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Abstract We here report on the progress of the HHH Workshop, that took place in Dubrovnik in July 2023. After the discovery of a particle that complies with the properties of the Higgs boson of the Standard Model, all Standard Model (SM) parameters are in principle determined. However, in order to verify or falsify the model, the full form of the potential has to be determined. This includes the measurement of the triple and quartic scalar couplings. We here report on ongoing progress of measurements for multi-scalar final states, with an emphasis on three SM-like scalar bosons at 125 $$\,\text {Ge}\hspace{-.08em}\text {V}$$ Ge V , but also mentioning other options. We discuss both experimental progress and challenges as well as theoretical studies and models that can enhance such rates with respect to the SM predictions.

Obesity and related comorbidities heighten risks for complications in kidney transplant settings. While pre-transplant patients often have access to nutrition counseling and health support, literature is limited on patients' perceptions of weight and motivation to lose weight prior to transplantation. We conducted a survey among ≥18-year-old patients on the kidney transplant waitlist at a single center. Questions addressed weight perception, motivation for weight loss, available resources, and engagement in physical activity. Medical records provided demographic and clinical data. Statistical tests analyzed quantitative data, while free-text responses were thematically grouped and described. Of 1055 patients, 291 responded and were matched with demographic data. Perceived weight changes correlated with actual changes in body mass index (BMI) (

Background: A vancomycin AUC/MIC (area under the curve/minimum inhibitory concentration) of 400–600 mg•h/L is associated with improved clinical outcomes for the treatment of methicillin resistant Staphylococcus aureus (MRSA) infections. Currently, there are still limited studies evaluating the relationship between vancomycin trough and AUC. Objectives: To evaluate the correlation between vancomycin trough and AUC/MIC and determine if trough-guided monitoring is an adequate predictor of AUC/MIC in the Urban Health population at St Paul’s Hospital. Methods: This was a retrospective chart review of 29 patients from November 2019 to February 2021. Patient demographics and laboratory data were collected from electronic medical records. The two-level equation-based approach was used to calculate AUC/MIC. The proportion of AUC/MIC values within target (400–600 mg•h/L) despite subtherapeutic troughs, and the proportion of AUC/MIC values supratherapeutic when trough is within target (15–20 mg/L) were the primary endpoints. Main Results: Fifty-seven sets of levels were collected and 75% of vancomycin troughs and AUC 24 were found to be discordant. When trough was 10–14.9 mg/L, AUC 24 was > 400 mg•h/L in 94% of cases and when trough was 15–20 mg/L, AUC 24 was > 600 mg•h/L in 69% of cases. There was a moderate correlation between vancomycin trough and AUC 24h ( R 2 = 0.57; p

Identifying the cellular origins and mapping the dendritic and axonal arbors of neurons have been century old quests to understand the heterogeneity among these brain cells. Current Brainbow based transgenic animals take the advantage of multispectral labeling to differentiate neighboring cells or lineages, however, their applications are limited by the color capacity. To improve the analysis throughput, we designed Bitbow, a digital format of Brainbow which exponentially expands the color palette to provide tens of thousands of spectrally resolved unique labels. We generated transgenic Bitbow Drosophila lines, established statistical tools, and streamlined sample preparation, image processing, and data analysis pipelines to conveniently mapping neural lineages, studying neuronal morphology and revealing neural network patterns with unprecedented speed, scale, and resolution.

The practice of delayed cord clamping (DCC) in premature infants has proven benefit to the neonate. In a community-based perinatal centre, the practice of DCC for more than 60 s for premature infants with gestational age of

In the United States (US), new firefighters' fitness and health behaviors deteriorate rapidly after fire academy graduation. Over the long-term, this increases their risks for chronic diseases. This study protocol describes the proposed usability testing and pilot study of a newly designed and developed healthy lifestyle smartphone app, "Surviving & Thriving", tailored towards young US firefighters. "Surviving & Thriving" will provide interactive educational content on four lifestyle factors; nutrition, sleep, physical activity, and resilience, and include a personalized journey, habit tracker, and elements of gamification to promote engagement and long-term healthy behavior change. The first phase of the app development entails alpha testing by the research team and pre-beta testing by a fire service expert panel which will help refine the app into a pre-consumer version. Upon completion of the full app prototype, beta 'usability' testing will be conducted among new fire academy graduates from two New England fire academies to collect qualitative and quantitative feedback via focus groups and satisfaction surveys, respectively. A last phase of piloting the app will evaluate the app's efficacy at maintaining/improving healthy lifestyle behaviors, mental health metrics, and physical fitness metrics. We will also evaluate whether firefighters' perceived "health cultures" scores (ratings of each fire station's/fire department's environments as to encouraging/discouraging healthy behaviors) modify the changes in health metrics after utilizing the app for three to six months. This novel user-friendly app seeks to help new firefighters maintain/improve their health and fitness more effectively, reducing their risk of lifestyle-related chronic disease. Firefighters who can establish healthy habits early in their careers are more likely to sustain them throughout their lives. [ABSTRACT FROM AUTHOR]

Abstract Background The Organ Procurement and Transplant Network (OPTN) Final Rule guides national organ transplantation policies, mandating equitable organ allocation and organ-specific priority stratification systems. Current allocation scores rely on mortality predictions. Methods We examined the alignment between the ethical priorities across organ prioritization systems and the statistical design of the risk models in question. We searched PubMed for literature on organ allocation history, policy, and ethics in the United States. Results We identified 127 relevant articles, covering kidney (19), liver (60), lung (24), and heart transplants (23), and transplant accessibility (1). Current risk scores emphasize model performance and overlook ethical concerns in variable selection. The inclusion of race, sex, and geographical limits as categorical variables lacks biological basis; therefore, blurring the line between evidence-based models and discrimination. Comprehensive ethical and equity evaluation of risk scores is lacking, with only limited discussion of the algorithmic fairness of the Model for End-Stage Liver Disease (MELD) and the Kidney Donor Risk Index (KDRI) in some literature. We uncovered the inconsistent ethical standards underlying organ allocation scores in the United States. Specifically, we highlighted the exception points in MELD, the inclusion of race in KDRI, the geographical limit in the Lung Allocation Score, and the inadequacy of risk stratification in the Heart Tier system, creating obstacles for medically underserved populations. Conclusions We encourage efforts to address statistical and ethical concerns in organ allocation models and urge standardization and transparency in policy development to ensure fairness, equitability, and evidence-based risk predictions.

Abstract Changes in protein turnover play an important role in dynamic physiological processes, including skeletal muscle regeneration, which occurs as an essential part of tissue repair after injury. The inability of muscle tissue to recapitulate this regenerative process can lead to the manifestation of clinical symptoms in various musculoskeletal diseases, including muscular dystrophies and pathological atrophy. Here, we employed a workflow that couples deuterated water (2H2O) administration with mass spectrometry (MS) to systematically measure in-vivo protein turnover rates across the muscle proteome in 8-week-old male C57BL6/J mice. We compared the turnover kinetics of over 100 proteins in response to cardiotoxin (CTX) induced muscle damage and regeneration at unique sequential stages along the regeneration timeline. This analysis is compared to gene expression data from mRNA-sequencing (mRNA-seq) from the same tissue. The data reveals quantitative protein flux signatures in response to necrotic damage, in addition to sequential differences in cell proliferation, energy metabolism, and contractile gene expression. Interestingly, the mRNA changes correlated poorly with changes in protein synthesis rates, consistent with post-transcriptional control mechanisms. In summary, the experiments described here reveal the signatures and timing of protein flux changes during skeletal muscle regeneration, as well as the inability of mRNA expression measurements to reveal changes in directly measured protein turnover rates. The results of this work described here provide a better understanding of the muscle regeneration process and could help to identify potential biomarkers or therapeutic targets.

Albuminuria is a hallmark of glomerular disease of various etiologies. It is not only a symptom of glomerular disease but also a cause leading to glomerulosclerosis, interstitial fibrosis, and eventually, a decline in kidney function. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly defined. In our genetic model of nephrotic syndrome (NS), we have identified CHOP (C/EBP homologous protein)-TXNIP (thioredoxin-interacting protein) as critical molecular linkers between albuminuriainduced ER dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1), and mitochondrial Trx2. However, very little is known about the regulation and function of TXNIP in NS. By utilizing Chop2/2 and Txnip2/2 mice as well as 68Ga-Galuminox, our molecular imaging probe for detection of mitochondrial reactive oxygen species (ROS) in vivo, we demonstrate that CHOP up-regulation induced by albuminuria drives TXNIP shuttling from nucleus to mitochondria, where it is required for the induction of mitochondrial ROS. The increased ROS accumulation in mitochondria oxidizes Trx2, thus liberating TXNIP to associate with mitochondrial nod-like receptor protein 3 (NLRP3) to activate inflammasome, as well as releasing mitochondrial apoptosis signalregulating kinase 1 (ASK1) to induce mitochondria-dependent apoptosis. Importantly, inhibition of TXNIP translocation and mitochondrial ROS overproduction by CHOP deletion suppresses NLRP3 inflammasome activation and p-ASK1-dependent mitochondria apoptosis in NS. Thus, targeting TXNIP represents a promising therapeutic strategy for the treatment of NS. [ABSTRACT FROM AUTHOR]

Autosomal dominant tubulointerstitial kidney disease (ADTKD)-uromodulin (UMOD) is the most common nonpolycystic genetic kidney disease, but it remains unrecognized due to its clinical heterogeneity and lack of screening test. Moreover, the fact that the clinical feature is a poor predictor of disease outcome further highlights the need for the development of mechanistic biomarkers in ADTKD. However, low abundant urinary proteins secreted by thick ascending limb cells, where UMOD is synthesized, have posed a challenge for the detection of biomarkers in ADTKD-UMOD. In the CRISPR/Cas9-generated murine model and patients with ADTKD-UMOD, we found that immunoglobulin heavy chain-binding protein (BiP), an endoplasmic reticulum chaperone, was exclusively upregulated by mutant UMOD in the thick ascending limb and easily detected by Western blot analysis in the urine at an early stage of disease. However, even the most sensitive ELISA failed to detect urinary BiP in affected individuals. We therefore developed an ultrasensitive, plasmon-enhanced fluorescence-linked immunosorbent assay (p-FLISA) to quantify urinary BiP concentration by harnessing the newly invented ultrabright fluorescent nanoconstruct, termed "plasmonic Fluor." p-FLISA demonstrated that urinary BiP excretion was significantly elevated in patients with ADTKD-UMOD compared with unaffected controls, which may have potential utility in risk stratification, disease activity monitoring, disease progression prediction, and guidance of endoplasmic reticulum-targeted therapies in ADTKD. [ABSTRACT FROM AUTHOR]

Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calcium elevation. The altered intracellular calcium homeostasis led to activation of calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER calcium depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stressinduced NS/FSGS. [ABSTRACT FROM AUTHOR]

Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme. It also recounts recent recommendations for clinical management of FSGS based on translational studies and clinical trials. The advent of next-generation sequencing promises to provide nephrologists with rapid and novel approaches for the diagnosis and treatment of FSGS. A stratified and targeted approach based on the underlying molecular defects is evolving. [ABSTRACT FROM AUTHOR]

Background Osteoporosis affects over 200 million people worldwide at a high cost to healthcare systems, yet gaps in management still exist. In response, we developed a multi-component osteoporosis knowledge translation (Op-KT) tool involving a patient-initiated risk assessment questionnaire (RAQ), which generates individualized best practice recommendations for physicians and customized education for patients at the point of care. The objective of this study was to evaluate the effectiveness of the Op-KT tool for appropriate disease management by physicians. Methods The Op-KT tool was evaluated using an interrupted time series design. This involved multiple assessments of the outcomes 12 months before (baseline) and 12 months after tool implementation (52 data points in total). Inclusion criteria were family physicians and their patients at risk for osteoporosis (women aged ⩾50 years, men aged ⩾65 years). Primary outcomes were the initiation of appropriate osteoporosis screening and treatment. Analyses included segmented linear regression modeling and analysis of variance. Results The Op-KT tool was implemented in three family practices in Ontario, Canada representing 5 family physicians with 2840 age eligible patients (mean age 67 years; 76% women). Time series regression models showed an overall increase from baseline in the initiation of screening (3.4%; P < 0.001), any osteoporosis medications (0.5%; P = 0.006), and calcium or vitamin D (1.2%; P = 0.001). Improvements were also observed at site level for all the three sites considered, but these results varied across the sites. Of 351 patients who completed the RAQ unprompted (mean age 64 years, 77% women), the mean time for completing the RAQ was 3.43 minutes, and 56% had any disease management addressed by their physician. Study limitations included the inherent susceptibility of our design compared with a randomized trial. Conclusions The multicomponent Op-KT tool significantly increased osteoporosis investigations in three family practices, and highlights its potential to facilitate patient self-management. Next steps include wider implementation and evaluation of the tool in primary care. [ABSTRACT FROM AUTHOR]

We present a breast tissue stabilization device that can be used in magnetic resonance imaging-guided biopsy. The device employs adjustable support plates with an optimized geometry to minimize the biopsy target displacement using smaller compression than the conventional parallel plates approach. It is expected that the reduced compression will cause less patient discomfort and improve image quality by enhancing the contrast intake. Precomputed optimal positions of the stabilization plates for a given biopsy target location are provided in a look-up table. The results of several experiments with a prototype of the device carried out on chicken breast tissue demonstrate the effectiveness of the new design when compared with conventional stabilization methods. The proposed stabilization mechanism provides excellent flexibility in selecting the needle insertion point and can be used in manual as well as robot-assisted biopsy procedures. [ABSTRACT FROM AUTHOR]

A pilot project was launched in order to spread internal awareness of e-Learning. It was demonstrated that, with a very limited amount of training, external subject matter expert (SME) knowledge could be delivered to students interactively and recorded for future viewing. The project aimed to develop a tool kit for teachers to use when considering course interventions with SME. The paper discusses the challenges of achieving the objectives of the project. [ABSTRACT FROM AUTHOR]

Abstract Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer’s patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

Abstract Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.

In the United States (US), new firefighters’ fitness and health behaviors deteriorate rapidly after fire academy graduation. Over the long-term, this increases their risks for chronic diseases. This study protocol describes the proposed usability testing and pilot study of a newly designed and developed healthy lifestyle smartphone app, “Surviving & Thriving”, tailored towards young US firefighters. “Surviving & Thriving” will provide interactive educational content on four lifestyle factors; nutrition, sleep, physical activity, and resilience, and include a personalized journey, habit tracker, and elements of gamification to promote engagement and long-term healthy behavior change. The first phase of the app development entails alpha testing by the research team and pre-beta testing by a fire service expert panel which will help refine the app into a pre-consumer version. Upon completion of the full app prototype, beta ‘usability’ testing will be conducted among new fire academy graduates from two New England fire academies to collect qualitative and quantitative feedback via focus groups and satisfaction surveys, respectively. A last phase of piloting the app will evaluate the app’s efficacy at maintaining/improving healthy lifestyle behaviors, mental health metrics, and physical fitness metrics. We will also evaluate whether firefighters’ perceived “health cultures” scores (ratings of each fire station’s/fire department’s environments as to encouraging/discouraging healthy behaviors) modify the changes in health metrics after utilizing the app for three to six months. This novel user-friendly app seeks to help new firefighters maintain/improve their health and fitness more effectively, reducing their risk of lifestyle-related chronic disease. Firefighters who can establish healthy habits early in their careers are more likely to sustain them throughout their lives.

Introduction: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.

The printability of reliable gate dielectrics and their influence on the stability of the device are some of the primary concerns regarding the practical application of printed transistors. Major ongoing research is focusing on the structural properties of dielectric materials and deposition parameters to reduce interface charge traps and hysteresis caused by the dielectric–semiconductor interface and dielectric bulk. This research focuses on improving the dielectric properties of a printed polymer material, cross-linked polyvinyl phenol (crPVP), by optimizing the cross-linking parameters as well as the aerosol jet printability. These improvements were then applied to the fabrication of completely printed carbon nanotube (CNT)-based thin-film transistors (TFT) to reduce the gate threshold voltage (Vth) and hysteresis in Vth during device operation. Finally, a fully aerosol-jet-printed CNT device was demonstrated using a 2:1 weight ratio of PVP with the cross-linker poly(melamine-co-formaldehyde) methylated (PMF) in crPVP as the dielectric material. This device shows significantly less hysteresis and can be operated at a gate threshold voltage as low as −4.8 V with an on/off ratio of more than 104.

Breast cancer is the leading cause of cancer deaths among women worldwide. There are many known risk factors for breast cancer, but the role of infectious disease remains unclear. Human cytomegalovirus (HCMV) is a widespread herpesvirus that usually causes little disease. Because HCMV has been detected in breast tumor biopsy samples and is frequently transmitted via human breast milk, we investigated HCMV replication in breast tumor cells. Four human breast cancer cell lines with different expression profiles for the key diagnostic markers of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were infected with a bacterial artificial chromosome-derived HCMV clinical strain TB40/E tagged with green fluorescent protein (GFP). Fluorescence microscopy confirmed that all four breast cancer cell lines supported virus entry. RNA was isolated from infected cells and the expression of immediate early (UL123), early (UL54), and late (UL111A) genes was confirmed using PCR. Viral proteins were detected by immunoblotting, and viral progeny were produced during the infection of breast tumor cells, as evidenced by subsequent infection of fibroblasts with culture supernatants. These results demonstrate that breast tumor cells support productive HCMV infection and could indicate that HCMV replication may play a role in breast cancer progression.

Emerging evidence has highlighted the pivotal role of microvasculature injury in the development and progression of renal fibrosis. Angiopoietin-1 (Ang-1) is a secreted vascular growth factor that binds to the endothelial-specific Tie2 receptor. Ang-1/Tie2 signaling is critical for regulating blood vessel development and modulating vascular response after injury, but is dispensable in mature, quiescent vessels. Although dysregulation of vascular endothelial growth factor (VEGF) signaling has been well studied in renal pathologies, much less is known about the role of the Ang-1/Tie2 pathway in renal interstitial fibrosis. Previous studies have shown contradicting effects of overexpressing Ang-1 systemically on renal tubulointerstitial fibrosis when different engineered forms of Ang-1 are used. Here, we investigated the impact of site-directed expression of native Ang-1 on the renal fibrogenic process and peritubular capillary network by exploiting a conditional transgenic mouse system [Pax8-rtTA/(TetO)7 Ang-1] that allows increased tubular Ang-1 production in adult mice. Using a murine unilateral ureteral obstruction (UUO) fibrosis model, we demonstrate that targeted Ang-1 overexpression attenuates myofibroblast activation and interstitial collagen I accumulation, inhibits the upregulation of transforming growth factor β1 and subsequent phosphorylation of Smad 2/3, dampens renal inflammation, and stimulates the growth of peritubular capillaries in the obstructed kidney. Our results suggest that Ang-1 is a potential therapeutic agent for targeting microvasculature injury in renal fibrosis without compromising the physiologically normal vasculature in humans.