Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates and drugs has become increasingly important in the ...pharmaceutical industry. There has been an increasing awareness of the enormous potential of microorganisms and enzymes derived there from for the transformation of synthetic chemicals with high chemo-, regio- and enatioselectivities. In this article, biocatalytic processes are described for the synthesis of chiral alcohols and unntural aminoacids for pharmaceuticals.
Clinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting.
To evaluate long-term safety of natalizumab and ...its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS).
The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings.
In this 5-year interim analysis, 4821 patients were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11-44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years. Lower annualised relapse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower baseline EDSS scores, and in patients with lower prenatalizumab relapse rates. Mean EDSS scores remained unchanged up to 5 years.
Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice.
NCT00493298.
Plant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer ...potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.
The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pronatriuretic function; particularly, AT2R expression and natriuretic function are ...enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are interdependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow and urinary Na excretion which were attenuated by simultaneous infusion of the AT2R antagonist PD123319 or the MasR antagonist A-779. Similarly, infusion of MasR agonist Ang-(1–7) in OZR increased urine flow and urinary Na excretion, which were attenuated by simultaneous infusion of A-779 or PD123319. Experiment in isolated renal proximal tubules of OZR revealed that both the agonists C21 and Ang-(1–7) stimulated NO which was blocked by either of the receptor antagonists. Dual labeling of AT2R and MasR in OZR kidney sections and human proximal tubule epithelial cells showed that AT2R and MasR are colocalized. The AT2R also coimmunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero-length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive to the reducing β-mercaptoethanol, suggesting involvement of -SH groups in cross-linking. Collectively, the study reveals that AT2R and MasR are colocalized and functionally interdependent in terms of stimulating NO and promoting diuretic/natriuretic response.
Summary
Background
Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy‐proven non‐alcoholic fatty liver disease ...(NAFLD).
Aim
To quantify pancreatic fat using a novel magnetic resonance imaging (MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD.
Methods
This is a cross‐sectional study including 43 adult patients with biopsy‐proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH‐CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction.
Results
The average MRI‐determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI‐determined pancreatic fat content increased significantly with increasing histology‐determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with histology‐determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1–2 fibrosis, and 6.9% in stage 3‐4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status.
Conclusions
In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD.
In India, agriculture serves as the backbone of the economy, and is a primary source of employment. Despite the setbacks caused by the COVID-19 pandemic, the agriculture and allied sectors in India ...exhibited resilience, registered a growth of 3.4% during 2020–2121, even as the overall economic growth declined by 7.2% during the same period. The improvement of the agriculture sector holds paramount importance in sustaining the increasing population and safeguarding food security. Consequently, researchers worldwide have been concentrating on digitally transforming agriculture by leveraging advanced technologies to establish smart, sustainable, and lucrative farming systems. The advancement in remote sensing (RS) and machine learning (ML) has proven beneficial for farmers and policymakers in minimizing crop losses and optimizing resource utilization through valuable crop insights. In this paper, we present a comprehensive review of studies dedicated to the application of RS and ML in addressing agriculture-related challenges in India. We conducted a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and evaluated research articles published from 2015 to 2022. The objective of this study is to shed light on the application of both RS and ML technique across key agricultural domains, encompassing “crop management”, “soil management”, and “water management, ultimately leading to their improvement. This study primarily focuses on assessing the current status of using intelligent geospatial data analytics in Indian agriculture. Majority of the studies were carried out in the crop management category, where the deployment of various RS sensors led yielded substantial improvements in agricultural monitoring. The integration of remote sensing technology and machine learning techniques can enable an intelligent approach to agricultural monitoring, thereby providing valuable recommendations and insights for effective agricultural management.
The hyperactive RAS and inflammation are closely associated. The angiotensin-II/AT1R axis of the RAS has been explored extensively for its role in inflammation and a plethora of pathological ...conditions. Understanding the role of AT2R in inflammation is an emerging area of research. The AT2R is expressed on a variety of immune and non-immune cells, which upon activation triggers the release of a host of cytokines and has multiple effects that coalesce to anti-inflammation and prevents maladaptive repair. The anti-inflammatory outcomes of AT2R activation are linked to its well-established signaling pathways involving formation of nitric oxide and activation of phosphatases. Collectively, these effects promote cell survival and tissue function. The consideration of AT2R as a therapeutic target requires further investigations.
The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side effect of this widely used ...antimalarial drug. Here, we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of
Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an
Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that
MrgprA3 is required for CQ responsiveness in mice. Furthermore,
MrgprA3-expressing neurons respond to histamine and coexpress gastrin-releasing peptide, a peptide involved in itch sensation, and
MrgprC11. Activation of these neurons with the MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore,
Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics.
East-Southeast Asia is currently one of the fastest urbanizing regions in the world, with countries such as China climbing from 20 to 50% urbanized in just a few decades. By 2050, these countries are ...projected to add 1 billion people, with 90% of that growth occurring in cities. This population shift parallels an equally astounding amount of built-up land expansion. However, spatially-and temporally-detailed information on regional-scale changes in urban land or population distribution do not exist; previous efforts have been either sample-based, focused on one country, or drawn conclusions from datasets with substantial temporal spatial mismatch and variability in urban definitions. Using consistent methodology, satellite imagery and census data for >1000 agglomerations in the East-Southeast Asian region, we show that urban land increased >22% between 2000 and 2010 (from 155 000 to 189 000 km2), an amount equivalent to the area of Taiwan, while urban populations climbed >31% (from 738 to 969 million). Although urban land expanded at unprecedented rates, urban populations grew more rapidly, resulting in increasing densities for the majority of urban agglomerations, including those in both more developed (Japan, South Korea) and industrializing nations (China, Vietnam, Indonesia). This result contrasts previous sample-based studies, which conclude that cities are universally declining in density. The patterns and rates of change uncovered by these datasets provide a unique record of the massive urban transition currently underway in East-Southeast Asia that is impacting local-regional climate, pollution levels, water quality availability, arable land, as well as the livelihoods and vulnerability of populations in the region.
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