Comparing mouse and human brains.

Inhibitory circuit motifs in the mouse brain and the human brain are strikingly similar.

The plasticitome of cortical interneurons.

Hebb postulated that, to store information in the brain, assemblies of excitatory neurons coding for a percept are bound together via associative long-term synaptic plasticity. In this view, it is unclear what role, if any, is carried out by inhibitory interneurons. Indeed, some have argued that inhibitory interneurons are not plastic. Yet numerous recent studies have demonstrated that, similar to excitatory neurons, inhibitory interneurons also undergo long-term plasticity. Here, we discuss the many diverse forms of long-term plasticity that are found at inputs to and outputs from several types of cortical inhibitory interneuron, including their plasticity of intrinsic excitability and their homeostatic plasticity. We explain key plasticity terminology, highlight key interneuron plasticity mechanisms, extract overarching principles and point out implications for healthy brain functionality as well as for neuropathology. We introduce the concept of the plasticitome - the synaptic plasticity counterpart to the genome or the connectome - as well as nomenclature and definitions for dealing with this rich diversity of plasticity. We argue that the great diversity of interneuron plasticity rules is best understood at the circuit level, for example as a way of elucidating how the credit-assignment problem is solved in deep biological neural networks.

Risk of drug-induced liver injury in chronic hepatitis B and tuberculosis co-infection: A systematic review and meta-analysis.

Patients with tuberculosis (TB) disease treated with multi-drug regimens are at risk of developing drug induced liver injury (DILI), and DILI risk might be even higher in patients with underlying liver disease. We aimed to evaluate whether underlying chronic hepatitis B virus (HBV) and TB co-infection are associated with a higher risk of TB therapy-related DILI. We conducted a systematic review and meta-analysis using MEDLINE/PubMed from inception to 31 December 2021. Primary outcome assessed was development of DILI following multi-drug TB treatment. Meta-analysis using random-effects models were utilized to evaluate whether underlying chronic HBV was associated with increased risk of DILI in patients undergoing active TB treatment. A total of 10 studies met inclusion criteria to be analysed, among which 520 patients had HBV-TB co-infection and 2988 patients had active TB disease without HBV. Prevalence of DILI was 21.9% in HBV-TB co-infected patients and 11.9% in TB patients without HBV. On meta-analysis, HBV-TB co-infected patients had significantly higher risk of DILI when treated with TB therapies compared with TB patients without HBV (pooled risk ratio 1.98, 95% CI 1.38-2.83, I2  = 68%). Sub-analysis of prospective cohort studies conducted after year 2000 detected a pooled risk ratio of 2.75 (95% CI 2.10-3.59, I2  = 0%). In conclusion, HBV-TB co-infected patients undergoing multi-drug TB therapy have 2-3 times higher risk of DILI compared with TB patients without HBV. Routine HBV screening prior to initiation of TB therapy is critical for early identification of HBV-TB co-infection, so that clinicians can modify TB and HBV treatment and management to reduce risks of DILI.

Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors.

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg2+-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αß deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg2+-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT.

Long term trends and racial/ethnic disparities in the prevalence of obesity.

Obesity is an epidemic associated with higher rates of hypertension, diabetes, and cardiovascular diseases. However, significant racial disparities in the prevalence of obesity have been reported. To evaluate racial disparities and trends in the prevalence of obesity and obesity-related diseases. A population-based retrospective cohort study utilized data from the 1985 to 2011 California Behavioral Risk Factor Survey. Trends in obesity prevalence were stratified by age, sex, race/ethnicity, and socioeconomic factors. Multivariate logistic regression models evaluated independent predictors of obesity. The prevalence of obesity in significantly increased from 1985 to 2011 (8.6 vs. 22.8%, p < 0.001). This increase was seen among men and women, and among all race/ethnic, age, and socioeconomic groups. Hypertension and diabetes also increased during this time period (hypertension 20.7-35.9%; diabetes 4.2-11.2%). Obesity prevalence was highest in blacks and Hispanics, and lowest in Asians (blacks 33.3%; Hispanics 28.8%; Asians 9.0%; p < 0.001). Obesity prevalence was associated with lower education level, lower income, and unemployment status. After adjustments for age, sex, co morbidities, and surrogates of socioeconomic status, the increased risk of obesity in blacks and Hispanics persisted (blacks OR 1.51; Hispanics OR 1.18), whereas Asians were less likely to be obese (OR 0.37). While the overall prevalence of obesity increased from 1985 to 2011, significant racial/ethnic disparities in obesity have developed, with the highest prevalence seen in blacks and Hispanics, and the lowest seen in Asians.

Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data.

There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease undergoing liver transplantation in the US. Our study utilized data from the 2002 to 2012 United Network for Organ Sharing registry to evaluate model for end-stage liver disease era trends in US liver transplantations focused on patients with non-alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease (ALD), and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan-Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index (BMI), and had higher prevalence of diabetes and cardiac disease. However, overall long-term survival was significantly higher in patients with NASH and ALD (p < 0.001). Compared to HCV, patients with NASH had significantly higher post-transplantation survival (HR 0.69, 95% CI 0.63-0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69-0.83). Despite having higher BMI and higher prevalence of diabetes and cardiac disease, patients with NASH had better post-liver transplantation survival compared to patients with HCV or HCC. Patients with ALD also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation.

Ethnic disparities in the association of body mass index with the risk of hypertension and diabetes.

Despite having lower body mass index (BMI) compared to other ethnic groups, Asians continue to develop significant metabolic diseases such as hypertension and diabetes. To evaluate the disparate association of BMI and risk of hypertension and diabetes in Asians. We retrospectively studied 150,753 adults from the 1985-2011 California Behavioral Risk Factor Survey. Trends in prevalence of obesity, hypertension, and diabetes were stratified by ethnicity. Multivariate logistic regression models evaluated the incremental effect of one unit BMI increase on risk of hypertension and diabetes and the disparate risks of hypertension and diabetes at different BMI thresholds. Asians had the lowest BMI among all groups. However, the impact of increasing BMI on risk of hypertension and diabetes was significantly greater in Asians. For each one unit increase in BMI, Asians were significantly more likely to have hypertension (OR 1.15; 95% CI 1.13-1.18) compared to non-Hispanic whites, blacks, and Hispanics. Similar trends were seen for diabetes (Asians: OR 1.15; 95% CI 1.13-1.18). The risk of hypertension in Asians with BMI ≥ 22 was similar to non-Hispanic whites with BMI ≥ 27 and blacks with BMI ≥ 28. The risk of diabetes in Asians with BMI ≥ 28 was similar to non-Hispanic whites with BMI ≥ 30. Despite lower overall BMI compared to other groups, weight gain in Asians is associated with significantly higher risks of hypertension and diabetes. Compared to other ethnic groups, similar risks of hypertension and diabetes are seen in Asians at much lower BMI.

A Rare Case of Icteric Acute Hepatitis C Infection Acquired Through Intranasal Methamphetamine Use.

Most patients with acute hepatitis C (HCV) infections are asymptomatic, while 15% present with jaundice. Intranasal drug use can uncommonly transmit HCV via contaminated instruments and nasal epithelial breakdown. Given a 15% prevalence of HCV infection in chronic methamphetamine users, recognition of potential transmission routes is important to target prevention and screening efforts in this population.

Clinical and infection control implications of Clostridium difficile infection with negative enzyme immunoassay for toxin.

In a prospective study of 132 patients with a diagnosis of Clostridium difficile infection (CDI) by polymerase chain reaction, 43 (32%) had enzyme immunoassay (EIA) results negative for toxin. EIA-negative patients with CDI did not differ in clinical presentation from EIA-positive patients and presented a similar risk for transmission of spores.

Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L.

The DNMT3-like protein, DNMT3L, is required for germ line DNA methylation, although it is inactive as a DNA methyltransferase per se. Previous studies have shown that DNMT3L physically associates with the active de novo DNA methyltransferases, DNMT3A and DNMT3B, and stimulates their catalytic activities in a cell culture system. However, the mechanism by which DNMT3L stimulates de novo methylation remains unclear. Here, we have purified the full-length human DNMT3A2 and DNMT3L proteins and determined unique conditions that allow for the proper reconstitution of the stimulation of DNMT3A2 de novo methyltransferase activity by DNMT3L. These conditions include the use of buffers resembling physiological conditions and the preincubation of the two proteins. Under these conditions, maximal stimulation is reached at equimolar amounts of DNMT3L and DNMT3A2 proteins, and the catalytic efficiency of DNMT3A2 is increased up to 20-fold. Biochemical analysis revealed that whereas DNMT3L on its own does not significantly bind to the methyl group donor, S-adenosyl-L-methionine (SAM), it strongly increases the binding of SAM to DNMT3A2. DNA binding, on the contrary, was not appreciably improved. Analysis of DNA methyltransferase complexes in solution using size exclusion chromatography revealed that DNMT3A2 forms large structures of heterogeneous sizes, whereas DNMT3L appears as a monomer. Binding of DNMT3L to DNMT3A2 promotes a dramatic reorganization of DNMT3A2 subunits and leads to the formation of specific complexes with enhanced DNA methyltransferase activity and increased SAM binding.