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Bimagrumab is a human monoclonal antibody that prevents activin type II receptors (ActRII) from functioning. This antibody has a higher affinity for muscle activin-2 receptors than natural ligands such as activin and myostatin, which act as negative muscle growth regulators. Blocking the activin receptor with bimagrumab could be a new pharmaceutical approach for managing patients with obesity and type 2 diabetes mellitus (T2DM). Bimagrumab has anabolic effects on skeletal muscle mass by preventing myostatin binding and other negative muscle growth regulators. Preclinical animal models have also shown that ActRII blockade promotes actions beyond skeletal muscle, including effects on brown adipose tissue (BAT) differentiation and activity. In a phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of total body fat mass (FM), lean mass (LM) gain, and metabolic improvements over 48 weeks in overweight or obese patients with type 2 diabetes. The trial involved [number of participants], and the results showed [specific findings]. Currently, Bimagrumab is being evaluated for its potential to treat muscle wasting, functional loss in hip fractures and sarcopenia, as well as obesity. However, it is essential to note that Bimagrumab also blocks the effects of other ActRII ligands, which play a role in the neurohormonal axes, pituitary, gonads, and adrenal glands. These observations suggest that bimagrumab might represent a new approach for treating patients with obesity and related metabolic disturbances. [ABSTRACT FROM AUTHOR]

Psoriasis is a persistent, inflammatory, and autoimmune condition that is difficult to treat. Estimates of the prevalence of psoriasis in people range from 0.27 % (95 % confidence interval 0.17 to 0.36) to 11.4 %, depending on factors such as age, sex, geography, ethnicity, genetics, and environmental factors. While systemic treatments are typically required for patients with moderate-to-severe instances of psoriasis, topical therapies are frequently effective for treating minor forms. In fact, phototherapy is frequently constrained by logistical considerations, and conventional systemic therapies are frequently avoided due to contraindications or the danger of adverse outcomes. In order to better serve the patient and achieve a greater level of quality of life, especially in order to sustain long-term efficacy, there is still a need for innovative therapies, which are always welcomed. Deucravacitinib is a first-in-class oral tyrosine kinase 2 (TYK2) inhibitor that is extremely selective. Through an allosteric mechanism, it stabilises an inhibitory connection between the regulatory and catalytic domains of TYK2's pseudokinase regulatory domain, which is catalytically inactive. This can be used to treat a variety of immune-mediated conditions, such as inflammatory bowel disease, lupus, psoriatic arthritis, and psoriasis. US-FDA has approved this drug on 9 September 2022 for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This article aims to review the current knowledge on the efficacy and safety of deucravacitinib for the management of psoriasis. [ABSTRACT FROM AUTHOR]

The humanised monoclonal antibody donanemab is being developed to treat early onset Alzheimer's disease (AD). This drug targets N-truncated pyroglutamate amyloid-peptide at position 3 (N3pG), a modified form of deposited amyloid-peptide. The symptoms of Alzheimer's disease include gradual memory loss and other cognitive impairments. This disease is characterized by amyloid plaques, which are formed as a result of an accumulation of amyloid-(A-β) peptides. Despite granting donanemab breakthrough therapy designation in June 2021, the FDA rejected donanemab's accelerated approval application in January 2023, due to inadequate safety data. According to the baseline amyloid level, the time to achieve plaque clearance (amyloid plaque level <24.1 centiloids) varied. Patients with higher baseline levels were more likely to achieve amyloid clearance. The safety of the drug was demonstrated by amyloid-related imaging abnormalities (ARIA), which ranged from 26.1 to 30.5 % in the studies. Clinical trial results have shown that donanemab delays cognitive and functional deterioration in patients with mild to moderate AD. However, it is not yet known whether donenameb offers therapeutic benefits that can change and improve the clinical condition of AD patients. To achieve significant clinical benefits in AD patients with cognitive impairment, further studies may be needed to investigate the interaction between A-β plaque reduction and toxic tau levels. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic continues to pose a serious global challenge, with the world engulfed in fighting second, third and fourth waves of the disease, which is reaching scary proportions in terms of cases and mortality in countries like India. Despite the urgent need of proven management protocols, there is still confusion about the best practices for treating COVID-19 with different pharmaceutical interventions. Antimicrobials are empirically used in COVID-19 patients. During the initial phase of this pandemic, hydroxychloroquine, ivermectin, azithromycin and doxycycline were widely suggested for possible prophylaxis or treatment for COVID-19 in outpatient as well as hospitalized settings. Various national and international guidelines recommended its use. However, cumulative evidence from subsequent clinical trials has revealed no significant clinical benefits in any setting, with the risk of adverse effects being high particularly in combination with azithromycin. Yet, there is continued use of antimicrobials particularly in outpatient settings which should be avoided because there is no justifiable rationale for doing so. Antimicrobial resistance (AMR) was one of the top problems for global public health before the coronavirus 2019 (COVID-19) pandemic began. AMR, which is already a difficult problem, must now be handled in the context of a changing healthcare sector. [ABSTRACT FROM AUTHOR]

The study was conducted to assess patterns of prescribed drug therapy and clinical predictors of need for therapy escalation in outpatients with diabetes mellitus (DM). This was a prospective cohort study, conducted at an apex tertiary care teaching hospital in central India for a period of 18 months. The demographic, clinical, and treatment details on the baseline and follow up visits were collected from the patients' prescription charts. Glycemic control, adherence, pill burdens along with pattern of antidiabetic therapy escalation, and deescalations were analyzed. A total of 1,711 prescriptions of 925 patients of diabetes with a mean age of 53.81 ± 10.42 years and duration of disease of 9.15 ± 6.3 years were analyzed. Approximately half of the patients (n=450) came for ≥1 follow up visits. Hypertension (59.35%) was the most common comorbidity followed by dyslipidemia and hypothyroidism. The mean total daily drugs and pills per prescription were 4.03 ± 1.71 and 4.17 ± 1.38, respectively. Metformin (30.42%) followed by sulphonylureas (SUs) (21.39%) constituted majority of the AHA's and dual and triple drug therapy regimens were most commonly prescribed. There were improvements in HbA1c, fasting/postprandial/random blood sugar (FBS/PPBS/RBS) as well as adherence to medication, diet, and exercise in the follow up visits. Among patients with follow ups, therapy escalations were found in 31.11% patients, among whom dose was increased in 12.44% and drug was added in 17.28%. Apart from Hb1Ac, FBS, and PPBS levels (p<0.001), characteristics such as age, BMI, duration of diagnosed diabetes, presence of hypertension and dyslipidemia, and daily pill burdens were found to be significantly higher in the therapy escalation group (p<0.05). Inadequate medication adherence increased the relative risk (RR) of therapy escalation by almost two times. Disease and therapy patterns are reflective of diabetes care as expected at a tertiary care center. Higher BMI, age, pill burden, duration of diabetes, presence of comorbidities, and poor medication adherence may be the predictors of therapy escalation independent of glycemic control and such patients should be more closely monitored. [ABSTRACT FROM AUTHOR]

Heterodimeric integrin adhesion receptors regulate diverse biological processes including angiogenesis, thrombosis and wound healing. The transmembrane-cytoplasmic domains (TMCDs) of integrins play a critical role in controlling activation of these receptors via an inside-out signaling mechanism, but the precise structural basis remains elusive. Here, we present the solution structure of integrin [alpha]IIb[beta]3 TMCD heterodimer, which reveals a right-handed coiled-coil conformation with 2 helices intertwined throughout the transmembrane region. The helices extend into the cytoplasm and form a clasp that differs significantly from a recently published [alpha]IIb[beta]3 TMCD structure. We show that while a point mutation in the clasp interface modestly activates [alpha]IIb[beta]3, additional mutations in the transmembrane interface have a synergistic effect, leading to extensive integrin activation. Detailed analyses and structural comparison with previous studies suggest that extensive integrin activation is a highly concerted conformational transition process, which involves transmembrane coiled-coil unwinding that is triggered by the membrane-mediated alteration and disengagement of the membrane-proximal clasp. Our results provide atomic insight into a type I transmembrane receptor heterocomplex and the mechanism of integrin inside-out transmembrane signaling. NMR | protein structure | transmembrane domain doi/ 10.1073/pnas.0909589106

In polarized epithelial cells, syntaxin 3 localizes to the apical plasma membrane and is involved in membrane fusion of apical trafficking pathways. We show that syntaxin 3 contains a necessary and sufficient apical targeting signal centered around a conserved FMDE motif. Mutation of any of three critical residues within this motif leads to loss of specific apical targeting. Modeling based on the known structure of syntaxin 1 revealed that these residues are exposed on the surface of a three-helix bundle. Syntaxin 3 targeting does not require binding to Munc18b. Instead, syntaxin 3 recruits Munc18b to the plasma membrane. Expression of mislocalized mutant syntaxin 3 in Madin-Darby canine kidney cells leads to basolateral mistargeting of apical membrane proteins, disturbance of tight junction formation, and loss of ability to form an organized polarized epithelium. These results indicate that SNARE proteins contribute to the overall specificity of membrane trafficking in vivo, and that the polarity of syntaxin 3 is essential for epithelial cell polarization.

The crystal structure of the helical linker domain and U-box domain of zebrafish CHIP (DrCHIP- HU) is presented. Results provide insight into conformational variability in the domain arrangement of CHIP and into U-box-mediated recruitment of UbcH5b for the ubiquitination of Hsp70 and Hsp90 substrates.