New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the ...highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.
Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance.The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV).Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.
Even though many varieties have been recommended across agro-climate zones of Himachal Pradesh, yet the information on stability is lacking in this State. Hence, the present investigation was carried ...out to identify high yielding stable genotypes among various pre-adapted landraces. The material consists of 20 chilli landraces including check i.e. DKC-8. The experiment was laid out in a RCBD. The data were recorded and analyzed to work out mean performances and the inferences were drawn for parameters of variability, correlation coefficients, path coefficients and stability analysis. As per mean performances, CS7 and CS9 were earliest in flowering, CS13 is earliest in days to ripe maturity, CS10 had highest plant height and CS9 had highest average fruit weight and ripe fruit yield plant
. High PCV and GCV were recorded for ripe fruit yield plant
. Heritability and genetic advance were recorded maximum for plant height in summer seasons and were recorded maximum for number of ripe fruits plant
in winter season. Correlation coefficients showed that number of ripe fruits plant
and average ripe fruit weight were positively and significantly correlated with ripe fruit yield plant
. Path coefficient analysis in summer and winter seasons showed that average ripe fruit weight had the highest positive direct effect on ripe fruit yield plant
. The pooled data over environments were analyzed to estimate the interaction effects between genotypes × environment. The mean sum of squares due to genotypes, environments and genotypes × environment interaction were significant for all the characteristics. CS1, CS3, CS6, CS10, CS13, CS15 were adapted to all environments, CS7 and CS9 were specifically adapted to favourable environment and CS2 was specifically adapted to unfavorable environment for 50% flowering, landraces CS1, CS2 and CS3were well adapted to all environments for ripe maturity whereas landraces CS6, CS10 and CS19 were well adapted to all environment for number of ripe fruit and ripe fruit yield.
Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC).
KEYNOTE-629 ...was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab.
Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 interquartile range (IQR), 12.6-17.2 months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% 95% confidence interval (CI), 36.1% to 63.9%, including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients.
The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.
•The phase II KEYNOTE-629 study assessed the efficacy and safety of pembrolizumab in cSCC.•Pembrolizumab showed rapid, robust, and durable antitumor activity in both LA and R/M cSCC.•Adverse events were generally consistent with the established safety profile of pembrolizumab.•Our data establish pembrolizumab as a promising treatment option for cSCC.
Eaf3, a component of the NuA4 histone acetylase and Rpd3 histone deacetylase complexes, is important for the global pattern of histone acetylation in
Saccharomyces cerevisiae. Preferential ...deacetylation of coding regions requires the Eaf3 chromodomain and H3-K36 methylation by Set2. The Eaf3 chromodomain interacts with methylated H3-K36 peptides, suggesting that this interaction leads to preferential association and histone deacetylation of the 3′ portions of coding regions by the Rpd3 complex. However, the Eaf3 chromodomain and H3-K36 methylation do not significantly affect acetylation at promoters, suggesting that Eaf3 has a distinct function, presumably in the NuA4 complex. Lastly, Eaf3 inhibits internal initiation within mRNA coding regions in a manner similar to FACT and Spt6. Our results link the pattern of preferential deacetylation at coding regions to the underlying patterns of H3-K36 methylation and phosphorylation of the RNA polymerase II C-terminal domain, and ultimately to the mechanism by which repressive chromatin structure is restored after transcriptional elongation.
X-linked agammaglobulinemia (XLA) is an inborn error of immunity characterized by insufficient production of immunoglobulins and lack of measurable antibody response to vaccines. The rise of novel ...infections limits the protective effect of immunoglobulin replacement in immunodeficient patients though. While XLA patients are not expected to mount an antibody response to COVID-19 vaccination, it has been demonstrated that XLA patients can mount a T-cell response to COVID-19 vaccines, similar to the influenza vaccine. We present three patients with XLA who received an mRNA COVID-19 vaccine. One patient demonstrated positive antibody response. Many XLA patients do not receive routine vaccinations due to ongoing immunoglobulin replacement therapy and lack of native antibody production, but in addition to T-cell response to vaccination, select XLA patients may mount a positive antibody response. Therefore, COVID-19 vaccination should be encouraged for all XLA patients.
Post‐traumatic stress disorder (PTSD) is often characterized by deficits in memory encoding and retrieval and aberrant fear and extinction learning. The hippocampus plays a critical role in memory ...and contextual processing and has been implicated in intrinsic functional connectivity networks involved in self‐referential thought and memory‐related processes. This review focuses on hippocampal activation findings during memory and fear and extinction learning tasks, as well as resting state hippocampal connectivity in individuals with PTSD. A preponderance of functional neuroimaging studies to date, using memory, fear learning, and extinction tasks, report decreased or “controls comparable” hippocampal activation in individuals with PTSD, which is usually associated with poorer performance on the task imaged. Existing evidence thus raises the possibility that greater hippocampal recruitment in PTSD participants may be required for similar performance levels. Studies of resting state functional connectivity in PTSD predominantly report reduced within‐network connectivity in the default mode network (DMN), as well as greater coupling between the DMN and salience network (SN) via the hippocampus. Together, these findings suggest that deficient hippocampal activation in PTSD may be associated with poorer performance during memory, extinction recall, and fear renewal tasks. Furthermore, studies of resting state connectivity implicate the hippocampus in decreased within‐network DMN connectivity and greater coupling with SN regions characteristic of PTSD.
The hippocampus plays a key role in memory, fear learning and extinction, and default mode network resting state connectivity, all processes which have known deficits in post‐traumatic stress disorder (PTSD). In this review, we examine recent fMRI studies on hippocampal function in PTSD and controls and identify critical areas for future research to explore.
•ZnO:GO and ZnO:rGO composite thin films were prepared by spin coating technique.•Structural parameters are investigated by XRD spectra.•Electrical resistivity is decreased on insertion of GO and ...rGO, making it suitable for the photoelectrode applications.
Due to excellent physical and chemical performances, graphene and its derivatives dominate the industrial and academic research aiming the commercialization, more specifically in optoelectronics-based energy harvesting. Owing to high electron movability, a lot of interest is shown in utilizing the zinc oxide (ZnO) as photoelectrode in such applications. In this study, graphene oxide (GO) and reduced graphene oxide (rGO) are synthesised through a simple modification of Hummer's method. ZnO:GO and ZnO:rGO composite thin films are deposited on glass substrates using the spin coating method. The structural, optical, and electrical properties are investigated in detail. The Fourier-transform infrared spectroscopy (FTIR) and x-ray diffraction (XRD) are used to determine the structure of the prepared films, which confirmed the presence of oxygen functionalities and the hexagonal wurtzite crystal structure. The increasing GO and rGO weight percentage has resulted in increasing the crystallite size, and in turn, decreased the resistivity. All the films exhibit transmittance around 90 % in UV–Visible region, which make them useful as an optical window in optoelectronic applications. The surface microstructure of the GO and rGO inserted samples are analysed using a high-resolution electron microscope.
The 2016 Kumamoto earthquake (M
JMA
7.3) struck central area of Kyushu Island, Japan. The presence of near surface low velocity layer greatly amplified the ground motions and caused severe damage in ...this region. Therefore, it is essential to study the site characteristics of Kumamoto region. For this purpose, the present research article describes the modification in existing semi-empirical technique of strong motion simply by incorporating the site effect. These site effects are calculated using Horizontal to Vertical ratio (
H
/
V
) method. The estimated predominant frequencies (
f
peak
) for these stations varies between 2.5 and 7.5 Hz. The sites with low
f
peak
indicate higher soil thickness cover and hence, locations are more susceptible to damage. The station KMMH06 used in this work lies in close proximity to one of the major landslide locations (Minami Aso Village), triggered during this earthquake. The low to intermediate
f
peak
value estimated at KMMH06 proposes the area prone to site amplification and severe damage. Also, the initial location and parameters of rupture model of this earthquake are considered based on past seismicity and other empirical relations available. The detailed analysis proposes nucleation point in extreme NW corner of the rupture plane. Afterwards, the developed source model and modified technique compositely used to simulate high frequency records at eight near field stations. This includes time histories, response spectra, predominant period (
T
p
) and mean period (
T
m
). The above comparison successfully validates modified semi-empirical and source model for 2016 Kumamoto earthquake. As far as we are aware, this work is the first to model rupture plane of 2016 Kumamoto earthquake by means of modified semi-empirical technique. It provides adequately reliable results which will be advantageous for seismic hazard assessment of this region.
Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder, best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances, is ...caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). However, in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed in all tissues, impairs other organ systems. Not surprisingly, cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with HD. Mitochondrial dysfunction in the brain and skeletal muscle in HD has been well documented, as the disease progresses. However, not much is known about mitochondrial abnormalities in the heart. In this study, we describe a role for Drp1/Fis1-mediated excessive mitochondrial fission and dysfunction, associated with lysosomal dysfunction in H9C2 expressing long polyglutamine repeat (Q73) and in human iPSC-derived cardiomyocytes transfected with Q77. Expression of long polyglutamine repeat led to reduced ATP production and mitochondrial fragmentation. We observed an increased accumulation of damaged mitochondria in the lysosome that was coupled with lysosomal dysfunction. Importantly, reducing Drp1/Fis1-mediated mitochondrial damage significantly improved mitochondrial function and cell survival. Finally, reducing Fis1-mediated Drp1 recruitment to the mitochondria, using the selective inhibitor of this interaction, P110, improved mitochondrial structure in the cardiac tissue of R6/2 mice. We suggest that drugs focusing on the central nervous system will not address mitochondrial function across all organs, and therefore will not be a sufficient strategy to treat or slow down HD disease progression.
Highlights ► Postnatal diet normalizes brain DHA levels in pups born to B12 -deficient mothers. ► Postnatal diet does not normalize the levels of brain neurotrophins. ► Omega 3 fatty acid ...supplementation to a micronutrient-imbalanced diet is beneficial.
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