Development of Potent and Selective CK1α Molecular Glue Degraders.

Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation.

Ribosome profiling reveals differences in global translational vs transcriptional gene expression changes during early biofilm formation.

a major human fungal pathogen, can form biofilms on a variety of inert and biological surfaces. biofilms allow for immune evasion, are highly resistant to antifungal therapies, and represent a significant complication for a wide variety of immunocompromised patients in clinical settings. While transcriptional regulators and global transcriptional profiles of biofilm formation have been well-characterized, much less is known about translational regulation of this important virulence property.

Restoring cefepime activity against multidrug-resistant KPC-producing by combination with boronic acid inhibitors, MB076 and S02030.

Foremost in the design of new β-lactamase inhibitors (BLIs) are the boronic acid transition state inhibitors (BATSIs). Two highly potent BATSIs being developed are S02030 and MB076 strategically designed to be active against cephalosporinases and carbapenemases, especially KPC. When combined with cefepime, S02030 and MB076 demonstrated potent antimicrobial activity against laboratory and clinical strains of expressing a variety of class A and class C β-lactamases, including and .

Machine learning reveals the dynamic importance of accessory sequences for outbreak clustering.

Unlabelled: Bacterial typing at whole-genome scales is now feasible owing to decreasing costs in high-throughput sequencing and the recent advances in computation. The unprecedented resolution of whole-genome typing is achieved by genotyping the variable segments of bacterial genomes that can fluctuate significantly in gene content. However, due to the transient and hypervariable nature of many accessory elements, the value of the added resolution in outbreak investigations remains disputed.

Laboratory evolution of with a natural vitamin B analog reveals roles for cobamide uptake and adenosylation in methionine synthase-dependent growth.

Bacteria encounter chemically similar nutrients in their environment, which impact their growth in distinct ways. Among such nutrients are cobamides, the structurally diverse family of cofactors related to vitamin B (cobalamin), which function as cofactors for diverse metabolic processes. Given that different environments contain varying abundances of different cobamides, bacteria are likely to encounter cobamides that enable them to grow robustly and also those that do not function efficiently for their metabolism.

Conformational flexibility is a critical factor in designing broad-spectrum human norovirus protease inhibitors.

Unlabelled: Human norovirus (HuNoV) is a leading cause of gastroenteritis worldwide and is associated with significant morbidity, mortality, and economic impact. There are currently no licensed antiviral drugs for the treatment of HuNoV-associated gastroenteritis. The HuNoV protease plays a critical role in the initiation of virus replication by cleaving the polyprotein.

Frequently arising ESX-1-associated phase variants influence fitness in the presence of host and antibiotic pressures.

Unlabelled: (Mtb) exhibits an impressive ability to adapt to rapidly changing environments, despite its genome's apparent stability. Recently, phase variation through indel formation in homopolymeric tracts (HT) has emerged as a potentially important mechanism promoting adaptation in Mtb. This study examines the impact of common phase variants associated with the ESX-1 type VII secretion system, focusing on a highly variable HT upstream of the ESX-1 regulatory factor, .

Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen.

In , the causative agent of Lyme disease, differential gene expression is primarily governed by the alternative sigma factor RpoS (σ). Understanding the regulation of RpoS is crucial for elucidating how is maintained throughout its enzootic cycle. Our recent studies have shown that the homolog of Fur/PerR repressor/activator BosR functions as an RNA-binding protein that controls the mRNA stability.

Evaluation of tumor-colonizing strains using the chick chorioallantoic membrane model.

The chick embryo chorioallantoic membrane (CAM) tumor model is a valuable preclinical model for studying the tumor-colonizing process of serovar Typhimurium. It offers advantages such as cost-effectiveness, rapid turnaround, reduced engraftment issues, and ease of observation. In this study, we explored and validated the applicability of the partially immune-deficient CAM tumor model.

Temporal Genomic Analysis of Homogeneous Tumor Models Reveals Key Regulators of Immune Evasion in Melanoma.

In this study, we find that Mif expression is associated with tumor growth and aggressiveness, specifically in tumors with low heterogeneity. These findings could facilitate the development of new strategies to treat patients with homogeneous, high MIF-expressing tumors that are unresponsive to immune checkpoint therapy.

The Influence of Temperature on Courtship and Mate Choice in a Wolf Spider: Implications for Mating Success in Variable Environments.

Selection on animal signal form often changes significantly with the environment, yet signal form may itself be environment dependent. Little is known about how variation in individual responses to changing environments affects the relationship between selection and the subsequent evolution of signal traits. To address this question, we assess the effects of variation in temperature on individual signaling and mating behavior responses across temperatures in the wolf spider Schizocosa floridana.

Comparing the hermaphroditic mating system of a parasitic flatworm between populations with an ancestral, 3-host life cycle and a derived, facultative-precocious life cycle.

Evolutionary changes in development and/or host number of parasite life cycles can have subsequent ecological and evolutionary consequences for parasites. One theoretical model based on the mating systems of hermaphroditic parasites assumes a life cycle with fewer hosts will result in more inbreeding, and predicts a truncated life cycle most likely evolves in the absence of inbreeding depression. Many populations of the hermaphroditic trematode Alloglossidium progeneticum maintain an ancestral obligate 3-host life cycle where obligate sexual reproduction occurs among adults in catfish third hosts.

Interim Results of Rigicon Penile Prosthesis Implantation in a Single Center: The Largest Series in Türkiye.

Objective: To analyze data from patient information forms (PIFs) submitted to the manufacturer of a new 3-piece inflatable penile prosthesis (IPP), the Rigicon Infla10® , to summarize interim outcomes of 250 implantations in a single center, which is the largest series in Türkiye.

Methods: A retrospective review of PIFs from 250 patients implanted with the IPP between January 2021 and December 2023 was performed to assess patient characteristics, surgical data, device durability, patient satisfaction, and rates of reoperation for any reason.

Results: The mean ± SD (range) follow-up was 21.

Analyzing free fatty acids in seminal plasma from asthenozoospermia patients undergoing antioxidant therapy.

Objective: Different aspects of the functions of free fatty acid (FFA) in seminal plasma and their implications on male fertility are known. However, the profile of FFA in seminal plasma in asthenozoospermic patients following antioxidant therapy has not been studied.

Methods: In this case-control study, the total antioxidant capacity (TAC) and FFA profile of the seminal plasma were determined in 80 patients (29 normozoospermic volunteers and 51 asthenozoospermic men) who were treated with antioxidants for three months.

Developmental and environmental effects on VTC2-dependent leaf ascorbate accumulation and functions.

In nature, environmental conditions strongly fluctuate, frequently subjecting plants to periods of immediate photo-oxidative stress. The small molecule ascorbate allows plants to cope with such stress conditions. Ascorbate scavenges reactive oxygen species and enables the rapid and full induction of photoprotective non-photochemical quenching (NPQ).

Respiratory complex I-mediated NAD regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21 expression by SIRT3 and SIRT7.

The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)-mediated NAD regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1) arrested the cell cycle at the G/S phase, accompanying upregulation of p21 cyclin-dependent kinase inhibitor expression.

Signatures of natural selection may indicate a genetic basis for the beneficial effects of oily fish intake in indigenous people from coastal Ecuador.

Atahualpa is a rural village located in coastal Ecuador, a region that has been inhabited by people as early as 10,000 years ago. The traditional diet of their indigenous inhabitants is rich in oily fish and they have, therefore, served as a model for investigating the beneficial effects of such a diet. However, the genetic background of this population has not been studied.

Characterisation of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances.

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterizsed by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease that deteriorate the patients' life quality, yet this is understudied and has not been delineated in animal models of the disease.

Development of Triphenylamine Derived Photosensitizers for Efficient Hydrogen Evolution from Water.

A series of new (donor)₂-donor-π-acceptor (D2-D-π-A) and (acceptor)₂-donor-π-acceptor (A2-D-π-A) organic photosensitizers based on the framework of (Z)-2-cyano-3-(5-(4-(diphenylamino)phenyl)thiophen-2-yl)acrylic acid have been synthesized and characterized. By incorporating groups with different electron-donating or withdrawing abilities, such as dibenzothiophene (DBT), dibenzofuran (DBF), and triazine (TA), into the triphenylamine segment, their photophysical properties have been regulated.  Theoretical calculations were used to explore how various donor-acceptor combinations influence their hydrogen production performance.

Inhibition of HMGA2 binding to AT-rich DNA by its negatively charged C-terminus.

The mammalian high mobility group protein AT-hook 2 (HMGA2) is a small DNA-binding protein that specifically targets AT-rich DNA sequences. Structurally, HMGA2 is an intrinsically disordered protein (IDP), comprising three positively charged 'AT-hooks' and a negatively charged C-terminus. HMGA2 can form homodimers through electrostatic interactions between its 'AT-hooks' and C-terminus.

Delving Into lncRNA-Mediated Regulation of Autophagy-Associated Signaling Pathways in the Context of Breast Cancer.

Breast cancer is a multifaceted and prevalent malignancy, impacting a considerable proportion of women globally. Numerous signaling pathways intricately regulate cellular functions such as growth, proliferation, and survival. Among the various regulators, lncRNAs have emerged as significant players despite their inability to encode proteins.

Mammary Gland Reactive Stroma Characterization at Aging After Bisphenol A Exposure During Hormonal Susceptibility Windows.

Mammary glands development is influenced by endocrine signaling, which remodels epithelial and stromal compartments. Reactive stroma phenotype is observed when stromal disturbances occur, leading to changes in extracellular matrix composition and occurrence of reactive cell types. One of the triggers of these alterations is endocrine-disrupting chemical exposure, such as bisphenol A (BPA).

Anticancer Attributes and Multifaceted Pharmacological Implications of Laetrile and Amygdalin.

Laetrile, known as vitamin B17, is often used interchangeably with amygdalin. Laetrile is a semi-synthesis product of amygdalin, whereas amygdalin is a naturally occurring substance in many plants. Both compounds have a nitrile functional group that, when activated by the intestinal enzyme β-glucosidases, releases hydrogen cyanide.

The potential of and bacteriocins in synergistic control of .

has developed resistance to most conventional antibiotics and is a causative agent of serious infections. Alternative therapies are urgently needed. Bacteriocins are ribosomally synthesized antimicrobial peptides produced by bacteria, including () and (), and represent a potential solution.

A Natural Autophagy Activator Castanea crenata Flower Alleviates Skeletal Muscle Ageing.

Background: Sarcopenia, characterized by a gradual decline in skeletal muscle mass and function with age, significantly impacts both quality of life and mortality. Autophagy plays a crucial role in maintaining muscle health. There is growing interest in leveraging autophagy to mitigate muscle ageing effects.