected and used for histological and molecular analyses. RESULTS: Translin KO mice show normal glucose tolerance whereas adiposity-matched WT mice, placed on a high-fat diet, do not. In addition, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. Unlike adiposity-matched WT mice, translin KO mice display three key features that have been shown to reduce susceptibility to insulin resistance: increased accumulation of subcutaneous fat, increased levels of circulating adiponectin, and decreased Tnfα expression in hepatic and adipose tissue. CONCLUSIONS: The ability of translin KO mice to retain normal glucose tolerance in the face of marked adipose tissue expansion may be due to the three protective factors noted above. Further studies aimed at defining the molecular bases for this combination of protective phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.

Sex-Based Differences in Left Ventricular Assist Device Utilization: Insights From the Nationwide Inpatient Sample 2004 to 2016.

BACKGROUND: Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs). During the early pulsatile-flow device era, women had higher post-LVAD mortality and increased complications. However, knowledge about these differences in the continuous-flow device era is limited. Therefore, we sought to explore temporal trends in LVAD utilization and post-LVAD mortality by sex. METHODS AND RESULTS: Patients with LVAD implantation from 2004 to 2016 were identified using the Nationwide Inpatient Sample. Trends in LVAD utilization and post-LVAD inpatient mortality were compared by sex and device era. Although LVADs are being increasingly utilized for patients with advanced systolic heart failure, women continue to represent a smaller proportion of LVAD recipients-25.8% in 2004 to 21.9% in 2016 (P for trend, 0.91). Women had increased inpatient mortality after LVAD implantation compared with men in the pulsatile-flow era (46.9% versus 31.1%, P<0.0001) but not in the continuous-flow era (13.3% versus 12.1%, P=0.27; P for interaction=0.0002). Inpatient mortality decreased for both sexes over time after LVAD, with a sharp fall in 2008 to 2009. Female sex was independently associated with increased post-LVAD inpatient mortality beyond adjustment for demographics and risk factors during the pulsatile-flow era (odds ratio, 2.13; 95% CI, 1.45-3.10; P<0.0001) but not during the continuous-flow era (1.18; 0.93-1.48; P=0.16). CONCLUSIONS: Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy. Prospective studies are needed to confirm these findings.