Search

Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.

Glucocorticoid (GC) resistance is a poor prognostic factor in T-cell acute lymphoblastic leukaemia (T-ALL). Interleukin-7 (IL-7) mediates GC resistance via GC-induced upregulation of IL-7 receptor (IL-7R) expression, leading to increased pro-survival signalling. IL-7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL-7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR-445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)-induced increase in cell surface IL-7R and overcomes IL-7-induced DEX resistance.

Purpose: As a multidisciplined combat sport, relationships between external and internal training loads and intensities of mixed martial arts (MMA) have not been described. The aim of this study was to determine the external loads and intensities of MMA training categories and their relationship to internal loads and intensities. Methods: Twenty MMA athletes (age = 23.3 [5.3] y, mass = 72.1 [7.2] kg, stature = 171.5 [8.4] cm) were observed for 2 consecutive weeks. Internal load and intensity (session rating of perceived exertion [sRPE]) were calculated using the Foster RPE for the session overall (sRPE-training load [TL]) and segmented RPE (segRPE-TL) for each training category: warm-up, striking drills, wrestling drills, Brazilian jiujitsu (BJJ) drills, striking sparring, wrestling sparring, BJJ sparring, and MMA sparring. External load and intensity were measured via Catapult OptimEye S5 for the full duration of each session using accumulated Playerload (PLdACC) and PLdACC per minute (PLdACC·min−1). Differences in loads between categories and days were assessed via Bayesian analysis of variance (BF10 ≥ 3). Predictive relationships between internal and external variables were calculated using Bayesian regression. Results: Session overall sRPE-TL = 448.6 (191.1) arbitrary units (AU); PLdACC = 310.6 (112) AU. Category segRPE-TL range = 33.8 (22.6) AU (warm-up) to 122.8 (54.6) AU (BJJ drills). Category PLdACC range = 44 (36.3) AU (warm-up) to 125 (58.8) AU (MMA sparring). Neither sRPE-TL nor PLdACC changed between days. PLdACC was different between categories. Evidence for regressions was strong-decisive except for BJJ drills (BF10 = 7, moderate). R2 range =.50 to.77, except for warm-up (R2 =.17), BJJ drills (R2 =.27), BJJ sparring (R2 =.49), and session overall (R2 =.13). Conclusions: While MMA training categories may be differentiated in terms of external load, overall session external load does not change within or between weeks. Resultant regression equations may be used to appropriately plan MMA technical/tactical training loads. [ABSTRACT FROM AUTHOR]

Purpose: Athlete stature and armspan is anecdotally assumed to provide an advantage in mixed martial arts (MMA), despite an absence of supporting data. In contrast, winners of MMA bouts have been shown to be younger than bouts losers. Whilst absolute measurements of stature, armspan and armspan:stature scale (A:S) have been shown to not distinguish between winners and losers of MMA bouts, relative differences between competitors have not been analysed. This study aimed to analyse 5 years of athlete age and morphological data to replicate and expand previous studies to determine whether absolute and/or relative age and morphological variables effect winning and losing in MMA. MethodsandResults: Bayes factor (BF>3) inferential analyses conducted on the cohort overall (n = 2,229 professional bouts), each year sampled and each individual body mass division found that only absolute (winners = 29.8 ± 4 years; losers = 30.7 ± 4.2 years) and relative age (winners = 0.82 ± 5.3 years younger than losers) differentiates between winners and losers across the whole cohort, in 4 of the 5 years, and in 4 of the 13 divisions sampled. Armspan appears to provide an advantage in heavyweight only (winners = 198.4 ± 6.6cm; losers = 196.1 ± 7.7cm), with greater A:S being a disadvantage (winners = 1.003 ± 0.022cm∙cm−1; losers = 1.010 ± 0.023 cm∙cm−1) in women's strawweight only. No variables had any effect on how bouts were won. Conclusions: These results confirm previous reports that the effect of athlete morphology is greatly overstated in MMA, appearing to be irrelevant in most divisions. Bout winners tend to be younger than losers, particularly in divisions displaying more diverse skill requirements. [ABSTRACT FROM AUTHOR]

Purpose: Combat-sport athletes commonly undergo rapid weight loss prior to prebout weigh-in and subsequently rapid weight gain (RWG) prior to competition. This investigation aimed to evaluate the effect of RWG and weight differential (WD) between opponents on competitive success. Methods: A retrospective cohort study was performed using data from professional mixed martial arts (MMA) and boxing events held between 2015 and 2019. The primary outcome was RWG (relative and absolute) between weigh-in and competition stratified by bout winners and losers. Binary logistic regression was used to explore the relationships among bout outcome, RWG, and WD between competitors on the day of their bout. Results: Among 708 MMA athletes included, winners regained more relative body mass (8.7% [3.7%] vs 7.9% [3.8%], P <.01) than losers. In 1392 included male boxers, winners regained significantly more relative body mass (8.0% [3.0%] vs 6.9% [3.2%], P <.01) than losers. Each percentage body mass increase resulted in a 7% increased likelihood of victory in MMA and a 13% increase in boxing. The relationship between RWG and competitive success remained significant in regional and male international MMA athletes, as well as boxers. WD predicted victory in international mixed martial artists and boxers. WD predicted victory by knockout or technical knockout in international MMA athletes and regional boxers. Conclusion: This analysis of combat-sport athletes indicates that RWG and WD influence competitive success. These findings raise fair-play and safety concerns in these popular sports and may help guide risk-mitigating regulation strategies. [ABSTRACT FROM AUTHOR]

The benefits of strength and conditioning (S&C) for improving judo performance and reducing injuries have been widely studied. However, the S&C practices used and perspectives held by those delivering S&C have yet to be elucidated. Therefore, this study investigated the S&C practices and perspectives of judokas and S&C coaches working within judo. Forty-two judokas and 9 S&C coaches completed an online survey comprising 6 sections: (a) written informed consent; (b) background information; (c) education, qualifications, and prescription; (d) views on S&C (e) exercise selection; and (f) issues and improvements. Frequency analysis was used to report responses to fixed-response questions and thematic analysis for open-ended questions. Results indicated that S&C coaches were primarily responsible for delivering S&C programs (60%), and S&C information was predominantly sourced from S&C coaches (43%). Strength and conditioning was deemed very important for randori (78-88%), overall judo performance (67-79%), and judo fitness (62-78%). Similarly, S&C was considered very important for the development of speed and power (76-89%), strength (71-89%), and injury reduction (69-78%). Novel findings were also observed, such as integrating judo-specific training within S&C practice, which may be partly explained by more S&C coaches holding judo belts (67%) than S&C qualifications (11%). This study supports practitioners delivering S&C in judo by offering a base of information to critique or align with their existing S&C practices and perspectives. Furthermore, our results may help identify potential gaps between methods used, proposed guidelines, and actual practice, facilitating the development of research and education resources tailored to the current climate. [ABSTRACT FROM AUTHOR]

Immunoproteasomes are a special class of proteasomes, which can be induced with IFN‐γ in an inflammatory environment. In recent years, it became evident that certain immune cell types constitutively express high levels of immunoproteasomes. However, information regarding the basal expression of proteolytically active immunoproteasome subunits in different types of immune cells is still rare. Hence, we quantified standard proteasome subunits (β1c, β2c, β5c) and immunoproteasome subunits (LMP2, MECL‐1, LMP7) in the major murine (CD4+ T cells, CD8+ T cells, CD19+ B cells, CD11c+ dendritic cells, CD49d+ natural killer cells, Ly‐6G+ neutrophils) and human immune cell (CD4+ T cells, CD8+ T cells, CD19+ B cells, CD1c+CD141+ myeloid dendritic cells, CD56+ natural killer cells, granulocytes) subsets. The different human immune cell types were isolated from peripheral blood and the murine immune cell subsets from spleen. We found that proteasomes of most immune cell subsets mainly consist of immunoproteasome subunits. Our data will serve as a reference and guideline for immunoproteasome expression and imply a special role of immunoproteasomes in immune cells. [ABSTRACT FROM AUTHOR]

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's "no presumption of advantage" principle disregards this reality. Studies show that transgender women (male‐born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of "meaningful competition" is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case‐by‐case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision‐making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports. [ABSTRACT FROM AUTHOR]

The proteasome inhibitor bortezomib has shown remarkable clinical success in the treatment of multiple myeloma. However, the efficacy and mechanism of action of bortezomib in solid tumor malignancies is less well understood. In addition, the use of this first-in-class proteasome inhibitor is limited by several factors, including off-target effects that lead to adverse toxicities. We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors. Both compounds promote upregulation of proapoptotic BIK and antiapoptotic MCL1, which serves to mediate and attenuate, respectively, the killing activities of these proteasome inhibitors. Both compounds also induce complete autophagic flux that is partially dependent on activation of the unfolded protein response (UPR) and upregulation of ATF4. Carfilzomib- and oprozomib-induced autophagy acts to promote HNSCC cell survival. Our study indicates that the therapeutic benefit of these promising proteasome inhibitors may be improved by inhibiting MCL1 expression or autophagy.

PurposeCarfilzomib is a selective, irreversible inhibitor of the chymotrypsin-like activity of the proteasome and is undergoing clinical evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable derivative. The activities of carfilzomib and ONX 0912 against solid tumor malignancies are less well understood. We investigated the impact and mechanisms of action of carfilzomib and ONX 0912 in preclinical models of head and neck squamous cell carcinoma (HNSCC).Experimental designThe effects of carfilzomib and ONX 0912 on HNSCC cell survival and xenograft tumor growth were evaluated. The impact and mechanisms of both agents on apoptosis and autophagy induction were also investigated. The contribution of the unfolded protein response (UPR) to autophagy induction and the role of autophagy in attenuating HNSCC cell death were determined.ResultsCarfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner.ConclusionsThese results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy.

Body mass (BM) manipulation via rapid weight loss (RWL) and rapid weight gain (RWG) is a common practice among mixed martial art (MMA) athletes to ensure qualification for the division in which the athlete wishes to compete. Professional MMA competitors in California are required to weigh in twice: 24 hr prior to competition and immediately prior to the bout after they have typically engaged in RWG. In analyzing data from five MMA events sanctioned by the Californian State Athletic Commission, the authors used Bayesian analyses to compare bout winners (n = 31) and losers (n = 31) in terms of in-competition BM (in kilograms) and the amount of BM regained between the two weigh-ins (in kilograms). These data do not support the hypothesis that differences in in-competition BM (Bayes factor [BF10] = 0.667, d = 0.23) or the amount of BM regained between the two weigh-ins (BF10 = 0.821, d = 0.23) determine winning or losing. In addition, there was no statistical difference between bouts ending via strikes, submission, or decision for either in-competition BM (BF10 = 0.686, ω2 < 0.01) or the amount of BM regained between the two weigh-ins (BF10 = 0.732, ω2 = 0.054). In conclusion, the authors report for the first time that the magnitude of RWG does not predict winning or losing in a professional cohort of MMA athletes. In addition, they also report that MMA athletes typically compete at a BM that is at least 1–2 divisions higher than the division in which they officially weighed-in. These analyses may provide impetus for governing bodies and coaches to enact changes at both professional and amateur levels to reduce negative health consequences associated with extreme RWL and RWG. [ABSTRACT FROM AUTHOR]

Aims The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts. However, the role and mechanisms of selective inhibition of a single immunoproteasome subunit to prevent immune-mediated vascular allograft rejection and TA is not clear. Methods and results The effect and potential mechanism of combined or individual inhibition of peptidolytically active immunoproteasome LMP7 (β5i) and LMP2 (β1i) subunits on immune rejection-mediated TA was investigated using the epoxyketone inhibitor ONX 0914, and the recently developed LMP7-selective inhibitor KZR-329 and LMP2-selective inhibitor KZR-504 in a rat aorta transplantation model. We find that co-inhibition of LMP7 and LMP2 in allogeneic recipients significantly suppressed T-cell activation and function by expressing inhibitory surface markers and then activating inhibitory signals. Moreover, co-inhibition of LMP7 and LMP2 substantially reduced the number of immunoglobulin G-secreting cells and plasma cells and production of alloantibodies through activating the unfolded protein response and incapacitating the survival niche of plasma cells in the bone marrow. Consequentially, the accumulation of inflammatory cytokines, complement, and antibodies is reduced and the apoptosis of vascular wall cells decreased in aortic allografts via LMP7 and LMP2 co-inhibition with ONX 0914 treatment or combined KZR-329 and KZR-504 treatment. However, neither individual inhibition of LMP7 by KZR-329 nor individual inhibition of LMP2 by KZR-504 showed suppression of immune rejection and TA. Conclusions We define a critical role of LMP7 and LMP2 in TA and strongly propose co-inhibition of both immunoproteasome subunits as promising therapeutic approach to suppress TA and allograft rejection. [ABSTRACT FROM AUTHOR]