In situ forming and self-crosslinkable protein hydrogels for localized cancer therapy and topical wound healing.

Proteins, inherently biocompatible and biodegradable, face a challenge in forming stable hydrogels without external chemical crosslinkers. Here, we construct a ring-shaped trimeric SpyTag-fused Proliferating Cell Nuclear Antigen Protein (ST-PCNA) as a core protein building block, and a dumbbell-shaped tandem dimeric SpyCatcher (SC-SC) as a bridging component. Self-crosslinked PCNA/SC-SC Protein (2SP) hydrogels are successfully formed by simply mixing the solutions of ST-PCNA and SC-SC, without chemical crosslinkers.

Developing Porous Protein Cage Nanoparticles as Cargo-Loadable and Ligand-Displayable Modular Delivery Nanoplatforms.

Protein cage nanoparticles, self-assembled from protein subunits, provide distinct exterior and interior spaces and can carry diagnostic and/or therapeutic cargo agents through chemical conjugation, disassembly/reassembly process, or assembly-mediated encapsulation. Here, we developed porous SpyCatcher-mi3 (SC-mi3) as modular delivery nanoplatforms, capable of loading cargos through pores and displaying targeting ligands using SpyCatchers (SC) as anchors for SpyTagged (ST) ligands. Fluorescent dyes (F5M and A647) and a pH-sensitive prodrug (Aldox) were conjugated to the interior surface cysteines of SC-mi3, forming F5M@SC-mi3, A647@SC-mi3, and Aldox@SC-mi3.

Signaling through the nicotinic acetylcholine receptor in the liver protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature.

Lactate oxidase/vSIRPα conjugates efficiently consume tumor-produced lactates and locally produce tumor-necrotic HO to suppress tumor growth.

Aggressive tumor formation often leads to excessive anaerobic glycolysis and massive production and accumulation of lactate in the tumor microenvironment (TME). To significantly curb lactate accumulation in TME, in this study, lactate oxidase (LOX) was used as a potential therapeutic enzyme and signal regulatory protein α variant (vSIRPα) as a tumor cell targeting ligand. SpyCatcher protein and SpyTag peptide were genetically fused to LOX and vSIRPα, respectively, to form SC-LOX and ST-vSIRPα and tumor-targeting LOX/vSIRPα conjugates were constructed via a SpyCatcher/SpyTag protein ligation system.

Internalization of muscularity and thinness ideals: Associations with body dissatisfaction, eating disorder symptoms, and muscle dysmorphic symptoms in at risk sexual minority men.

Objective: In the tripartite influence model, appearance-ideal internalization is identified as a prominent risk factor for the development of body dissatisfaction and subsequent eating disorder (ED) behaviors. For men, prior research has emphasized the importance of both thin-ideal internalization and muscular-ideal internalization in explaining later ED behaviors and muscle dysmorphia (MD) symptoms. Previous research in heterosexual men has shown that the associations between muscular-ideal internalization and ED or MD symptoms may depend on whether the individual has also internalized the thin ideal.

Directing ricin-based immunotoxins with targeting affibodies and KDEL signal peptide to cancer cells effectively induces apoptosis and tumor suppression.

The plant toxin ricin, especially its cytotoxic A chain (RTA), can be genetically engineered with targeting ligands to develop specific anti-cancer recombinant immunotoxins (RITs). Here, we used affibody molecules targeting two cancer biomarkers, the receptors HER2 and EGFR, along with the KDEL signal peptide to construct two cancer-specific ricin-based RITs, HER2Afb-RTA-KDEL and EGFRAfb-RTA-KDEL. The affibodies successfully provided target-specificity and subsequent receptor-mediated endocytosis and the KDEL signal peptide routed the RITs through the retrograde transport pathway, effectively delivering RTA to the cytosol as well as avoiding the alternate recycling pathway that typical cancer cells frequently have.

Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism.

Research focusing on adipose immunometabolism has been expanded from inflammation in white fat during obesity development to immune cell function regulating thermogenic fat, energy expenditure, and systemic metabolism. This opinion discusses our current understanding of how resident immune cells within the thermogenic fat niche may regulate whole-body energy homeostasis. Furthermore, various types of immune cells can synthesize acetylcholine (ACh) and regulate important physiological functions.

TRAIL & EGFR affibody dual-display on a protein nanoparticle synergistically suppresses tumor growth.

The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer drug candidate because it selectively binds to the proapoptotic death receptors, which are frequently overexpressed in a wide range of cancer cells, subsequently inducing strong apoptosis in these cells. However, the therapeutic benefit of TRAIL has not been clearly proven, mainly because of its poor pharmacokinetic characteristics and frequent resistance to its application caused by the activation of a survival signal via the EGF/epidermal growth factor receptor (EGFR) signaling pathway. Here, a lumazine synthase protein cage nanoparticle isolated from Aquifex aeolicus (AaLS) was used as a multiple ligand-displaying nanoplatform to display polyvalently both TRAIL and EGFR binding affibody molecules (EGFRAfb) via a SpyTag/SpyCatcher protein-ligation system, to form AaLS/TRAIL/EGFRAfb.

The Adipose Tissue Macrophages Central to Adaptive Thermoregulation.

White fat stores excess energy, and thus its excessive expansion causes obesity. However, brown and beige fat, known as adaptive thermogenic fat, dissipates energy in the form of heat and offers a therapeutic potential to counteract obesity and metabolic disorders. The fat type-specific biological function is directed by its unique tissue microenvironment composed of immune cells, endothelial cells, pericytes and neuronal cells.

CHRNA2: a new paradigm in beige thermoregulation and metabolism.

The contribution of thermogenic adipocytes to maintain systemic metabolic homeostasis has been increasingly appreciated in recent years. It is now recognized that different types (e.g.

Acetylcholine-synthesizing macrophages in subcutaneous fat are regulated by β -adrenergic signaling.

Non-neuronal cholinergic signaling, mediated by acetylcholine, plays important roles in physiological processes including inflammation and immunity. Our group first discovered evidence of non-neuronal cholinergic circuitry in adipose tissue, whereby immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis. Here, we reveal that macrophages are the cellular protagonists responsible for secreting acetylcholine to regulate thermogenic activation in subcutaneous fat, and we term these cells cholinergic adipose macrophages (ChAMs).

Target-switchable Gd(III)-DOTA/protein cage nanoparticle conjugates with multiple targeting affibody molecules as target selective T contrast agents for high-field MRI.

Magnetic resonance imaging (MRI) is a non-invasive in vivo imaging tool, providing high enough spatial resolution to obtain both the anatomical and the physiological information of patients. However, MRI generally suffers from relatively low sensitivity often requiring the aid of contrast agents (CA) to enhance the contrast of vessels and/or the tissues of interest from the background. The targeted delivery of diagnostic probes to the specific lesion is a powerful approach for early diagnosis and signal enhancement leading to the effective treatment of various diseases.

Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.

The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of under DR but not those fed , revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC.

Sexual orientation and gender identity disparities in co-occurring depressive symptoms and probable substance use disorders in a national cohort of young adults.

This study examined sexual orientation and gender identity differences in co-occurring depressive symptoms and substance use disorders (SUDs) among young adults in the Growing Up Today Study national cohort (n = 12,347; ages 20-35; 93% non-Hispanic white). Self-administered questionnaires assessed recent co-occurring depressive symptoms and probable nicotine dependence, alcohol use disorder, and drug use disorder. Multinomial logistic regressions with generalized estimating equations quantified differences in prevalences of depressive symptoms only, SUDs only, and co-occurrence, among sexual minorities (mostly heterosexual; lesbian, gay, and bisexual [LGB]) compared to completely heterosexual participants, and gender minorities compared to cisgender participants.

A critical role for hepatic protein arginine methyltransferase 1 isoform 2 in glycemic control.

Appropriate control of hepatic gluconeogenesis is essential for the organismal survival upon prolonged fasting and maintaining systemic homeostasis under metabolic stress. Here, we show protein arginine methyltransferase 1 (PRMT1), a key enzyme that catalyzes the protein arginine methylation process, particularly the isoform encoded by Prmt1 variant 2 (PRMT1V2), is critical in regulating gluconeogenesis in the liver. Liver-specific deletion of Prmt1 reduced gluconeogenic capacity in cultured hepatocytes and in the liver.

Adrenergic-Independent Signaling via CHRNA2 Regulates Beige Fat Activation.

Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting β-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2.

Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis.

Thermogenesis in brown adipose tissue (BAT) declines with age; however, what regulates this process remains poorly understood. Here, we identify mitochondria lipoylation as a previously unappreciated molecular hallmark of aged BAT in mice. Using mitochondrial proteomics, we show that mitochondrial lipoylation is disproportionally reduced in aged BAT through a post-transcriptional decrease in the iron-sulfur (Fe-S) cluster formation pathway.

Effects of familial and non-familial warmth during childhood and adolescence on sexual-orientation disparities in alcohol use trajectories and disorder during emerging adulthood.

Background: We investigated sexual-orientation differences in typologies of self-reported familial and non-familial warmth in childhood (before age 11) and adolescence (ages 11-17); and tested whether warmth explained sexual minority emerging adults' (ages 18-25) heightened odds of having heavier alcohol use trajectories (AUTs) and heightened risk for past-year alcohol use disorder (AUD) compared to completely heterosexuals.

Methods: Using self-reported data from the U.S.

Sexual orientation and gender identity disparities in substance use disorders during young adulthood in a United States longitudinal cohort.

Background: This study examined associations of sexual orientation and gender identity with prevalence of substance use disorders (SUDs) and co-occurring multiple SUDs in the past 12-months during young adulthood in a United States longitudinal cohort.

Methods: Questionnaires self-administered in 2010 and 2015 assessed probable past 12-month nicotine dependence, alcohol abuse and dependence, and drug abuse and dependence among 12,428 participants of an ongoing cohort study when they were ages 20-35 years. Binary or multinomial logistic regressions using generalized estimating equations were used to estimate differences by sexual orientation and gender identity in the odds of SUDs and multiple SUDs, stratified by sex assigned at birth.

Stress, Coping, and Context: Examining Substance Use Among LGBTQ Young Adults With Probable Substance Use Disorders.

Objective: The authors qualitatively examined how lesbian, gay, bisexual, transgender, and queer (LGBTQ) young adults with probable substance use disorders conceptualized their substance use vis-à-vis their LGBTQ identities.

Methods: Individual, in-depth, semistructured interviews were conducted with 59 LGBTQ young adults (ages 21-34) who were participants in a larger longitudinal cohort study and who met criteria for a probable substance use disorder. Data were analyzed via iterative, thematic analytic processes.

Protein Arginine Methyltransferase 1 Interacts With PGC1α and Modulates Thermogenic Fat Activation.

Protein arginine methyltransferases (PRMTs) are enzymes that regulate the evolutionarily conserved process of arginine methylation. It has been reported that PRMTs are involved in many metabolic regulatory pathways. However, until now, their roles in adipocyte function, especially browning and thermogenesis, have not been evaluated.

Gender Expression and Sexual Orientation Differences in Diet Quality and Eating Habits from Adolescence to Young Adulthood.

Background: Diet and eating habits during youth have implications on diet and eating habits during adulthood, however, little longitudinal research has examined sexual orientation and gender expression differences in diet.

Objective: Our aim was to examine sexual orientation and gender expression differences in diet quality and eating habits from adolescence to young adulthood.

Design: Data across multiple time points from the longitudinal Growing Up Today Study cohorts (1997 to 2011) were used.

Structural stigma and sexual orientation-related reproductive health disparities in a longitudinal cohort study of female adolescents.

Introduction: Sexual minority female adolescents have worse reproductive health than heterosexual peers; research into the origins of these disparities is limited. Our objective was to examine whether exposure to structural stigma (e.g.