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Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.

Up to 40% of patients with estrogen receptor (ER)-positive breast cancer will develop resistance against the majority of current ER-directed therapies. Resistance can arise through various mechanisms such as increased expression levels of coregulators, and key mutations acquired in the receptor’s ligand binding domain rendering it constitutively active. To overcome these resistance mechanisms, we explored targeting the ER Activation Function 2 (AF2) site, which is essential for coactivator binding and activation. Using artificial intelligence and the deep docking methodology, we virtually screened > 1 billion small molecules and identified 290 potential AF2 binders that were then characterized and validated through an iterative screening pipeline of cell-based and cell-free assays. We ranked the compounds based on their ability to reduce the transcriptional activity of the estrogen receptor and the viability of ER-positive breast cancer cells. We identified a lead compound, VPC-260724, which inhibits ER activity at low micromolar range. We confirmed its direct binding to the ER-AF2 site through a PGC1α peptide displacement experiment. Using proximity ligation assays, we showed that VPC-260724 disrupts the interaction between ER-AF2 and the coactivator SRC-3 and reduces the expression of ER target genes in various breast cancer models including the tamoxifen resistant cell line TamR3. In conclusion, we developed a novel ER-AF2 binder, VPC-260724, which shows antiproliferative activity in ER-positive breast cancer models. The use of an ER-AF2 inhibitor in combination with current treatments may provide a novel complementary therapeutic approach to target treatment resistance in ER-positive breast cancer.

With declines in development assistance for health and growing interest in country ownership, donors are increasingly faced with the task of transitioning health programs to local actors towards a path to sustainability. Yet there is little available guidance on how to measure and evaluate the success of a transition and its subsequent effects. This study assesses the transition of the Avahan HIV/AIDS prevention program in India to investigate how preparations for transition affected continuation of program activities post-transition. Two rounds of two surveys were conducted and supplemented by data from government and Avahan Computerized Management Information Systems (CMIS). Exploratory factor analysis was used to develop two measures: 1) transition readiness pre-transition, and 2) institutionalization (i.e. integration of initial program systems into organizational procedures and behaviors) post-transition. A fixed effects model was built to examine changes in key program delivery outcomes over time. An ordinary least square regression was used to assess the relationship between transition readiness and sustainability of service outcomes both directly, and indirectly through institutionalization. Transition readiness data revealed 3 factors (capacity, alignment and communication), on a 15-item scale with adequate internal consistency (alpha 0.73). Institutionalization was modeled as a unidimensional construct, and a 12-item scale demonstrated moderate internal consistency (alpha 0.60). Coverage of key populations and condom distribution were sustained compared to pre-transition levels (p<0.01). Transition readiness, but not institutionalization, predicted sustained outcomes post-transition. Transition readiness did not necessarily lead to institutionalization of key program elements one year after transition. Greater preparedness prior to transition is important to achieve better service delivery outcomes post-transition. This paper illustrates a methodology to measure transition readiness pre-transition to identify less ready organizations or program components in advance, improving the likelihood of service sustainability. Further research is needed around the conceptualization and development of measures of institutionalization and its effects on long-term program sustainability.

Between 2009-2013 the Bill and Melinda Gates Foundation transitioned its HIV/AIDS prevention initiative in India from being a stand-alone program outside of government, to being fully government funded and implemented. We present an independent prospective evaluation of the transition. The evaluation drew upon (1) a structured survey of transition readiness in a sample of 80 targeted HIV prevention programs prior to transition; (2) a structured survey assessing institutionalization of program features in a sample of 70 targeted intervention (TI) programs, one year post-transition; and (3) case studies of 15 TI programs. Transition was conducted in 3 rounds. While the 2009 transition round was problematic, subsequent rounds were implemented more smoothly. In the 2011 and 2012 transition rounds, Avahan programs were well prepared for transition with the large majority of TI program staff trained for transition, high alignment with government clinical, financial and managerial norms, and strong government commitment to the program. One year post transition there were significant program changes, but these were largely perceived positively. Notable negative changes were: limited flexibility in program management, delays in funding, commodity stock outs, and community member perceptions of a narrowing in program focus. Service coverage outcomes were sustained at least six months post-transition. The study suggests that significant investments in transition preparation contributed to a smooth transition and sustained service coverage. Notwithstanding, there were substantive program changes post-transition. Five key lessons for transition design and implementation are identified.

Background and Aims: While performing laryngoscopy during nasotracheal intubation (NTI), the tip of the advancing endotracheal tube (ETT) generally lies along the posterior pharyngeal wall. The inflation of the ETT cuff brings it anterior towards the glottis. The present study was planned to compare the intubating conditions for NTI with standard direct Macintosh laryngoscope versus C-MAC® video laryngoscope (VL) employing ETT cuff inflation technique. Methods: This prospective randomised study was carried out on 50 patients, American Society of Anesthesiologists physical status I-II, age 18-60 years of either sex with an indication for NTI under general anaesthesia. They were randomly divided into two groups: group VL (n = 25): C-MAC® VL and group ML (n = 25): Macintosh laryngoscope. The primary outcome was to compare the total duration of NTI (T), while the secondary outcomes were to compare the need for cuff inflation or assistance with Magill forceps for successful NTI, the total number of attempts to achieve successful NTI, haemodynamic effects and complications. Results: T was significantly higher in group ML than group VL (P < 0.001). The intubation was successful with cuff inflation in all the patients in group VL, however, six patients of group ML required assistance with Magill forceps (P = 0.022). The haemodynamic parameters were all significantly higher at 3 min in group ML in comparison to group VL. Conclusion: The cuff inflation technique when used along with C-MAC® VL had more success rate, required lesser time and had minimal postoperative complications in comparison to the Macintosh laryngoscope.

Accurate prediction of sweet potato yield is crucial for effective crop management. This study investigates the use of vegetation indices (VIs) extracted from multispectral images acquired by a small unmanned aerial vehicle (UAV) throughout the growing season, along with in situ-measured plant physiological parameters, to predict sweet potato yield. The data acquisition process through UAV field imaging is discussed in detail along with the extraction process for the multispectral bands that we use as features. The experiment is designed with a combination of different nitrogen application rates and cover crop treatments. The dependence of VIs and crop physiological parameters, such as leaf chlorophyll content, plant biomass, vine length, and leaf nitrogen content, on yield is evaluated through feature selection methods and model performance. Classical machine learning (ML) approaches and tree-based algorithms, like XGBoost and Random Forest, are implemented. Additionally, a soft-voting ML model ensemble approach is employed to improve performance of yield prediction. Individual models are trained and tested for different cover crop and nitrogen treatments to capture the relationships between the treatments and the target yield variable. The performance of the ML algorithms is evaluated using various popular model performance metrics like R2, RMSE, and MAE. Through modelling the data for cover crops and nitrogen treatment rates using individual models, the relationships and effects of different treatments on yield are explored. Important VIs useful for the study are identified through feature selection and model performance evaluation.

The study titled Examining the Influence of Emotional Intelligence on Stress & Well-Being in Employees of National Thermal Power Corporation - Power Management Institute, Noida, India aimed to understand the levels of emotional intelligence, the nature of stress, and the impact of stress on well-being through the lived experiences of NTPC PMI employees. [...]gaps in formal mental health services were noted. Keywords: Emotional intelligence, stress, well-being, semi-structured interview, thematic analysis Intelligence, Emotions, and Emotional Intelligence (EI) Modern society, with its tempo and interconnection, is more or less a global theatre where people face challenges to their faculties, emotional and intellectual, on a daily basis at the workplace. Intelligence that was once attributed as the essence of human capital allows people to reason and bowl conceptually, and make decisions knowingly, which form the bedrock of problem solving and flexibility (Gleiser, 2025).

The functional properties of pumpkin seed proteins remain unutilized in numerous food and industrial applications. Several current approaches aim to improve the functional properties of pumpkin seed proteins, allowing their innovative potential to develop and modify significantly. Several strategies can be implemented to alter the functional properties of proteins isolated from pumpkin seeds. The first is enzymatic hydrolysis, regardless of whether, proteases may free peptide binding and profoundly impact the protein structure and functionality. Thermal treatment can include heating and cooling to replace protein conformation and increase solubility, emulsification, and gelation properties. Chemical modification techniques, including acylation and glycation, can also be used to improve stability, viscosity, and foaming ability. Functional properties and, where possible, ingredients with many applications may include exceptional possibilities for proteins modified in food preparations, such as dairy replacements, plant-based meat analogues, and free gluten that have an outstanding aspect, satisfactory quality, and nutritional profiles. As multiple different proteins act as precursors of active peptides, they can also be used to generate bio-specific foods. This review briefly provides information about various types of protein extraction techniques and functional properties that are modified by different types of processing technologies.

Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40–50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.

The purpose of this study was to develop and evaluate a sublingual tablet of lercanidipine hydrochloride for the direct compression method of treating hypertension by using a solid dispersion technique. The dihydropyridine calcium-channel blocker lercanidipine Hydrochloride is used to treat hypertension, Prinz metal’s variant angina, and chronic stable angina pectoris. It can be administered alone or in combination with an angiotensin-converting enzyme inhibitor. The biological half-life of lercanidipine hydrochloride is 8–10hours, and its duration of action is up to 24hours. Because of its first pass metabolism, lercanidipine hydrochloride has a less than 10% oral bioavailability. BCS class II was applied to lercanidipine hydrochloride due to its high permeability and poor solubility. The aforementioned features and attributes render Lercanidipine Hydrochloride a fitting contender for a sublingual tablet created by robust dispersion and integrating Gelucire 50/13. When compared to pure lercanidipine Hydrochloride, the solubility is high when Gelucire 50/13 was used at the highest concentration. This is the first attempt to improve the solubility of pure lercanidipine HCl free base by the use of various solid dispersion methods, including solvent evaporation, fusion, and physical mixing. Lercanidipine HCl kneading solid dispersion, made with Gelucire 50/13 (1:1)., The prepared lercanidipine HCl sublingual tablets prevent first pass metabolism, avoid swallowing-related issues, particularly in elderly patients, and enhance solubility. The tablet disintegrated in 50 seconds, according to the results. Similarly, a dissolution study conducted in vitro revealed 96.68% drug release in 10 minutes. The prepared lercanidipine HCl sublingual tablets containing a complex with Gelucire 50/13 solid dispersion were found to significantly improve patient compliance and bioavailability.