KRAS4b:RAF-1 Homogenous Time-Resolved Fluorescence Resonance Energy Transfer Assay for Drug Discovery.

Homogenous time-resolved FRET (HTRF) assays have become one of the most popular tools for pharmaceutical drug screening efforts over the last two decades. Large Stokes shifts and long fluorescent lifetimes of lanthanide chelates lead to robust signal to noise, as well as decreased false positive rates compared to traditional assay techniques. In this chapter, we describe an HTRF protein-protein interaction (PPI) assay for the KRAS4b G-domain in the GppNHp-bound state and the RAF-1-RBD currently used for drug screens. Application of this assay contributes to the identification of lead compounds targeting the GTP-bound active state of K-RAS.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Datathons: fostering equitability in data reuse in ecology.

Approaches to rapidly collecting global biodiversity data are increasingly important, but biodiversity blind spots persist. We organized a three-day Datathon event to improve the openness of local biodiversity data and facilitate data reuse by local researchers. The first Datathon, organized among microbial ecologists in Uruguay and Argentina assembled the largest microbiome dataset in the region to date and formed collaborative consortia for microbiome data synthesis.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

A Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement.

Development of new targeted inhibitors for oncogenic KRAS mutants may benefit from insight into how a given mutation influences the accessibility of protein residues and how compounds interact with mutant or wild-type KRAS proteins. Targeted proteomic analysis, a key validation step in the KRAS inhibitor development process, typically involves both intact mass- and peptide-based methods to confirm compound localization or quantify binding. However, these methods may not always provide a clear picture of the compound binding affinity for KRAS, how specific the compound is to the target KRAS residue, and how experimental conditions may impact these factors. To address this, we have developed a novel top-down proteomic assay to evaluate in vitro KRAS4B-compound engagement while assessing relative quantitation in parallel. We present two applications to demonstrate the capabilities of our assay: maleimide-biotin labeling of a KRAS4BG12D cysteine mutant panel and treatment of three KRAS4B proteins (WT, G12C, and G13C) with small molecule compounds. Our results show the time- or concentration-dependence of KRAS4B-compound engagement in context of the intact protein molecule while directly mapping the compound binding site.

Microplastic abundance in sludge-treated fields: Variance and estimated half-life.

This study investigated the abundance of microplastic (MP) in agricultural soil fertilised with sludge, assessing the variation in MP count and estimated mass in three long-term field trials treated excessively with sludge in 2003-2012. Ten samples were taken from each of the three fields with concentrations ranging from 2392 to 48,791 counts kg-1, where over 50 % of the MPs were polyester and acrylic. Due to the considerable variation in concentration, the impact of the number of sub-samples on the predicted measured concentration was estimated applying a Monto Carlo simulation approach. Choosing the number of sampling points is a compromise between acceptable sampling error and available resources. The simulations showed an increasingly high risk of obtaining an outlier when taking less than approx. ten subsamples. When ending fertilisation with sludge, the estimated half-life for the MPs measured by counts was approx. 2.5 years, whereas the half-life for the MP estimated mass was approx. 4 years. Hence, smaller particles seemed to degrade and/or migrate elsewhere the fastest.

Bridging Metabolic-Associated Steatotic Liver Disease and Cardiovascular Risk: A Potential Role for Ketogenesis.

The prevalence of cardiovascular diseases (CVDs) is a growing global health concern. Recent advances have demonstrated significant reductions in acute cardiovascular events through the management of modifiable cardiovascular risk factors. However, these factors are responsible for about 50% of the global cardiovascular disease burden. Considering that CVDs are one of the top mortality causes worldwide, the concept of residual cardiovascular risk is an important emerging area of study. Different factors have been proposed as sources of residual risk markers, including non-HDL particles characterization, as well as inflammation measured by serum and imaging technics. Among these, metabolic-associated steatotic liver disease (MASLD) remains controversial. Two opposing viewpoints contend: one positing that fatty liver disease merely reflects classical risk factors and thus adds no additional risk and another asserting that fatty liver disease independently impacts cardiovascular disease incidence. To address this dilemma, one hypothetical approach is to identify specific hepatic energy-yielding mechanisms and assess their impact on the cardiovascular system. Ketogenesis, a metabolic intermediate process particularly linked to energy homeostasis during fasting, might help to link these concepts. Ketogenic metabolism has been shown to vary through MASLD progression. Additionally, newer evidence supports the significance of circulating ketone bodies in cardiovascular risk prediction. Furthermore, ketogenic metabolism modification seems to have a therapeutic impact on cardiovascular and endothelial damage. Describing the relationship, if any, between steatotic liver disease and cardiovascular disease development through ketogenesis impairment might help to clarify MASLD's role in cardiovascular risk. Furthermore, this evidence might help to solve the controversy surrounding liver steatosis impact in CVD and might lead to a more accurate risk assessment and therapeutic targets in the pursuit of precision medicine.

Use of pedicled flaps after oncologic resections in pediatric patients.

The aim of this study is to review the indications of pedicled flaps and analyze the results. A observational retrospective study of under 18-year-old oncology patients who required reconstructive surgery with pedicled flaps between 2011 and 2022 was performed. Demographic and clinical variables, indications, complications, and outcomes were collected. 236 patients were reviewed and 13 met inclusion criteria, eight girls and five boys (mean age: 10.6 years). Indications were Ewing's sarcoma (5), osteosarcoma (5), neuroblastoma, desmoid tumor, and neurofibroma. Preoperative PET-CT, MRI and bone scintigraphy were performed. The flaps were used on costal and extremity reconstruction: latissimus dorsi (5), pectoralis (2), medial gastrocnemius (2), combined latissimus dorsi, trapezius and serratus muscle, biceps femoris, fascio-neuro-cutaneous saphenous and cutaneous advancement-rotation. Two were performed on allograft and eight on prosthesis. All allowed immediate and complete closure. Six patients received intraoperative radiotherapy. One flap infection and two vascular complications were reported, a total necrosis, which required a new flap, and a partial necrosis, treated with a local plasty. Chemotherapy was resumed after 21 days (15-31). Mean follow-up time was 5.34 years. Flaps are an effective therapeutic option allowing reconstruction of large defects after pediatric oncologic surgeries. The most frequent complication was vascular.

Antidiabéticos orales y trastornos depresivos: ¿riesgo o protección? / Oral antidiabetics and depressive disorders: Risk or protection?

Introducción la diabetes mellitus y los trastornos del estado de ánimo son 2 entidades que se entrelazan entre sí con mecanismos fisiopatológicos en común. Los hipoglucemiantes orales son un pilar fundamental para obtener el control glucémico en los individuos diabéticos y, recientemente, la alta prevalencia de estas 2 patologías en un mismo paciente han hecho que los estudios clínicos se enfoquen en analizar el efecto de los hipoglucemiantes orales en los pacientes con diabetes mellitus tipo 2 y trastorno depresivo. Objetivo realizar una revisión de la literatura disponible sobre la medicación hipoglucemiante en el contexto de los pacientes con diabetes mellitus y trastorno depresivo. Conclusiones si bien los antidiabéticos orales han mostrado tener un efecto antidepresivo en ciertos modelos experimentales, en la práctica clínica la evidencia es escasa, pero llama particularmente la atención el menor riesgo de depresión con ciertos antidiabéticos dejando abierta las posibilidades de futuros estudios con la naturaleza adecuada que permita aclarar el efecto de los hipoglucemiantes orales en la población con diabetes mellitus y trastorno depresivo. (AU)

Introduction Diabetes mellitus and mood disorders are two entities that are intertwined with common pathophysiological mechanisms. Oral hypoglycemic agents are a fundamental pillar in obtaining adequate glucose control in diabetic individuals and, recently, the high prevalence of these two pathologies in the same patient have led clinical studies to focus on analyzing the effect of oral hypoglycemic agents in diabetics. patients with type 2 diabetes mellitus and depressive disorder. Objective To carry out a review of the available literature on hypoglycemic medication in the context of patients with diabetes mellitus and depressive disorder. Conclusions Although oral antidiabetics have been shown to have an antidepressant effect in certain experimental models, in clinical practice the evidence is scarce, but the lower risk of depression with certain antidiabetics is particularly noteworthy, leaving open the possibilities of future studies with the adequate nature that allows clarifying the effect of oral hypoglycemic agents in the population with diabetes mellitus and depressive disorder. (AU)

Spin-Crossing in the (Z)-Selective Alkyne Semihydrogenation Mechanism Catalyzed by Mo3S4 Clusters: A Density Functional Theory Exploration.

Semihydrogenation of internal alkynes catalyzed by the air-stable imidazolyl amino [Mo3S4Cl3(ImNH2)3]+ cluster selectively affords the (Z)-alkene under soft conditions in excellent yields. Experimental results suggest a sulfur-based mechanism with the formation of a dithiolene adduct through interaction of the alkyne with the bridging sulfur atoms. However, computational studies indicate that this mechanism is unable to explain the experimental outcome: mild reaction conditions, excellent selectivity toward the (Z)-isomer, and complete deuteration of the vinylic positions in the presence of CD3OD and CH3OD. An alternative mechanism that explains the experimental results is proposed. The reaction begins with the hydrogenation of two of the Mo3(µ3-S)(µ-S)3 bridging sulfurs to yield a bis(hydrosulfide) intermediate that performs two sequential hydrogen atom transfers (HAT) from the S-H groups to the alkyne. The first HAT occurs with a spin change from singlet to triplet. After the second HAT, the singlet state is recovered. Although the dithiolene adduct is more stable than the hydrosulfide species, the large energy required for the subsequent H2 addition makes the system evolve via the second alternative pathway to selectively render the (Z)-alkene with a lower overall activation barrier.

An Outbreak of Acute Chagas Disease Possibly Spread through Oral Transmission Involving Animal Reservoirs in Eastern Colombia.

Chagas disease (CD) is a parasitic infection caused by the parasite Trypanosoma cruzi. Reports of CD cases associated with oral transmission have increased, particularly in Colombia, Brazil, and Venezuela. In this investigation, parasitological, serological, and molecular tests were conducted on samples obtained from humans, mammal reservoirs, and hosts involved in the assessment of a suspected oral transmission outbreak in Cubara, Boyaca, Colombia. Seropositivity was observed in 60% (3 of 5) of index patients and 6.4% (5 of 78) of close contacts. Trypanosoma cruzi DNA was detected by quantitative polymerase chain reaction in 100% of index cases, 6.4% (5 of 78) of close contacts, 60% (6 of 10) of canines, and 100% (5 of 5) of opossums. In all index cases, the TcI lineage was identified, along with two cases of mixed infection (TcI/TcII-TcVI). Hemoculture revealed a flagellate presence in 80% of opossums, whereas all triatomine bugs tested negative. Our findings suggest a potential oral transmission route through contamination with opossum secretions.

Cognitive function, self-management, and outcomes among liver transplant recipients: LivCog, a multicenter, prospective study.

Liver transplantation is a life-saving option for decompensated cirrhosis. Liver transplant recipients require advanced self-management skills, intact cognitive skills, and care partner support to improve long-term outcomes. Gaps remain in understanding post-liver transplant cognitive and health trajectories, and patient factors such as self-management skills, care partner support, and sleep. Our aims are to (1) assess pre-liver transplant to post-liver transplant cognitive trajectories and identify risk factors for persistent cognitive impairment; (2) evaluate associations between cognitive function and self-management skills, health behaviors, functional health status, and post-transplant outcomes; and (3) investigate potential mediators and moderators of associations between cognitive function and post-liver transplant outcomes. LivCog is a longitudinal, prospective observational study that will enroll 450 adult liver transplant recipients and their caregivers/care partners. The duration of the study is 5 years with 24 additional months of patient follow-up. Data will be collected from participants at 1, 3, 12, and 24 months post-transplant. Limited pre-liver transplant data will also be collected from waitlisted candidates. Data collection methods include interviews, surveys, cognitive assessments, and actigraphy/sleep diary measures. Patient measurements include sociodemographic characteristics, pretransplant health status, cognitive function, physical function, perioperative measures, medical history, transplant history, self-management skills, patient-reported outcomes, health behaviors, and clinical outcomes. Caregiver measures assess sociodemographic variables, health literacy, health care navigation skills, self-efficacy, care partner preparedness, nature and intensity of care, care partner burden, and community participation. By elucidating various health trajectories from pre-liver transplant to 2 years post-liver transplant, LivCog will be able to better characterize recipients at higher risk of cognitive impairment and compromised self-management. Findings will inform interventions targeting health behaviors, self-management, and caregiver supports to optimize outcomes.

3D designed in-house positioning and cutting guide system for genioplasty surgery. Technical note and case report.

Advances in 3D printing technology have the potential to significantly improve the workflow of maxillofacial surgical planning. In-house fabricated custom positioning and cutting guides allow for intraoperative reproduction of pre-planned osteotomy cuts, which can result in greater surgical accuracy and patient safety while maintaining an acceptable cost-effectiveness ratio. The design and creation of the customized surgical guides is performed in our hospital fab lab, which allows time savings, from an average of 10 days to just 24 hours, and a cost reduction of more than 90%. The process begins with the import of the pre-surgical facial CT scan into 3D software that allows to perform the surgical cuts virtually and the manipulation of the segments. Once the virtual planning of the surgery has been performed, the next step is the creation of the cutting and positioning guides. The final step is the printing of the guides in surgical resin and their sterilization. In addition, post-surgical models can be 3D printed to pre-mold the plates on them, which saves surgical time. The mentoplasty surgery is a simple example of how 3D surgery can be applied to maxillofacial surgery in an efficient way obtaining all the advantages of customized surgery with a limited investment in time and resources. Key words:3Dsurgery, customized, personalized medicine, genioplasty, surgical guides, in house.

Insights on microstructural evolution and capacity fade on diatom [Formula: see text] anodes for lithium-ion batteries.

[Formula: see text] is a promising material for developing high-capacity anodes for lithium-ion batteries (LIBs). However, microstructural changes of [Formula: see text] anodes at the particle and electrode level upon prolonged cycling remains unclear. In this work, the causes leading to capacity fade on [Formula: see text] anodes were investigated and simple strategies to attenuate anode degradation were explored. Nanostructured [Formula: see text] from diatomaceous earth was integrated into anodes containing different quantities of conductive carbon in the form of either a conductive additive or a nanometric coating layer. Galvanostatic cycling was conducted for 200 cycles and distinctive trends on capacity fade were identified. A thorough analysis of the anodes at selected cycle numbers was performed using a toolset of characterization techniques, including electrochemical impedance spectroscopy, FIB-SEM cross-sectional analysis and TEM inspections. Significant fragmentation of [Formula: see text] particles surface and formation of filigree structures upon cycling are reported for the first time. Morphological changes are accompanied by an increase in impedance and a loss of electroactive surface area. Carbon-coating is found to restrict particle fracture and to increase capacity retention to 66%, compared to 47% for uncoated samples after 200 cycles. Results provide valuable insights to improve cycling stability of [Formula: see text] anodes for next-generation LIBs.

Observational analysis of clinical and pathological characteristics and their prognostic impact in Mexican patients with breast cancer: A multi-center study.

Breast cancer is the most incidental and deadly neoplasm worldwide; in Mexico, very few epidemiologic reports have analyzed the pathological features and its impact on their clinical outcome. Here, we studied the relation between pathological features and the clinical presentation at diagnosis and their impact on the overall and progression-free survival of patients with breast cancer. For this purpose, we collected 199 clinical records of female patients, aged at least 18 years old (y/o), with breast cancer diagnosis confirmed by biopsy. We excluded patients with incomplete or conflicting clinical records. Afterward, we performed an analysis of overall and progression-free survival and associated risks. Our results showed an average age at diagnosis of 52 y/o (24-85), the most common features were: upper outer quadrant tumor (32%), invasive ductal carcinoma (76.8%), moderately differentiated (44.3%), early clinical stages (40.8%), asymptomatic patients (47.8%), luminal A subtype (47.8%). Median overall survival was not reached, but median progression-free survival was 32.2 months (29.75-34.64, CI 95%) associated risk were: clinical stage (p < 0.0001) symptomatic presentation (p = 0.009) and histologic grade (p = 0.02). Therefore, we concluded that symptom presence at diagnosis impacts progression-free survival, and palpable symptoms are related to an increased risk for mortality.

Production and Partial Characterization of Bioactive Compounds from Underutilized Marine Bioresources for a Cosmetic Formulation: Cytotoxicity and Bioactivity Evaluation.

Hydrolyzed collagen, glycogen, and hyaluronic acid, obtained through the biotechnological valorization of underutilized marine bioresources, fulfill cosmetic industry requirements for sustainable products produced under circular economy principles. Hydrolyzed collagen was obtained by hydrolyzing blue shark collagen with papain and ultrafiltration. Glycogen was isolated from industrial mussel cooking wastewaters through ultrafiltration, precipitation, and selective polysaccharide separation. Hyaluronic acid was produced by fermentation, purification, and depolymerization. The main objective was to test the feasibility of including these three biomolecules in a cosmetic formulation as bioactive compounds. For this, the in vitro irritant potential of the three ingredients and also that of the cosmetic formulation was assayed according to the Reconstituted Human Epithelium Test method OECD 439. Moreover, an in vitro assessment of the effect of hydrolyzed collagen and hyaluronic acid combinations on mRNA expression and collagen type I synthesis was evaluated in adult human fibroblasts. This study establishes, for the first time, the potential use of particular hydrolyzed collagen and hyaluronic acid combinations as stimulators of collagen I synthesis in fibroblast cultures. Besides, it provide safety information regarding potential use of those biomolecules in the formulation of a cosmetic preparation positively concluding that both, ingredients and cosmetic preparation, resulted not irritant for skin following an international validated reference method.

How specific molecules can lead to overeating.

A molecular pathway involving compounds found in processed foods and biogenic amines increases food intake and aging in the roundworm C. elegans.

Osmotic Demyelination Syndrome in a Normonatremic Patient Under Treatment With Proton Pump Inhibitors.

A 66-year-old woman was admitted to the emergency department with diarrhea, nausea, and vomiting as well as low-grade fever. She was initially treated with ciprofloxacin and metronidazole with symptomatic improvement and was discharged. One week later, she returned to the emergency department for gait instability, dizziness, and vomiting and had a witnessed generalized tonic-clonic seizure in the hospital. During both admissions, the presence of ionic alterations such as severe hypomagnesemia, hypophosphatemia, and hypokalemia stood out, while sodium levels remained normal. Among her antecedents, she had a hiatal hernia and had been receiving treatment with omeprazole for years.

Eosinophilic Granulomatosis With Polyangiitis Presentation After Nandrolone Withdrawal.

A 41-year-old man was admitted to the Emergency Department with bilateral numbness in lower extremities and left femoral palsy. He also reported constitutional symptoms, vomiting and non-bloody diarrhoea for the last several months. He had a previous history of eosinophilic asthma with erratic follow-up. During admission, eosinophil count was 66% of white blood cells. Sural nerve biopsy revealed vasculitis with eosinophilic infiltration. Further evaluations consisted of colonoscopy and nasal endoscopy that confirmed eosinophil infiltrates on colonic ulcers and nasal polypi. The patient was started on systemic corticosteroids and cyclophosphamide. Among his personal records, he had been taking nandrolone decanoate without medical prescription, and had withdrawn a few years before the first asthma exacerbation.

Insulin and the kidneys: a contemporary view on the molecular basis.

Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.