Scripps Research, previously known as The Scripps Research Institute (or TSRI) is a nonprofit American medical research facility that focuses on research and education in the biomedical sciences. Headquartered in La Jolla, California with a sister facility in Jupiter, Florida, the institute has over 200 laboratories employing 2,400 scientists, technicians, graduate students, and administrative and other staff, making it the largest private, non-profit biomedical research organization in the United States and among the largest in the world.The institute holds nearly 1,000 patents, produced 9 FDA-approved therapeutics, and has generated over 50 spin-off companies. According to the 2017 Nature Innovation Index, Scripps Research is the #1 most influential research institution in the world. The Scripps Research graduate program is ranked 10th nationally in the biological sciences, 5th for organic chemistry, and 2nd for biochemistry.
Cellular senescence plays a significant role in age-related conditions like osteoarthritis (OA) and intervertebral disc degeneration, in part due to the accumulation of senescent cells (SCs) in musculoskeletal tissues. Identifying novel therapeutics that can clear SCs is crucial for improving musculoskeletal health in the elderly. The present study aimed to elucidate the changes in Class I histone deacetylases (HDACs) and their role during senescence. All Class I HDACs except HDAC1 were downregulated during senescence in the human TC28a2 immortalized human chondrocyte cell line. Knockdown experiments showed that HDAC1 is essential for maintaining the viability of both non-senescent cells (NSCs) and SCs, while HDAC2 plays a key role in modulating inflammation in part by targeting the NF-κB signaling pathway. Mocetinostat, an HDAC inhibitor, selectively kills senescent TC28a2 cells and primary human knee chondrocytes via apoptosis while not affecting the viability of NSCs. Mocetinostat also affected both inflammation-associated and chondrogenesis-associated genes. Overall, our findings demonstrate a key role of Class I HDACs in regulating chondrocyte survival and ECM gene expression. Mocetinostat holds promise as a senolytic therapeutic for OA and potentially other aging-related musculoskeletal disorders.
Sperm aging impacts male fertility and offspring health, highlighting the need for reliable aging biomarkers to guide reproductive decisions. However, the molecular determinants of sperm fitness during aging remain ill-defined. Here, we profiled sperm small non-coding RNAs (sncRNAs) using PANDORA-seq, which overcomes RNA modification–induced detection bias to capture previously undetectable sncRNA species associated with mouse and human spermatozoa throughout the lifespan. We identified an “aging cliff” in mouse sperm RNA profiles—a sharp age-specific transition marked by significant shifts in genomic and mitochondrial tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs). Notably, rsRNAs in mouse sperm heads exhibited a transformative length shift, with longer rsRNAs increasing and shorter ones decreasing with age, suggesting altered biogenesis or processing with age. Remarkably, this sperm head-specific shift in rsRNA length was consistently observed in two independent human aging cohorts. Moreover, transfecting a combination of tsRNAs and rsRNAs resembling the RNA species in aged sperm was able to induce transcriptomic changes in mouse embryonic stem cells, impacting metabolism and neurodegeneration pathways, mirroring the phenotypes observed in offspring fathered by aged sperm. These findings provide novel insights into longitudinal dynamics of sncRNAs during sperm aging, highlighting an rsRNA length shift conserved in mice and humans. The molecular determinants of sperm fitness during aging remain ill-defined. Here, advanced sequencing to profile sperm small non-coding RNAs (sncRNAs) during mouse aging uncovers a sperm-head–specific shift in RNA length, which is conserved in humans and functionally reprograms mouse embryonic stem cell (mESC) gene expression. Longitudinal PANDORA-seq profiling of small non-coding RNAs in spermatozoa uncovers unexpected dynamics during lifespan with functional relevance for gene expression.
Highly pathogenic H5Ny influenza A viruses are causing unprecedented, season-independent outbreaks across avian and mammalian species, including dairy cattle, a novel reservoir. The sialoside-binding properties of influenza A hemagglutinin (HA) are strongly related to its ability to infect and transmit between hosts. Mucin-like O-glycans, omnipresent in respiratory tracts, have been understudied as viral receptors due to their complexity. To address this, we synthesized 25 O-linked glycans with diverse sialosides, including modifications by fucosides and sulfates. Our findings reveal that H5Ny 2.3.4.4b viruses bind core 3 sialyl-Lewisx and Sia-Gal-β3GalNAc, O-linked glycans not recognized by classical H5 or other avian viruses. By determining crystal structures, we resolved the structural features of four glycans in an H5 hemagglutinin (HA) from a 2016 2.3.4.4b virus. While these viruses do not bind human-type receptors, their broad receptor specificity enhances binding to human tracheal tissues, suggesting that O-glycan recognition could contribute to the continues spillover of this clade.
Type I/II cytokine receptors mediate cytokine-specific biological responses by employing a defined combination of four Janus kinases (JAKs) and seven signal transducers and activators of transcription (STATs) for cellular signal transduction. Deregulation of the JAK-STAT pathway leads to various diseases, with JAK and STAT proteins representing attractive therapeutic targets. Fifteen JAK inhibitors are approved for several immunological and haematological diseases, offering significant benefits for patients. However, safety restrictions have limited their clinical use. Mechanistic and structural insights are driving current drug development approaches focused on improving their potency, selectivity and safety. Development of STAT inhibitors has been more challenging, and none has yet received clinical approval, although promising new compounds are now entering clinical trials. This Review discusses the recent advances in JAK and STAT inhibitor development and presents emerging therapeutic indications for JAK-STAT inhibition.
Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by 1 of 16 different simian-human immunodeficiency viruses (SHIVs). We identified the V2 apex region of the envelope (Env) as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is a primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as vaccine platforms.
