Isolation and characterisation of PR3-specific B cells and their immunoglobulin sequences.

BACKGROUND: PR3 autoantibodies are essential to the diagnosis and monitoring of granulomatosus with polyangiitis, but to date no PR3 autoantibody sequences have been published. OBJECTIVES: To identify and characterise PR3-specific B cells from the peripheral blood of patients with PR3 autoantibodies. METHODS: Peripheral blood mononuclear cells from seven patients with PR3 autoantibodies were stained with PR3. B cells that bound PR3 underwent single cell sorting, transcriptome sequencing, and their immunoglobulin sequences expressed as antibodies and tested for PR3-specificity by ELISA. RESULTS: We identified 19 PR3-specific B cells from only one PR3-seropositive patient at a low frequency (0.0075 % of B cells) in the peripheral blood. These were polyclonal, IgG+ and enriched for IgG4, lambda pairing, IGHJ6 gene usage, CDRH3 length, IGHE and CD71 expression. They demonstrated relatively low levels of somatic hypermutation and variably reduced PR3 binding when reverted to germline. CONCLUSIONS: Identifying PR3-specific B cells in the peripheral blood is possible but challenging and those we did identify exhibited features suggesting that PR3-self reactivity may occur early in B-cell development.

Evaluation of the 'Sip Til Send' regimen before elective caesarean delivery using bedside gastric ultrasound: A paired cohort pragmatic study.

BACKGROUND: Pre-operative fasting is routinely advocated to avoid pulmonary aspiration. The European Society of Anaesthesiology and Intensive Care (ESAIC) recommends a fasting period of 2 h for liquids before surgery. Liberal drinking policies such as the 'Sip Til Send' are a suggested alternative to maintain hydration before surgery. OBJECTIVES: To compare residual gastric volumes in fully fasted nonlabouring parturients before elective caesarean delivery with the 'Sip Til Send' with water liberal drinking protocol. Our hypothesis was the 'Sip Til Send' would be noninferior to standard fasting at minimising the residual gastric volume immediately before surgery. DESIGN: A paired cohort prospective observational pragmatic study using gastric ultrasound, analysed by an operator blinded to the fasting status of each scan. SETTING: A tertiary maternity hospital in Dublin, Ireland. The study was conducted between January and June 2023. PARTICIPANTS: Pregnant women about to undergo elective caesarean delivery who had followed ESAIC fasting guidelines before admission. INTERVENTIONS: Each participant underwent two pairs (semi-recumbent and the semi-recumbent right lateral positions) of standardised ultrasound examinations of the gastric antrum: the order of these scans was randomised. The first pair of scans occurred on admission before the 'Sip Til Send' protocol commenced, the other pair just before spinal anaesthesia for caesarean delivery, after a variable time following the 'Sip Til Send' protocol. MAIN OUTCOME MEASURE: The primary outcome was the difference in antral cross-sectional area (CSA) between the fully fasted women on admission and the same women after following the 'Sip Til Send' protocol until just before spinal anaesthesia. RESULTS: Fifty-eight women were randomised for the study: 55 and 54 scans in the semi-recumbent position on admission, and 55 and 54 scans in the right lateral position just before spinal anaesthesia. The mean differences (95% CI) in CSA in the semi-recumbent and RL positions were 0.07 (-0.39 to 0.53) cm 2 and 0.04 (-0.60 to 0.68) cm 2 , respectively. Since the of 95% CIs did not cross the predefined noninferiority margin of 0.88 cm 2 , 'Sip Til Send' was noninferior to fully fasting in in terms of the antral CSA. CONCLUSION: The 'Sip Til Send' protocol of liberal hydration with water was noninferior to standard fasting prior to elective caesarean delivery. TRIAL REGISTRY NUMBER: NCT05783427 ClinicalTrials.gov.

Scrambling Transition in a Radiative Random Unitary Circuit.

We study quantum information scrambling in a random unitary circuit that exchanges qubits with an environment at a rate p. As a result, initially localized quantum information not only spreads within the system, but also spills into the environment. Using the out-of-time-order correlator (OTOC) to characterize scrambling, we find a nonequilibrium phase transition in the directed percolation universality class at a critical swap rate p_{c}: for pp_{c} the OTOC fails to percolate within the system and vanishes uniformly within a finite timescale, indicating that all local operators are rapidly swapped into the environment. To elucidate its information-theoretic consequences, we demonstrate that the transition in operator spreading coincides with a transition in an observer's ability to decode the system's initial quantum information from the swapped-out, or "radiated," qubits. We present a simple decoding scheme which recovers the system's initial information with perfect fidelity in the nonpercolating phase, and with continuously decreasing fidelity with decreasing swap rate in the percolating phase. Depending on the initial state of the swapped-in qubits, we further observe a corresponding entanglement transition in the coherent information from the system into the radiated qubits.

C-Nitrosothioformamide: A Donor Template for Dual Release of HNO and H2 S.

C-Nitrosothioformamide was demonstrated to be a donor template for dual release of HNO and COS triggered by a retro-Diels-Alder reaction. COS is an H2 S precursor in the presence of carbonic anhydrase. This process produces HNO and H2 S in a slow but steady manner. As such, the direct reaction between HNO and H2 S under this situation appears to be minor. This may provide a useful tool for studying the synergistic effects of HNO and H2 S.

The Path to Controlled Delivery of Reactive Sulfur Species.

Reactive sulfur species (RSS) play regulatory roles in many physiological and pathological processes. Since the discovery of hydrogen sulfide (H2S) as a nitric oxide (NO)-like signaling molecule, understanding the chemical biology of H2S and H2S-related RSS, such as hydropersulfides (RSSH) and polysulfides (H2Sn), has become a fast-growing research field. However, the research on these RSS has technical difficulties due to their high reactivity and instability. To solve this problem, considerable efforts have been put into the development of unique RSS releasing compounds (e.g., donors) or in situ RSS generation systems. This Account tells the story of our research group's effort to develop novel RSS donors.We began with exploring molecular entities that were stable by themselves but could be triggered by biologically relevant factors, such as pH, thiols, light, or enzymes, to release H2S in a controllable fashion. These studies led to the discovery of a series of novel H2S donors. We later expanded our interests to other RSS including RSSH, H2Sn, RSeSH, HSNO, RSOH, etc. The fundamental chemistry of these RSS was studied and applied to the development of the corresponding donors. In addition to small molecule donors, we also worked on H2S-releasing biomaterials and their applications. This Account summarizes our work and systematically explains how each RSS donor template was proposed and evaluated. The Account covers the following key points: (1) rational chemistry design of each RSS donor template, (2) evaluation and mechanistic insights of each donor template, and (3) properties and biological applications of the donors.

Time to return to full training and recurrence of rectus femoris injuries in elite track and field athletes 2010-2019; a 9-year study using the British Athletics Muscle Injury Classification.

Rectus femoris (RF) injuries are common in sports requiring maximal acceleration and sprinting. The British Athletics Muscle Injury Classification (BAMIC) describes acute muscle injury based on the anatomical site of injury and has been associated with return to play in hamstring and calf muscle injury. The aim of this study was to describe and compare the time to return to full training (TRFT) and injury recurrence for BAMIC-classified RF injuries sustained by elite track and field (T&F) athletes over a 9-year period. All rectus femoris injuries sustained by elite T&F athletes on the British Athletics World Class Program between September 2010 and September 2019 that were investigated with an MRI within 7 days of acute onset anterior thigh pain were included. Injuries were graded from the MRI by a specialist musculoskeletal radiologist using the BAMIC, and TRFT and injury recurrence were determined by evaluation of the Electronic Medical Record. Athlete demographics and World Athletics event discipline were recorded. Specific injury details including mechanism, location of injury, and whether surgical or rehabilitation management was undertaken were recorded. There were 38 RF injuries in 27 athletes (24.7 ± 2.3 years; 10 male, 17 female). Average TRFT for rehabilitation managed cases was 20.4 ± 14.8 days. Grade 1 injuries had significantly shorter TRFT compared with grades 2 (p = 0.04) and 3 (p = 0.01). Intratendinous (c) and surgically managed RF injuries each had significantly longer TRFT compared with other injury classes (p < 0.001). Myofascial (a) injuries had reduced repeat injury rates compared with b or c classes (p = 0.048). Grade 3 injuries had an increased repeat injury rate compared with other grades (p = 0.02). There were 4 complete (4c) proximal free tendon injuries sustained during sprinting and all in female athletes. The average TRFT for RF injuries in elite T&F is similar to that previously identified in elite football and Australian Rules. Similar to previous research in hamstring and calf injury, RF injuries extending into the tendon (BAMIC class c) had delayed TRFT which may reflect the longer duration required for tendon healing and adaptation. Grade 3 injuries had in increased repeat injury rate compared with grades 1 and 2. The BAMIC diagnostic framework may provide useful information for clinicians managing rectus femoris injuries in T&F.

A 4-year study of hamstring injury outcomes in elite track and field using the British Athletics rehabilitation approach.

OBJECTIVES: The British Athletics Muscle Injury Classification (BAMIC) correlates with return to play in muscle injury. The aim of this study was to examine hamstring injury diagnoses and outcomes within elite track and field athletes following implementation of the British Athletics hamstring rehabilitation approach. METHODS: All hamstring injuries sustained by elite track and field athletes on the British Athletics World Class Programme between December 2015 and November 2019 that underwent an MRI and had British Athletics medical team prescribed rehabilitation were included. Athlete demographics and specific injury details, including mechanism of injury, self-reported gait phase, MRI characteristics and time to return to full training (TRFT) were contemporaneously recorded. RESULTS: 70 hamstring injuries in 46 athletes (24 women and 22 men, 24.6±3.7 years) were included. BAMIC grade and the intratendon c classification correlated with increased TRFT. Mean TRFT was 18.6 days for the entire cohort. Mean TRFT for intratendon classifications was 34±7 days (2c) and 48±17 days (3c). The overall reinjury rate was 2.9% and no reinjuries were sustained in the intratendon classifications. MRI variables of length and cross-sectional (CSA) area of muscle oedema, CSA of tendon injury and loss of tendon tension were associated with TRFT. Longitudinal length of tendon injury, in the intratendon classes, was not associated with TRFT. CONCLUSION: The application of BAMIC to inform hamstring rehabilitation in British Athletics results in low reinjury rates and favourable TRFT following hamstring injury. The key MRI variables associated with longer recovery are length and CSA of muscle oedema, CSA of tendon injury and loss of tendon tension.

Effect of Active Photons on Dynamical Frustration in Cavity QED.

We study the far-from-equilibrium dynamical regimes of a many-body spin-boson model with disordered couplings relevant for cavity QED and trapped ion experiments, using the discrete truncated Wigner approximation. We focus on the dynamics of spin observables upon varying the disorder strength and the frequency of the photons, finding that the latter can considerably alter the structure of the system's dynamical responses. When the photons evolve at a similar rate as the spins, they can induce qualitatively distinct frustrated dynamics characterized by either logarithmic or algebraically slow relaxation. The latter illustrates resilience of glassylike dynamics in the presence of active photonic degrees of freedom, suggesting that disordered quantum many-body systems with resonant photons or phonons can display a rich diagram of nonequilibrium responses, with near future applications for quantum information science.

Utilization of high-speed imaging for atmospheric scintillation studies.

Atmospheric scintillation studies have been traditionally undertaken utilizing nonimaging detection. When imaging devices are used, they typically detect the resultant signal at the receiver plane. Here, a high-speed camera has been utilized in atmospheric scintillation field trials, imaging a laser source (i.e., imaging the object plane) over a near ground path length of 1.5 km. The statistical nature of the acquired atmospheric scintillation data is characterized using a range of probability density functions. The exponentiated Weibull function was found to best describe the nature of scintillation over the broadest range of a scintillation index typical of atmospheric scintillation. A preliminary investigation into the relationship between the fit variables of three of the better-performing probability density functions and the scintillation index is presented, along with suggestions for future use of digital cameras in atmospheric scintillation studies.

Injury epidemiology in professional ballet: a five-season prospective study of 1596 medical attention injuries and 543 time-loss injuries.

OBJECTIVES: To describe the incidence rate, severity, burden and aetiology of medical attention and time-loss injuries across five consecutive seasons at a professional ballet company. METHODS: Medical attention injuries, time-loss injuries and dance exposure hours of 123 professional ballet dancers (women: n=66, age: 28.0±8.3 years; men: n=57, age: 27.9±8.5 years) were prospectively recorded between the 2015/2016 and 2019/2020 seasons. RESULTS: The incidence rate (per 1000 hours) of medical attention injury was 3.9 (95% CI 3.3 to 4.4) for women and 3.1 (95% CI 2.6 to 3.5) for men. The incidence rate (per 1000 hours) of time-loss injury was 1.2 (95% CI 1.0 to 1.5) for women and 1.1 (95% CI 0.9 to 1.3) for men. First Soloists and Principals experienced between 2.0-2.2 additional medical attention injuries per 1000 hours and 0.9-1.1 additional time-loss injuries per 1000 hours compared with Apprentices (p≤0.025). Further, intraseason differences were observed in medical attention, but not time-loss, injury incidence rates with the highest incidence rates in early (August and September) and late (June) season months. Thirty-five per cent of time-loss injuries resulted in over 28 days of modified dance training. A greater percentage of time-loss injuries were classified as overuse (women: 50%; men: 51%) compared with traumatic (women: 40%; men: 41%). CONCLUSION: This is the first study to report the incidence rate of medical attention and time-loss injuries in professional ballet dancers. Incidence rates differed across company ranks and months, which may inform targeted injury prevention strategies.

Hamstring rehabilitation in elite track and field athletes: applying the British Athletics Muscle Injury Classification in clinical practice.

RATIONALE: Hamstring injuries are common in elite sports. Muscle injury classification systems aim to provide a framework for diagnosis. The British Athletics Muscle Injury Classification (BAMIC) describes an MRI classification system with clearly defined, anatomically focused classes based on the site of injury: (a) myofascial, (b) muscle-tendon junction or (c) intratendinous; and the extent of the injury, graded from 0 to 4. However, there are no clinical guidelines that link the specific diagnosis (as above) with a focused rehabilitation plan. OBJECTIVE: We present an overview of the general principles of, and rationale for, exercise-based hamstring injury rehabilitation in British Athletics. We describe how British Athletics clinicians use the BAMIC to help manage elite track and field athletes with hamstring injury. Within each class of injury, we discuss four topics: clinical presentation, healing physiology, how we prescribe and progress rehabilitation and how we make the shared decision to return to full training. We recommend a structured and targeted diagnostic and rehabilitation approach to improve outcomes after hamstring injury.

O→S Relay Deprotection: A General Approach to Controllable Donors of Reactive Sulfur Species.

Reactive sulfur species (RSS) are biologically important molecules. Among them, H2 S, hydrogen polysulfides (H2 Sn, n>1), persulfides (RSSH), and HSNO are believed to play regulatory roles in sulfur-related redox biology. However, these molecules are unstable and difficult to handle. Having access to their reliable and controllable precursors (or donors) is the prerequisite for the study of these sulfur species. Reported in this work is the preparation and evaluation of a series of O-silyl-mercaptan-based sulfur-containing molecules which undergo pH- or F- -mediated desilylation to release the corresponding H2 S, H2 Sn , RSSH, and HSNO in a controlled fashion. This O→S relay deprotection serves as a general strategy for the design of pH- or F- -triggered RSS donors. Moreover, we have demonstrated that the O-silyl groups in the donors could be changed into other protecting groups like esters. This work should allow the development of RSS donors with other activation mechanisms (such as esterase-activated donors).

Both the autophagy and proteasomal pathways facilitate the Ubp3p-dependent depletion of a subset of translation and RNA turnover factors during nitrogen starvation in Saccharomyces cerevisiae.

Protein turnover is an important regulatory mechanism that facilitates cellular adaptation to changing environmental conditions. Previous studies have shown that ribosome abundance is reduced during nitrogen starvation by a selective autophagy mechanism termed ribophagy, which is dependent upon the deubiquitinase Ubp3p. In this study, we asked whether the abundance of various translation and RNA turnover factors are reduced following the onset of nitrogen starvation in Saccharomyces cerevisiae. We found distinct differences in the abundance of the proteins tested following nitrogen starvation: (1) The level of some did not change; (2) others were reduced with kinetics similar to ribophagy, and (3) a few proteins were rapidly depleted. Furthermore, different pathways differentially degraded the various proteins upon nitrogen starvation. The translation factors eRF3 and eIF4GI, and the decapping enhancer Pat1p, required an intact autophagy pathway for their depletion. In contrast, the deadenylase subunit Pop2p and the decapping enzyme Dcp2p were rapidly depleted by a proteasome-dependent mechanism. The proteasome-dependent depletion of Dcp2p and Pop2p was also induced by rapamycin, suggesting that the TOR1 pathway influences this pathway. Like ribophagy, depletion of eIF4GI, eRF3, Dcp2p, and Pop2p was dependent upon Ubp3p to varying extents. Together, our results suggest that the autophagy and proteasomal pathways degrade distinct translation and RNA turnover factors in a Ubp3p-dependent manner during nitrogen starvation. While ribophagy is thought to mediate the reutilization of scarce resources during nutrient limitation, our results suggest that the selective degradation of specific proteins could also facilitate a broader reprogramming of the post-transcriptional control of gene expression.

Identification and functional validation of RAD23B as a potential protein in human breast cancer progression.

Identification of protein targets that play a role in breast cancer invasion may help to understand the rapid progression of cancer and may lead to the development of new biomarkers for the disease. In this study, we compared two highly invasive and two poorly invasive breast cancer cell lines using comparative label-free LC-MS profiling in order to identify differentially expressed proteins that may be linked to the invasive phenotype in vitro. Forty-five proteins were found to be upregulated, and 34 proteins, downregulated. UV excision repair protein RAD23 homologue B (RAD23B) was found among the downregulated proteins in highly invasive breast cancer cell lines. In poorly invasive breast cancer cell lines, siRNA-mediated downregulation of RAD23B subsequently led to an increase in invasion and adhesion in vitro. Immunohistochemistry analysis of 164 specimens of invasive breast cancer showed that having a high percentage (>80%) of RAD23B positive nuclei was significantly associated with histopathological grades 1 and 2 breast cancer and with low mitotic activity. In addition, a high staining intensity for RAD23B in the cytoplasm was significantly associated with histopathological grade 3 breast cancer. This study suggests a potential role of RAD23B in breast cancer progression and may further imply a tumor suppressor role of nuclear RAD23B in breast cancer.

Epidemiology of bone injuries in elite athletics: A prospective 9-year cohort study.

OBJECTIVES: To describe bone injury patterns in elite track and field athletes. To investigate relationships between bone injury and athlete characteristics to inform future injury prevention strategies. DESIGN: Descriptive epidemiology study. SETTING: Elite athletics training centres across the United Kingdom and internationally, observed between 2012 and 2020. PARTICIPANTS: 207 Olympic programme senior track and field athletes. MAIN OUTCOME MEASURES: Injury number, Incidence, Severity, Burden, Time Loss. RESULTS: There were 78 fractures during the study period. Gradual repetitive bone injuries were the most common type of injury mode. The foot, pelvis and the lumbar spine were the regions with the highest number of bone stress injuries. Stress fractures had a higher burden overall compared to stress reactions. Average return to full training was 67.4 days (±73.1) for stress reactions and 199 (±205.2) days for stress fractures. There was no relationship between bone injury type and age, sex, ethnicity, side dominance or event group. CONCLUSION: Bone stress injuries in athletics have a high severity and burden warranting continued efforts to prevent their occurrence and optimize management. Age, sex, ethnicity, side dominance and event region do not have any relationship with bone injury occurrence and are therefore unlikely to increase risk in this cohort.

Epidemiology and management of ankle sprain injuries over seven seasons in an elite professional ballet company.

OBJECTIVES: To investigate the epidemiology and management of ankle ligament sprains over seven seasons in a professional ballet company. DESIGN: Descriptive epidemiology study. METHODS: Medical attention injury, time-loss injury, and exposure data pertaining to 140 professional ballet dancers were prospectively recorded by Chartered Physiotherapists over seven seasons (2015/16-2021/22); a period including the COVID-19 global pandemic. RESULTS: Sixty-nine ankle sprains (46 time-loss) in 45 dancers (32 %) were recorded: 51 sprains were classified as grade I, 15 were classified as grade II, and three were classified as grade III; 53 sprains affected only one ligament, whilst 16 were multi-ligament sprains. For time-loss injuries, median time-loss durations varied by grading (I - 31 days, II - 54 days, and III - 147 days) and the number of ligaments affected (one - 31 days, two - 54 days, three - 134 days, four - 137 days), with time-loss ranging from 1 to 188 days. Of the 46 time-loss ankle sprains, eight were mild, nine were moderate, and 29 were severe. The incidence rate (injuries·1000 h-1) of medical attention ankle sprains was 0.073 (95 % CI: 0.046 to 0.117) in male dancers and 0.101 (95 % CI: 0.069 to 0.148) in female dancers, and the incidence of time-loss ankle sprains was 0.044 (95 % CI: 0.024 to 0.080) in male dancers and 0.064 (95 % CI: 0.040 to 0.103) in female dancers. No significant effect of sex was observed on either medical attention (p = .304) or time-loss (p = .327) ankle sprain incidence rates. Ten percent of dancers sustained multiple sprains across the seven seasons. Fifty and 39 % of ankle sprains in female and male dancers, respectively, were preceded by a history of ankle sprains. Jumping and landing (30 sprains) and non-dance movements (16 sprains) were the most common inciting movements. Bone bruising and synovitis were the most common concurrent pathologies. CONCLUSIONS: Ankle sprains placed a considerable burden on the ballet company studied. These time-loss durations specified by number and grade of ligament sprain, injury history, and secondary pathologies can guide return-to-dance rehabilitation pathways.

Relative energy deficiency in dance (RED-D): a consensus method approach to REDs in dance.

Relative energy deficiency in sport (REDs) is a potentially severe, challenging, broad-spectrum syndrome with potential negative health and performance outcomes. The numerous research publications and International Olympic Committee consensus statements relating to REDs testify to the challenges faced in early identification or screening, diagnosis and management. Like sport, dance, in its simplest form, can be identified as an activity resulting in physiological energy demands and, as such, requires appropriate energy availability concerning energy expenditures. However, the specificity of physiological and psychological demands in dance must be considered when considering REDs. An environment where physical activity can exceed 30 hours per week and where culture may instil a value that thinness is required puts dancers at increased risk for REDs. The purpose of this study was to provide dance-specific guidance dance on this complex condition. An RAND/UCLA Delphi Panel method with nominal group technique was used to review the literature from REDs to evaluate how it may relate to dance. In addition to the EP, which was assembled from a multidisciplinary background with expertise in REDs and multiple genres of dance, six focus groups were commissioned. Four of the focus groups were drawn from the EP members and two additional focus groups formed by dancers and artistic leaders. These panels were used to guide the development of a RED-D diagnosis pathway, management plan and risk stratification and return to dance pathway. The dance-specific pathways are designed to be a practical tool for guiding and supporting clinicians managing RED-D. Furthermore, this paper represents an important focus of this area in dance and serves to stimulate discussion and further research within the sector.

Foot and Ankle MRI Findings in Asymptomatic Professional Ballet Dancers.

Background: Previous research in sport populations has demonstrated that abnormal magnetic resonance imaging (MRI) findings may be present in individuals without symptoms or known pathology. Extending this understanding to ballet, particularly in relation to the foot and ankle, is important to guide medical advice given to dancers. Purpose: To assess foot and ankle MRI scans in asymptomatic ballet dancers focusing on bone marrow edema and the posterior ankle and to investigate whether these MRI findings would become symptomatic within 1 year. Study Design: Case series; Level of evidence, 4. Methods: In total, 31 healthy dancers (62 feet/ankles; 15 male and 16 female; age, 26.5 ± 4.3 years) who were dancing in full capacity were recruited from an elite professional ballet company. Orthogonal 3-plane short tau inversion recovery imaging of both feet and ankles was obtained using 3T MRI and the images were reviewed using a standardized evaluation form by 2 musculoskeletal radiologists. Injuries in the company were recorded and positive MRI findings were assessed for correlation with any injuries requiring medical attention during the subsequent 12 months. Results: A total of 51 (82%) of the 62 feet and ankles had ≥1 area of bone marrow edema. The most common locations of bone marrow edema were the talus (n = 41; 66%), followed by first metatarsal (n = 14; 23%). Os trigonum and Stieda process were seen in 5 (8%) and 8 (13%) ankles, respectively. Among them, 2 os trigona showed bone marrow edema. Fluid in the anterior and posterior talocrural joints and the subtalar joint was observed in 48%, 63%, and 63% of these joints, respectively. Fluid around foot and ankle tendons was observed, with the most prevalent being the flexor hallucis longus tendon (n = 13; 21%). Two dancers who had positive findings on their MRI subsequently developed symptoms during the next 12 months. Conclusion: Positive MRI findings are commonplace in the foot and ankle of asymptomatic professional ballet dancers. The majority do not result in the development of symptoms requiring medical attention within 12 months. Careful interpretation of MRI findings with the dancer's clinical picture is required before recommending activity modification or further intervention.

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels.

Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

Increased Inflammation as well as Decreased Endoplasmic Reticulum Stress and Translation Differentiate Pancreatic Islets of Pre-symptomatic Stage 1 Type 1 Diabetes and Non-diabetic Cases.

Aims/hypothesis: Progression to type 1 diabetes (T1D) is associated with genetic factors, the presence of autoantibodies, and a decline in ß cell insulin secretion in response to glucose. Very little is known regarding the molecular changes that occur in human insulin-secreting ß-cells prior to the onset of T1D. Herein, we applied an unbiased proteomics approach to identify changes in proteins and potential mechanisms of islet dysfunction in islet autoantibody-positive organ donors with pre-symptomatic stage 1 T1D (HbA1c ≤ 6). We aimed to identify pathways in islets that are indicative of ß-cell dysfunction. Methods: Multiple islet sections were collected through laser microdissection of frozen pancreatic tissues of organ donors positive for islet autoantibodies (AAb+, n=5), compared to age/sex-matched nondiabetic controls (ND, n=5) obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD). Islet sections were subjected to mass spectrometry-based proteomics and analyzed with label-free quantification followed by pathway and functional annotations. Results: Analyses resulted in ~4,500 proteins identified with low false discovery rate (FDR) <1%, with 2,165 proteins reliably quantified in every islet sample. We observed large inter-donor variations that presented a challenge for statistical analysis of proteome changes between donor groups. We therefore focused on the three multiple AAb+ cases (mAAb+) with high genetic risk and their three matched controls for a final statistical analysis. Approximately 10% of the proteins (n=202) were significantly different between mAAb+ cases versus ND. The significant alterations clustered around major functions for upregulation in the immune response and glycolysis, and downregulation in endoplasmic reticulum (ER) stress response as well as protein translation and synthesis. The observed proteome changes were further supported by several independent published datasets, including proteomics dataset from in vitro proinflammatory cytokine-treated human islets and single cell RNA-seq data sets from AAb+ cases. Conclusion/interpretation: In-situ human islet proteome alterations at the stage 1 of AAb+ T1D centered around several major functional categories, including an expected increase in immune response genes (elevated antigen presentation / HLA), with decreases in protein synthesis and ER stress response, as well as compensatory metabolic response. The dataset serves as a proteomics resource for future studies on ß cell changes during T1D progression and pathogenesis.