New Potent Inhibitor of Transforming Growth Factor-Beta (TGFβ) Signaling that is Efficacious against Microsatellite Stable Colorectal Cancer Metastasis in Combination with Immune Checkpoint Therapy in Mice.

Blockade of the TGFβ signaling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has shown little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGFβ receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favorable safety profile.

MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis.

The eukaryotic helicase MCM2-7, is loaded by ORC, Cdc6 and Cdt1 as a double-hexamer onto replication origins. The insertion of DNA into the helicase leads to partial MCM2-7 ring closure, while ATP hydrolysis is essential for consecutive steps in pre-replicative complex (pre-RC) assembly. Currently it is unknown how MCM2-7 ring closure and ATP-hydrolysis are controlled.

Hair Today, OR Tomorrow: A Multicenter Case Series of Gastric Bezoars in Children Diagnosed With Point-of-Care Ultrasound.

Point-of-care ultrasound (POCUS) can expedite the diagnosis of pediatric abdominal pathologies including appendicitis and intussusception. In this patient series, we present cases from multiple pediatric emergency departments that demonstrate the use of POCUS in the diagnosis of trichobezoars in children. POCUS findings include the presence of an intragastric hyperechoic mass or a hyperechoic arch and associated posterior acoustic shadowing.

Mfn2 induces NCLX-mediated calcium release from mitochondria.

Mfn2 is a mitochondrial outer membrane fusion protein with the additional role of tethering mitochondria to the ER. Here, we describe a novel connection between Mfn2 and calcium release from mitochondria. We show that Mfn2 controls the mitochondrial inner membrane sodium-calcium exchange protein NCLX, which is a major source for calcium release from mitochondria.

Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition.

Ceftolozane-tazobactam (CT) is used for the treatment of complicated infections and for multidrug-resistant strains of Pseudomonas aeruginosa and extended-spectrum beta-lactamase-producing enterobacteria. In certain cases, simultaneous administration of CT and parenteral nutrition (PN) may be required, but compatibility of Y-site co-administration is unknown. The aim of this study was to analyse the physicochemical compatibility of CT Y-site administered with PN.

A Protocol for Using Point-of-Care Ultrasound as an Adjunct in Pediatric Cardiac Arrest: Pediatric Ultrasound for Life-Supporting Efforts.

Pediatric cardiac arrest is a rare but time-critical event that poses significant challenges to health care providers. Initiation of point-of-care ultrasound (POCUS) early in resuscitation can help optimize the location of chest compressions, identify inadequate compressions, evaluate for sonographic pulse, and help direct management. Although several algorithms currently exist to incorporate POCUS into adult cardiac arrest, none, to our knowledge, currently exist for the pediatric population.

Consumption of Ultra-Processed Foods in the Brazilian Amazon during COVID-19.

Background: A COVID-19 pandemic erupted, causing a global viral pneumonia outbreak, marking the most significant public health crisis of the 21st century. These changes profoundly impacted population health and well-being, leading to shifts in dietary habits. This study aimed to evaluate the consumption of ultra-processed foods in the Brazilian Amazon before, during, and after the COVID-19 pandemic.

Analyzing the COVID-19 Transmission Dynamics in Acre, Brazil: An Ecological Study.

The north region of Brazil is characterized by significant vulnerabilities, notably surpassing national poverty indicators. These disparities exacerbated the impact of respiratory illnesses on the healthcare system during the COVID-19 pandemic, particularly in areas with limited healthcare resources, inadequate infrastructure, and barriers to healthcare access. The crisis was further influenced by multiple lineages that emerged as significant virus variants associated with increased transmissibility.

Pediatric Emergency Medicine Ultrasound Fellowship Programs.

Point of care ultrasound (POCUS) has undergone important growth in the field of Pediatric Emergency Medicine (PEM) in the last 14 years and is recognized as a critical diagnostic tool in the care of ill and injured children. The first PEM POCUS fellowship was established in 2010. Now, there are currently 30 ultrasound fellowships that offer training to PEM physicians.

Cyclometallated Imides as Templates for the H-Bond Directed Iridium-Catalyzed Asymmetric Hydrogenation of N-Methyl, N-Alkyl and N-Aryl Imines.

A combined computational and experimental approach allowed us to develop overall the most selective catalyst for the direct hydrogenation of N-methyl, N-alkyl and N-aryl imines described to date. Iridium catalysts with a cyclometallated cyclic imide group provide selectivity of up to 99 % enantiomeric excess. Computational studies show that the selectivity results from the combined effect of H-bonding of the imide C=O with the substrate iminium ion and a stabilizing π-π interaction with the cyclometallated ligand.

Concentrations and distribution of Pb in bird feathers and its potential for tracing age and flight times.

Bird feathers have been widely used as environmental indicators, providing key information on environmental pollution. However, there is little available information on the adsorption of natural radioactivity in bird feathers and consequently, its impact on the field of movement ecology is not yet known. This study investigates the concentration and distribution of Pb in wing- and tail-feathers of different bird species with contrasting migratory strategies, and discusses its potential use as a tracer of age and flight times.

Is it Smoke and Mirrors? Detection of Inferior Vena Cava Thrombus by Focused Cardiac Ultrasound.

Inferior vena cava assessment is a standard component of focused cardiac ultrasound, traditionally used to qualify intravascular volume status. In this case series, we demonstrate that pediatric focused cardiac ultrasound can also diagnose inferior vena cava thrombi and masses, while distinguishing them from a potentially benign smoke-like artifact.

Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.

Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them.

Global inventory of species categorized by known underwater sonifery.

A working group from the Global Library of Underwater Biological Sounds effort collaborated with the World Register of Marine Species (WoRMS) to create an inventory of species confirmed or expected to produce sound underwater. We used several existing inventories and additional literature searches to compile a dataset categorizing scientific knowledge of sonifery for 33,462 species and subspecies across marine mammals, other tetrapods, fishes, and invertebrates. We found 729 species documented as producing active and/or passive sounds under natural conditions, with another 21,911 species deemed likely to produce sounds based on evaluated taxonomic relationships.

Rational optimization of a transcription factor activation domain inhibitor.

Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening.

The importance of context in the acoustic behaviors of marine, subtropical fish speciesa).

Despite the importance of acoustic signaling in fishes, the prevalence of the behavioral contexts associated with their active (i.e., intentional) sound production remains unclear.

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.

MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread.

Qualitative Point-of-Care Ultrasound Enema Management for Constipation.

We discuss 10 cases where the qualitative evaluation of hard stool in the rectum with point-of-care ultrasound helped guide enema administration in a pediatric emergency department. Point-of-care ultrasound findings were especially valuable in cases where the presenting symptoms were undifferentiated, a language barrier was present, or the guardian and child denied that constipation was an active problem. When sodium phosphate enema administration was done in the pediatric emergency department, evacuation of the rectal stool burden was observed in most cases before final disposition.

P-Stereogenic Ir-MaxPHOX: A Step toward Privileged Catalysts for Asymmetric Hydrogenation of Nonchelating Olefins.

The Ir-MaxPHOX-type catalysts demonstrated high catalytic performance in the hydrogenation of a wide range of nonchelating olefins with different geometries, substitution patterns, and degrees of functionalization. These air-stable and readily available catalysts have been successfully applied in the asymmetric hydrogenation of di-, tri-, and tetrasubstituted olefins (ee's up to 99%). The combination of theoretical calculations and deuterium labeling experiments led to the uncovering of the factors responsible for the enantioselectivity observed in the reaction, allowing the rationalization of the most suitable substrates for these Ir-catalysts.

Enantioselective Ir-Catalyzed Hydrogenation of Terminal Homoallyl Sulfones: Total Synthesis of (-)-Curcumene.

A novel methodology for the preparation of chiral methyl benzylic compounds is reported. Terminal homoallyl sulfones were prepared from homoallyl alcohols, which are easily accessible through the recently reported Lewis acid isomerization of oxetanes. The iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones afforded γ-chiral sulfones with excellent enantioselectivities (up to 98% ee).

Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α.

We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines.

Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen.

In the last four decades, treatment of oestrogen receptor positive (ER+) breast cancer (BCa), has focused on targeting the estrogenic receptor signaling pathway. This signaling function is pivotal to sustain cell proliferation. Tamoxifen, a competitive inhibitor of oestrogen, has played a major role in therapeutics.