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Evidence for a flavor asymmetry between the ū and d¯ quark distributions in the proton has been found in deep-inelastic scattering and Drell-Yan experiments. The pronounced dependence of this flavor asymmetry on x (fraction of nucleon momentum carried by partons) observed in the Fermilab E866 Drell-Yan experiment suggested a drop of the d¯(x)/ū(x) ratio in the x>0.15 region. We report results from the SeaQuest Fermilab E906 experiment with improved statistical precision for d¯(x)/ū(x) in the large x region up to x=0.45 using the 120 GeV proton beam. Two different methods for extracting the Drell-Yan cross section ratios, σpd/2σpp, from the SeaQuest data give consistent results. The d¯(x)/ū(x) ratios and the d¯(x)-ū(x) differences are deduced from these cross section ratios for 0.13

In Fig. 1c of this Article, the x-axis scale was inadvertently duplicated from Fig. 1b. The original Article has been corrected online.

The fundamental building blocks of the proton-quarks and gluons-have been known for decades. However, we still have an incomplete theoretical and experimental understanding of how these particles and their dynamics give rise to the quantum bound state of the proton and its physical properties, such as its spin1. The two up quarks and the single down quark that comprise the proton in the simplest picture account only for a few per cent of the proton mass, the bulk of which is in the form of quark kinetic and potential energy and gluon energy from the strong force2. An essential feature of this force, as described by quantum chromodynamics, is its ability to create matter-antimatter quark pairs inside the proton that exist only for a very short time. Their fleeting existence makes the antimatter quarks within protons difficult to study, but their existence is discernible in reactions in which a matter-antimatter quark pair annihilates. In this picture of quark-antiquark creation by the strong force, the probability distributions as a function of momentum for the presence of up and down antimatter quarks should be nearly identical, given that their masses are very similar and small compared to the mass of the proton3. Here we provide evidence from muon pair production measurements that these distributions are considerably different, with more abundant down antimatter quarks than up antimatter quarks over a wide range of momenta. These results are expected to revive interest in several proposed mechanisms for the origin of this antimatter asymmetry in the proton that had been disfavoured by previous results4, and point to future measurements that can distinguish between these mechanisms.

The SeaQuest spectrometer at Fermilab was designed to detect oppositely-charged pairs of muons (dimuons) produced by interactions between a 120 GeV proton beam and liquid hydrogen, liquid deuterium and solid nuclear targets. The primary physics program uses the Drell–Yan process to probe antiquark distributions in the target nucleon. The spectrometer consists of a target system, two dipole magnets and four detector stations. The upstream magnet is a closed-aperture solid iron magnet which also serves as the beam dump, while the second magnet is an open aperture magnet. Each of the detector stations consists of scintillator hodoscopes and a high-resolution tracking device. The FPGA-based trigger compares the hodoscope signals to a set of pre-programmed roads to determine if the event contains oppositely-signed, high-mass muon pairs.

Objectives: To assess whether the publication of the EVAR Trial 1 (June 2005) had an impact on practice in our centre.Methods: A retrospective study of all patients undergoing abdominal aortic aneurysm (AAA) repair in Leicester, from the year before publication of EVAR Trial 1 data to the year after (July 2004 - June 2006). Data from the study period was then compared with practice over the last six years (January 2000 - December 2006).Results: The proportion of endovascular aneurysm repairs (EVARs) did not change significantly in the year following publication of EVAR Trial 1 data (52% VS 57%, p=0.64). The mean age of patients offered open repair (OR) fell in the year following publication (69 years +/- 6.68 vs 72 years +/- 5.71, p<0.05). Despite this, there was no significant change in their fitness (physiological POSSUM scores: 19.2 +/- 3.91 vs 18.2 +/- 3.74, P=0.30). There was an overall increase in the percentage of EVARs in the years 2000 (28%) to 2006 (57%).Conclusion: There was no significant difference in the percentage of EVARs between the two years of study. However, over the last six years, there has been an increasing number performed in our unit and we now do more EVARs than ORs. [ABSTRACT FROM AUTHOR]

CONTEXT: Computerized neuropsychological testing is used in athletics; however, normative data on an athletic population are lacking. OBJECTIVE: To investigate factors, such as sex, SAT score, alertness, and sport, and their effects on baseline neuropsychological test scores. A secondary purpose was to begin establishing preliminary reference data for nonsymptomatic collegiate athletes. DESIGN: Observational study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: The study population comprised 327 National Collegiate Athletic Association Division I athletes from 12 men's and women's sports. MAIN OUTCOME MEASURE(S): Athletes were baseline tested before their first competitive season. Athletes completed demographics forms and self-reported history of concussion (1 or no concussion and 2 or more concussions) and SAT scores (<1000, 1000 to 1200, and >1200). The 108 women had a mean age of 18.39 +/- 0.09 years, height of 167.94 +/- 0.86 cm, and mass of 62.36 +/- 1.07 kg. The 219 men had a mean age of 18.49 +/- 0.07 years, height of 183.24 +/- 1.68 cm, and mass of 88.05 +/- 1.82 kg. Sports participation included women's soccer, lacrosse, basketball, and field hockey; men's football, soccer, lacrosse, and wrestling; and women's and men's track and cheerleading. We used the Automated Neuropsychological Assessment Metrics (Army Medical Research and Materiel Command, Ft Detrick, MD) and measured throughput scores (the number of correct responses per minute) as the dependent variable for each subtest, with higher scores reflecting increased speed and accuracy of responses. Subsets included 2 simple reaction time (SRT) tests, math processing (MTH), Sternberg memory search (ST6), matching to sample pairs (MSP), procedural reaction time (PRO), code digit substitution (CDS), and the Stanford sleep scale Likert-type score. RESULTS: Women scored better than men on the ST6 (P < .05), while men scored significantly better than women on the SRT and MSP tests. The highest-scoring SAT group performed better than other SAT groups on selected subtests (SRT, MTH, ST6, MSP, and CDS) (P < .05), and athletes tested during their season were more likely to score lower on the alertness scale (chi(2) (2)[n = 322] = 11.32, P = .003). The lowest alertness group performed worse on the MSP and CDS subtests (P < .05). No differences were found between the group with a history of 1 or no concussion and the group with a history of 2 or more concussions (P > .05). CONCLUSIONS: Performance on computerized neuropsychological tests may be affected by a number of factors, including sex, SAT scores, alertness at the time of testing, and the athlete's sport. To avoid making clinical misinterpretations, clinicians should acknowledge that individual baselines vary over time and should account for this variation. [ABSTRACT FROM AUTHOR]

Context: Deficits in static and dynamic stability during singleleg stance have been noted in individuals with chronic ankle instability (CAI), but few investigators have tested subjects for subtle deficits in dynamic balance. Subtle deficits in dynamic balance during a double-leg stance may reveal changes in the sensorimotor system because of CAI. Objective: To use a standardized tibial nerve stimulation as a perturbation to test for dynamic balance deficits between a group of recreational athletes with CAI and a group of recreational athletes with stable ankles. Design: Case-control study. Setting: Laboratory. Patients or Other Participants: Twenty recreational athletes with CAI and 20 recreational athletes with stable ankles. Intervention(s): Balance deficits were assessed for each subject during static and dynamic trials. Main Outcome Measure(s): Time to stabilization and centerof- pressure excursion path length, velocity, and area from ground reaction forces during double-leg stance were collected through a forceplate. We used an accelerometer to measure tibial acceleration. Data were collected during static stance and during a bilateral perturbation using maximal motor neuron recruitment elicited by electric stimulation of the tibial nerve. Results: Only time to stabilization in the anterior-posterior direction was significantly different between groups (P = .04), with the CAI group taking longer to return to a stable range of ground reaction forces. We found no other differences in stability measures between the groups. Conclusions: Dynamic balance in double-leg stance as measured by time to stabilization appears to be affected in individuals with CAI. Deficits in the response to external perturbation may indicate subtle central sensorimotor changes. [ABSTRACT FROM AUTHOR]

Background: Biofortified Zinc Flour to Eliminate Deficiency in Pakistan (BiZiFED) is a nutritional research program that evaluates the impact of consuming zinc biofortified wheat flour on zinc status and associated health outcomes of vulnerable communities in northwest Pakistan. Measuring zinc status from blood samples is fraught with problems. This feasibility study evaluated whether metabolite changes in tear biofluids could be used to understand zinc status., Methods: Zinc deficiency is particularly prevalent amongst the female population in Pakistan. Therefore, a crossover trial was developed in which 25 women of reproductive age received standard, wheat flour, and another 25 received zinc-biofortified wheat flour for 8 weeks. At the end of this period, the nutritional intervention was switched between the groups for another 8 weeks. Tear biofluid was collected using Schirmer strips at baseline and after 8 and 16 weeks. Metabolomic analysis was conducted using the MxP ® Quant 500 kit on the tear biofluid from a subset of the study participants., Results: Two metabolites had a significantly negative correlation with plasma zinc concentration: tiglylcarnitine and valine. Compared to baseline metabolite concentrations, acetylcarnitine, glutamine, two lysophosphatidylcholines (lysoPC a C16:0 and lysoPC a C18:1), and four sphingomyelins (SM (OH) C16:1, SM C16:0, SM C16:1, and SM C24:0) were all significantly decreased post-zinc intervention, whilst a ceramide (Cer(d18:1/18:0) was significantly increased., Conclusion: These results highlight the potential of using tear biofluids as an alternative source for metabolomic biomarkers, both for the assessment of the zinc status of individuals enrolled in nutritional studies and for indicating physiological changes that arise from nutritional supplementation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brown, Shahzad, Zaman, Pan, Green, Lowe and Lengyel.)

The Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII) is a ubiquitous mediator of cellular Ca 2+ signals with both enzymatic and structural functions. Here, we briefly introduce the complex regulation of CaMKII and then provide a comprehensive overview of the expanding toolbox to study CaMKII. Beyond a variety of distinct mutants, these tools now include optical methods for measurement and manipulation, with the latter including light-induced inhibition, stimulation, and sequestration. Perhaps most importantly, there are now three mechanistically distinct classes of specific CaMKII inhibitors, and their combined use enables the interrogation of CaMKII functions in a manner that is powerful and sophisticated yet also accessible. This review aims to provide guidelines for the interpretation of the results obtained with these tools, with careful consideration of their direct and indirect effects., Competing Interests: Declaration of interests K.U.B. is co-founder and board member of Neurexis Therapeutics, a company that seeks to develop a CaMKII inhibitor into a therapeutic drug for cerebral ischemia., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether individuals with a prior concussion exhibit biomechanical alterations in balance, gait and jump-landing tasks with and without cognitive demands that are associated with risk of lateral ankle sprain (LAS) and anterior cruciate ligament (ACL) injury., Design: Systematic review and meta-analysis., Data Sources: Five electronic databases (Web of Science, Scopus, PubMed, SPORTDiscus and CiNAHL) were searched in April 2023., Eligibility Criteria: Included studies involved (1) concussed participants, (2) outcome measures of spatiotemporal, kinematic or kinetic data and (3) a comparison or the data necessary to compare biomechanical variables between individuals with and without concussion history or before and after a concussion., Results: Twenty-seven studies were included involving 1544 participants (concussion group (n=757); non-concussion group (n=787)). Individuals with a recent concussion history (within 2 months) had decreased postural stability (g=0.34, 95% CI 0.20 to 0.49, p<0.001) and slower locomotion-related performance (g=0.26, 95% CI 0.11 to 0.41, p<0.001), both of which are associated with LAS injury risk. Furthermore, alterations in frontal plane kinetics (g=0.41, 95% CI 0.03 to 0.79, p=0.033) and sagittal plane kinematics (g=0.30, 95% CI 0.11 to 0.50, p=0.002) were observed in individuals approximately 2 years following concussion, both of which are associated with ACL injury risk. The moderator analyses indicated cognitive demands (ie, working memory, inhibitory control tasks) affected frontal plane kinematics (p=0.009), but not sagittal plane kinematics and locomotion-related performance, between the concussion and non-concussion groups., Conclusion: Following a recent concussion, individuals display decreased postural stability and slower locomotion-related performance, both of which are associated with LAS injury risk. Moreover, individuals within 2 years following a concussion also adopt a more erect landing posture with greater knee internal adduction moment, both of which are associated with ACL injury risk. While adding cognitive demands to jump-landing tasks affected frontal plane kinematics during landing, the altered movement patterns in locomotion and sagittal plane kinematics postconcussion persisted regardless of additional cognitive demands., Prospero Registration Number: CRD42021248916., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging., Design: Experimental study with clinicopathological correlation., Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison., Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient., Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease., Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole., Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Crown Copyright © 2023 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology.)

Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) 1-3 . However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP 4-8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B 9-14 . Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked., (© 2023. The Author(s).)

The Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with the neuroprotective peptide tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. These results were obtained with ≥500-fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce the return of spontaneous circulation. Of additional importance for therapy development, our preliminary cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, although prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy., Competing Interests: Conflict of interest K. U. B. is co-founder and board member of Neurexis Therapeutics, a company that seeks to develop the tatCN19o inhibitor of CaMKII into a therapeutic drug for cerebral ischemia. O. R. B. is director of research and development at the same company., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Herein, we report the crystal structure of 2,7-dichlorofluorescein methyl ester (DCF-ME) and its fluorescence response to hydroxyapatite binding. The reported fluorophore is very selective for staining the bone matrix and provides turn-on fluorescence upon hydroxyapatite binding. The reported fluorophore can readily pass the cell membrane of the C2C12 cell line, and it is non-toxic for the cell line. The reported fluorophore DCF-ME may find applications in monitoring bone remodeling and microcalcification as an early diagnosis tool for breast cancer and age-related macular degeneration., Competing Interests: Conflicts of interest R. B. T. is a principal of Pokegama Technologies, Inc.; no conflict declared.

Context: Health care utilization and the occurrence of non-time-loss (NTL) lateral ankle sprains is not well documented in collegiate athletes but could provide better estimates of injury burden and inform clinician workload., Design: Descriptive epidemiologic study., Methods: Lateral ankle sprain injury occurrence for Division I collegiate student-athletes in a conference with 32 sports representing 732 team seasons was collected during the 2018-2019 through 2020-2021 academic years. Injuries were designated as acute or overuse, and time-loss (TL) or NTL. Associated health care utilization, including athletic training services (AT services), and physician encounters were reported along with anatomical structures involved and season of occurrence., Results: A total of 1242 lateral ankle sprains were reported over the 3 years from 732 team seasons and 17,431 player seasons, resulting in 12,728 AT services and 370 physician encounters. Most lateral ankle sprains were acute-TL (59.7%), which were associated with the majority of AT services (74.1%) and physician encounters (70.0%). Acute-NTL sprains represented 37.8% of lateral ankle sprains and were associated with 22.3% of AT services and 27.0% of physician encounters. On average, there were 12.7 (5.8) AT services per acute-TL sprain and 6.0 (3.6) per acute-NTL sprain. Most sprains involved "ankle lateral ligaments" (45.6%), and very few were attributed to overuse mechanisms (2.4%)., Conclusions: Lateral ligament sprains are a common injury across many sports and result in substantial health care utilization from ATs and physicians, including NTL lateral ankle sprains. Although TL injuries were the majority of sprains, a substantial proportion of sprains were NTL and accounted for a considerable proportion of health care utilization.

Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this Aβ-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct Aβ binding. However, our study did not find any evidence for direct effects of Aβ on CaMKII: Aβ did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation, or kinase activity in vitro . Most importantly, in neurons, the Aβ-induced impairment of CaMKII synaptic accumulation was prevented by an ATP-competitive CaMKII inhibitor that would not interfere with the putative direct Aβ binding. Together, our results indicate that synaptic Aβ effects are not mediated by direct binding to CaMKII, but instead require CaMKII activation via indirect signaling events., Competing Interests: The University of Colorado holds the patent rights for a CaMKII inhibitor mentioned in this study, tatCN21, its derivatives, and their uses (PCT/US08/077934 ‘‘Compositions and methods for improved CaMKII inhibitors and uses thereof’’). K.U.B. is co-founder and board member of Neurexis Therapeutics., (© 2022 The Authors.)

The role of mechanical laxity and viscoelastic tissue properties in chronic ankle instability (CAI) is unclear, but may influence repeated injury. The purpose was to determine if lateral ankle complex stiffness and hysteresis was altered in CAI individuals with and without mechanical laxity, compared to copers and uninjured controls. Thirty-five recreational athletes (19 females, 22.1 ± 2.7 years, 69.7 ± 15.7 kg, 168.4 ± 10.7 cm) were assessed for ankle injury history and self-reported instability. An instrumented arthrometer was applied and laxity, stiffness and hysteresis values were captured. Results from ANOVA tests indicated the CAI with laxity group had lower beginning- (3.2 ± 0.6 N/mm) and end-range stiffness (4.5 ± 0.4 N/mm) than the CAI without laxity group (4.7 ± 0.6; 6.0 ± 0.6 N/mm) and uninjured controls (4.6 ± 1.1; 5.8 ± 0.8 N/mm, p < 0.003). Hysteresis was greater in the CAI with laxity group than without laxity (91.0 ± 17.3 vs 62.8 ± 12.0 dN•mm; p = 0.03). Altered tissue properties in a CAI with laxity group likely indicate diminished ability of the lateral ankle complex to respond to loading. Accurately assessing, then avoiding or restoring tissue impairments after injury, may encourage better patient outcomes.

During a visit to Europe in the autumn of 1882, Henry Augustus Rowland, Professor of Physics at Johns Hopkins University, displayed diffraction gratings produced on a ruling engine he had designed and built, which were bigger and much higher quality than any previously made. Some were of a novel type, ruled on concave surfaces, which he used in a simple but equally novel spectroscope that he had devised, to reveal spectral lines in great detail, and by means of photography to record spectral data much more rapidly than previously possible. Over about twenty years Rowland built three ruling engines, published photographic maps of the solar spectrum, compiled a catalogue of the wavelengths of lines in the solar spectrum correlated with laboratory-produced spectra of almost all the chemical elements, and produced and sold the diffraction gratings used by spectroscopists everywhere. For decades after his death Rowland's ruling engines remained practically the only source of good-quality diffraction gratings. This paper describes and analyses this work of Rowland and of the other men, Theodore Schneider, John Brashear, and Lewis Jewell, who played major roles in it.

The Ca 2+ /Calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity and has been implicated in various neurological conditions, including schizophrenia. Here, we characterize six different CaMKIIα variants found in patients with schizophrenia. Only R396stop disrupted the 12-meric holoenzyme structure, GluN2B binding, and synaptic localization. Additionally, R396stop impaired T286 autophosphorylation that generates Ca 2+ -independent "autonomous" kinase activity. This impairment in T286 autophosphorylation was shared by the R8H mutation, the only mutation that additionally reduced stimulated kinase activity. None of the mutations affected the levels of CaMKII expression in HEK293 cells. Thus, impaired CaMKII function was detected only for R396stop and R8H. However, two of the other mutations have been later identified also in the general population, and not all mutations found in patients with schizophrenia would be expected to cause disease. Nonetheless, for the R396stop mutation, the severity of the biochemical effects found here would predict a neurological phenotype., Competing Interests: K.U.B. is co-founder and board member of Neurexis Therapeutics, a company that seeks to develop a CaMKII inhibitor into a therapeutic drug for cerebral ischemia. The other authors declare that they have nothing to disclose., (© 2021 The Author(s).)

Clinical Scenario: Ulnar collateral ligament injuries are common in baseball pitchers, with excessive elbow varus torque linked to medial elbow injuries. Trunk tilt, or motion in the frontal plane, could be an identifiable and modifiable factor in medial elbow loading. Clinical Question: In high school through professional baseball pitchers, how does increased contralateral trunk tilt compared with no/limited contralateral trunk tilt influence elbow varus torque? Summary of Key Findings: Four studies were included: all were labeled as "controlled" or "descriptive laboratory studies," representing cross-sectional observational analytic design. One study compared biomechanics of professional pitchers with and without ulnar collateral ligament reconstruction. Two studies measured biomechanics in college pitchers, one of which also included simulations of joint angles. The fourth study measured biomechanics of high school pitchers. All studies measured trunk tilt and its relationship to elbow varus torque, with 3 of the studies linking increased contralateral trunk tilt with increased elbow varus torque. Clinical Bottom Line: Moderate evidence indicated as contralateral trunk tilt increased, so did elbow varus torque, indicating trunk tilt may be a modifiable factor to decrease medial elbow loading during pitching. Strength of Recommendation: Majority consistent findings from the level 3 cross-sectional observational analytic designs suggest grade B evidence in support of trunk tilt as a factor in increasing elbow varus torque.

The purpose of the present study was to examine the effect of chronic ankle instability (CAI) on lower-extremity joint coordination and stiffness during landing. A total of 21 female participants with CAI and 21 pair-matched healthy controls participated in the study. Lower-extremity joint kinematics were collected using a 7-camera motion capture system, and ground reaction forces were collected using 2 force plates during drop landings. Coupling angles were computed based on the vector coding method to assess joint coordination. Coupling angles were compared between the CAI and control groups using circular Watson-Williams tests. Joint stiffness was compared between the groups using independent t tests. Participants with CAI exhibited strategies involving altered joint coordination including a knee flexion dominant pattern during 30% and 70% of their landing phase and a more in-phase motion pattern between the knee and hip joints during 30% and 40% and 90% and 100% of the landing phase. In addition, increased ankle inversion and knee flexion stiffness were observed in the CAI group. These altered joint coordination and stiffness could be considered as a protective strategy utilized to effectively absorb energy, stabilize the body and ankle, and prevent excessive ankle inversion. However, this strategy could result in greater mechanical demands on the knee joint.

Many surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy. Genes associated with lysosomal biogenesis and function were decreased in sham surgery and UNX kidneys. In both sham surgery and UNX, there was suppressed autophagic flux in the kidney as indicated by the lack of an increase in LC3-II or autophagosomes seen on immunoblot, IF and EM after bafilomycin A1 administration and a concomitant increase in p62, a marker of autophagic cargo. There was a massive increase in pro-inflammatory cytokines, which are known to activate ERK1/2, in the serum after sham surgery and UNX. There was a large increase in ERK1/2 in sham surgery and UNX kidneys, which was blocked by the MEK1/2 inhibitor, trametinib. Trametinib also resulted in a significant decrease in p62. In summary, there was an intense systemic inflammatory response, an ERK-mediated increase in p62 and suppressed autophagic flux in the kidney after sham surgery and UNX. It is important that researchers are aware that changes in systemic pro-inflammatory cytokines, ERK1/2 and autophagy can be caused by sham surgery as well as the kidney injury/disease itself.

Background: Enhanced recovery after surgery (ERAS) is increasingly used in plastic surgery to optimize patient care. Mitigating the risk of postoperative complications is particularly important in patients with risk factors, such as obesity. The objective of this study is to evaluate the impact of the ERAS pathway in patients, stratified by BMI, undergoing free flap breast reconstruction on length of stay and complications., Methods: A retrospective review of all patients who underwent abdominally based free flap breast reconstruction from January 2014 to December 2017 was performed. Data collected include participation in the ERAS protocol, patient demographics, length of stay (LOS), complications (minor and major), and 30-day reoperation rates., Results: A total of 123 patients met the inclusion criteria, with 36 non-ERAS and 87 ERAS patients. ERAS patients had a shorter length of stay than non-ERAS patients (4.14 vs. 4.69, p = 0.049). Higher BMI patients progressively benefited from their involvement in an ERAS pathway: class I obese patients had an LOS decrease of 0.99 days (p = 0.048) and class II+ obese patients had an LOS decrease of 1.35 days (p = 0.093). Minor complications, major complications, and reoperation rates were similar between ERAS and non-ERAS patients (p>0.05)., Conclusion: Utilization of an ERAS protocol for free flap breast reconstruction safely decreases LOS, especially with increasing BMI. Patients benefit from an ERAS protocol without increasing risk of postoperative complications, compared to non-ERAS patients of similar BMIs., Competing Interests: Declaration of Competing Interest All authors do not have any financial or personal relationships with other people or organizations that could inappropriately influence this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Understanding the mechanisms underpinning individual variance in addiction vulnerability requires the development of validated, high-throughput screens. In a prior study of a large sample of male isogenic C57BL/6J mice, the direction and magnitude of methamphetamine (MA)-induced place-conditioning predicts the propensity to acquire oral MA self-administration, as well as the efficacy of MA to serve as a reinforcer. The present study examined whether or not such a predictive relationship also exists in females. Adult C57BL/6J females underwent a 4-day MA place-conditioning paradigm (once daily injections of 2 mg/kg) and were then trained to nose-poke for delivery of a 20 mg/L MA solution under increasing schedules of reinforcement, followed by dose-response testing (5-400 mg/L MA). Akin to males, 53 % of the females exhibited a conditioned place-preference, while 32 % of the mice were MA-neutral and 15 % exhibited a conditioned place-aversion. However, unlike males, the place-conditioning phenotype did not transfer to MA-reinforced nose-poking behavior under operant-conditioning procedures, with 400 mg/L MA intake being inversely correlated place-conditioning. While only one MA-conditioning dose has been assayed to date, these data indicate that sex does not significantly shift the proportion of C57BL/6J mice that perceive MA's interoceptive effects as positive, neutral or aversive. However, a sex difference appears to exist regarding the predictive relationship between the motivational valence of MA and subsequent drug-taking behavior; females exhibit MA-taking behavior and reinforcement, despite their initial perception of the stimulant interoceptive effects as positive, neutral or negative., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by kidney cyst growth often resulting in end-stage renal disease. There is growing attention on understanding the role of impaired autophagy in ADPKD. Trehalose (TRE) has been shown to increase both protein stability and aggregate clearance and induce autophagy in neurodegenerative diseases. TRE treatment in wild type mice compared to vehicle resulted in increased expression in the kidney of Atg12-5 complex and increased Rab9a, autophagy-related proteins that play a role in the formation of autophagosomes. Thus, the aim of the study was to determine the effect of TRE on cyst growth and autophagy-related proteins, in the hypomorphic Pkd1 RC/RC mouse model of ADPKD. Pkd1 RC/RC mice were treated 2% TRE in water from days 50 to 120 of age. TRE did not slow cyst growth or improve kidney function or affect proliferation and apoptosis in Pkd1 RC/RC kidneys. In Pkd1 RC/RC vs. wild type kidneys, expression of the Atg12-5 complex was inhibited by TRE resulting in increased free Atg12 and TRE was unable to rescue the deficiency of the Atg12-5 complex. Rab9a was decreased in Pkd1 RC/RC vs. wild type kidneys and unaffected by TRE. The TRE-induced increase in p62, a marker of autophagic cargo, that was seen in normal kidneys was blocked in Pkd1 RC/RC kidneys. In summary, the autophagy phenotype in Pkd1 RC/RC kidneys was characterized by decreases in crucial autophagy-related proteins (Atg12-5 complex, Atg5, Atg16L1), decreased Rab9a and increased mTORC1 (pS6 S240/244 , pmTOR S2448 ) proteins. TRE increased Atg12-5 complex, Rab9a and p62 in normal kidneys, but was unable to rescue the deficiency in autophagy proteins or suppress mTORC1 in Pkd1 RC/RC kidneys and did not protect against cyst growth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1 RC/RC and Pkd2 WS25/+ mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1 RC/RC mouse model of PKD. In 70 day old Pkd1 RC/RC hearts, on immunoblot analysis, there was a large increase in p-AMPK Thr172 , a known autophagy inducer, and an increase in p-Akt Ser473 and p-Akt Thr308 , but no increase in other mTORC1/2 proteins (p-S6 Ser240/244 , p-mTOR Ser2448 ). In 150 day old Pkd1 RC/RC hearts, there was an increase in mTORC1 (p-S6 Ser240/244 ) and mTOR-related proteins (p-Akt Thr308 , p-GSK3β Ser9 , p-AMPK Thr172 ). As the mTOR pathway is the master regulator of autophagy, autophagy proteins were measured. There was an increase in p-Beclin-1 (BECN1), an autophagy regulator and activating molecule in Beclin-1-regulated autophagy (AMBRA1), a regulator of Beclin that play a role in autophagosome formation, an early stage of autophagy. There was a defect in the later stage of autophagy, the fusion of the autophagosome with the lysosome, known as autophagic flux, as evidenced by the lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin, in both 70 day old and 150 day old hearts. To determine the role of autophagy in causing increased heart weight, Pkd1 RC/RC were treated with 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide, agents known to induce autophagy. 2-DG treatment from 150 to 350 days of age, a time period when increased heart weight developed, did not reduce the increased heart weight. Unexpectedly, Tat-Beclin 1 peptide treatment from 70 to 120 days of age resulted in increased heart weight. In summary, there is suppressed autophagic flux in the heart at an early age in Pkd1 RC/RC mice. Increased mTOR signaling in older mice is associated suppressed autophagic flux. There was a large increase in p-AMPK Thr172 , a known autophagy inducer, in both young and old mice. 2-DG treatment did not impact increased heart weight and Tat-Beclin1 peptide increased heart weight., (Copyright © 2020 Elsevier Inc. All rights reserved.)

CaMKII is an important mediator of forms of synaptic plasticity that are thought to underly learning and memory. The CaMKII mutants K42M and K42R have been used interchangeably as research tools, although some reported phenotypic differences suggest that they may differ in the extent to which they impair ATP binding. Here, we directly compared the two mutations at the high ATP concentrations that exist within cells (~4 mM). We found that both mutations equally blocked GluA1 phosphorylation in vitro and GluN2B binding within cells. Both mutations also reduced but did not completely abolish CaMKII T286 autophosphorylation in vitro or CaMKII movement to excitatory synapses in neurons. Thus, despite previously suggested differences, both mutations appear to interfere with ATP binding to the same extent., Competing Interests: No authors have competing interests.

One of the highest concentrations of swine and poultry concentrated animal feeding operations (CAFOs) in North America is located on the Coastal Plain of North Carolina, in which the Cape Fear River basin is located. The CAFOs produce vast amounts of manure causing loading of nutrients and other pollutants to receiving waters. With the Cape Fear River basin vulnerable to nutrient pollution, as are many other watersheds with CAFOs, δ 13 C and δ 15 N stable isotopic signatures were identified from water samples collected within the Northeast Cape Fear, Black, and lower Cape Fear River watersheds to trace nutrient sources and their distribution downstream. The spatial and temporal variability of nutrients and isotopic signatures were also identified to understand water quality impacts of animal waste spraying season and proximity to CAFOs. Our results showed that significantly enriched δ 15 N signatures characterized sites in close proximity to CAFOs as well as point-source wastewater discharge areas, while the opposite was true for an unimpacted control stream and two estuarine sites. Additionally, the impacted sites yielded significantly (p < 0.05) higher nitrate concentrations than control and estuarine sites. Statistical analyses demonstrated that nitrate concentrations were positively correlated with heavier δ 15 N signatures, suggesting that animal waste, as well as human wastewater, are relatively more important sources of N to this large watershed than fertilizers from traditional row crop agriculture. Our results also suggested that during appropriate hydrological conditions CAFO-derived N can be detected many kilometers downstream from freshwater sources areas to the estuary.

In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) G12V mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI. Genes that were significantly decreased by U0126 were heat shock protein 1, cyclin-dependent kinase 4 (CDK4) and stratifin (14-3-3σ). U0126 resulted in a significant decrease in tumor weight and volume and significantly increased the chemotherapeutic effect of cisplatin. Trametinib, a MEK1/2 inhibitor that is FDA-approved for the treatment of cancer, did not result in functional protection against AKI or worse AKI, but dramatically decreased tumor growth more than cisplatin. Smaller tumors in cisplatin or MEK1/2 inhibitor-treated mice were not related to changes in microtubule-associated proteins 1A/1B light chain 3B (LC3-II), p62, cleaved caspase-3, granzyme B, or programmed death-ligand 1 (PD-L1). In summary, despite ERK inhibition by both U0126 and trametinib, only U0126 protected against AKI suggesting that the protection against AKI by U0126 was due to an off-target effect independent of ERK inhibition. The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14-3-3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical Scenario: Deformation of the arch, as measured by navicular drop (ND), is linked to lower-extremity musculoskeletal injuries. The short foot exercise (SFE) has been used to strengthen the intrinsic foot muscles that support the arch. Clinical Question: Does the SFE decrease ND in healthy adults? Summary of Key Findings: Three studies that examined the use of the SFE on ND were included. A randomized control trial that compared the SFE to a towel-curl exercise and a control group found no significant differences between the 3 groups. A randomized control trial compared the SFE to the use of arch support insoles in individuals with a flexible flatfoot and found a significant improvement in the SFE group. A prospective cohort study, without a control group, reported a significant decrease in ND following a 4-week SFE intervention without a regression at an 8-week follow-up. Overall, two of the three studies reported a significant reduction in ND following an SFE. Clinical Bottom Line: There is preliminary data supporting the use of the SFE to decrease ND-particularly in individuals with a flexible flatfoot. However, issues with the study designs make it difficult to interpret the data. Strength of Recommendation: Due to limited evidence, there is grade B evidence to support the use of the SFE to decrease ND.

Objective: Purpose of the study was to compare lower-limb kinematics and interlimb asymmetry during stair ascent in individuals post-medial or lateral unicompartmental knee arthroplasty (UKA)., Methods: 60 patients (20 medial; 10 lateral) post-UKA and 30 matched healthy controls performed stair ascent. Spatio-temporal, lower-limb kinematics and interlimb asymmetries during stair ascent were compared., Results: Medial-UKA group displayed 5° less knee extension of the UKA limb than controls (p = 0.005) and 2° less than the contralateral limb during stance phase. No interlimb asymmetries were found for lateral-UKA., Conclusion: Patients post-UKA demonstrate satisfactory lower-limb kinematics and minimal interlimb asymmetry during stair ascent compared to healthy individuals., Competing Interests: Study was supported by a research grant from 10.13039/100007307Arthrex, Inc., (© 2020 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Problems associated with the abuse of amphetamine-type stimulants, including methamphetamine (MA), pose serious health and socioeconomic issues world-wide. While it is well-established that MA's psychopharmacological effects involve interactions with monoamine neurotransmission, accumulating evidence from animal models implicates dysregulated glutamate in MA addiction vulnerability and use disorder. Recently, we discovered an association between genetic vulnerability to MA-taking and increased expression of the glutamate receptor scaffolding protein Homer2 within both the shell and core subregions of the nucleus accumbens (NAC) and demonstrated a necessary role for Homer2 within the shell subregion in MA reward and reinforcement in mice. This report extends our earlier work by interrogating the functional relevance of Homer2 within the NAC core for the conditioned rewarding and reinforcing properties of MA. C57BL/6J mice with a virus-mediated knockdown of Homer2b expression within the NAC core were first tested for the development and expression of a MA-induced conditioned place-preference/CPP (four pairings of 2 mg/kg MA) and then were trained to self-administer oral MA under operant-conditioning procedures (5-80 mg/L). Homer2b knockdown in the NAC core augmented a MA-CPP and shifted the dose-response function for MA-reinforced responding, above control levels. To determine whether Homer2b within NAC subregions played an active role in regulating MA reward and reinforcement, we characterized the MA phenotype of constitutive Homer2 knockout (KO) mice and then assayed the effects of virus-mediated overexpression of Homer2b within the NAC shell and core of wild-type and KO mice. In line with the results of NAC core knockdown, Homer2 deletion potentiated MA-induced CPP, MA-reinforced responding and intake, as well as both cue- and MA-primed reinstatement of MA-seeking following extinction. However, there was no effect of Homer2b overexpression within the NAC core or the shell on the KO phenotype. These data provide new evidence indicating a globally suppressive role for Homer2 in MA-seeking and MA-taking but argue against specific NAC subregions as the neural loci through which Homer2 actively regulates MA addiction-related behaviors., (Copyright © 2020 Brown, Fultz, Ferdousian, Rogers, Lustig, Page, Shahin, Flaherty, Von Jonquieres, Bryant, Kippin and Szumlinski.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, characterized by cyst formation and growth. Hyperproliferation is a major contributor to cyst growth. At the nexus of regulating proliferation, is 4E-BP1. We demonstrate that ADPKD mouse and rat models, ADPKD patient renal biopsies and PKD1-/- cells exhibited hyperphosphorylated 4E-BP1, a biomarker of increased translation and proliferation. We hypothesized that expression of constitutively active 4E-BP1 constructs (4E-BP1F113A and 4E-BP1R13AF113A) would decrease proliferation and reduce cyst expansion. Utilizing the Pkd1RC/RC mouse, we determined the effect of 4E-BP1F113A on PKD. Unexpectedly, 4E-BP1F113A resulted in increased cyst burden and suppressed apoptosis markers, increased anti-apoptotic Bcl-2 protein and increased mitochondrial proteins. Exogenous 4E-BP1 enhanced proliferation, decreased apoptosis, increased anti-apoptotic Bcl-2 protein, impaired NADPH oxidoreductase activity, increased mitochondrial proteins and increased superoxide production in PKD patient-derived renal epithelial cells. Reduced 4E-BP1 expression suppressed proliferation, restored apoptosis and improved cellular metabolism. These findings provide insight into how cyst-lining cells respond to 4E-BP1., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The synovial fluid (SF) that lubricates articular joints exhibits complex rheological and tribological properties due to the interactions and behaviors of its various molecular components. Under shear, SF films abruptly thicken by more than 300% and large, dense aggregates form within the fluid. In this study, we used the Surface Force Apparatus to elucidate which SF components are involved in this shear-induced transformation by (i) determining which (if any) of all major SF components replicate the behavior of SF under shear and (ii) observing the effect of removing implicated components from SF by enzymatic digestion. While most previous studies of SF have focused on the tribological roles of lubricin or hyaluronic acid, our results indicate that albumin is a key contributor to the formation of aggregates in SF under shear. Our results also suggest that SF aggregation is associated with efficient surface protection against wear. As our findings are based on experiments involving rigid, nonporous surfaces, they may be used to investigate shear-mediated aggregation mechanisms occurring during the lubrication of artificial joints, ultimately advancing our current vision of implant design.

Background: The Identification of Functional Ankle Instability (IdFAI) is a valid and reliable tool to identify chronic ankle instability; however, it was developed in English, thus limiting its usage only to those who can read and write in English. The objectives of our study were to (1) cross-culturally adapt a Chinese (Mandarin) version of the IdFAI and (2) determine the psychometric properties of the Chinese version IdFAI., Methods: The cross-cultural adaptation procedures used by the investigators and translators followed previously published guidelines and included 6 stages: (1) initial translation, (2) synthesis of the translations, (3) back translation, (4) developing the pre-final version for field testing, (5) testing the pre-final version, and (6) finalizing the Chinese version of IdFAI (IdFAI-C). Five psychometric properties of the IdFAI-C were assessed from results of 2 participant groups: bilingual ( n = 20) and Chinese ( n = 625)., Results: A high degree of agreement was found between the English version of IdFAI and IdFAI-C (intra-class correlation 2,1 = 0.995). An excellent internal consistency (Cronbach's α = 0.89), test-retest reliability (intra-class correlation 2,1 = 0.970), and construct validity ( r (625) = 0.67) was also found for the IdFAI-C. In addition, the results of exploratory and confirmatory factor analysis indicated that ankle instability was the only construct measured from the IdFAI., Conclusion: The IdFAI-C is a highly reliable and valid self-report questionnaire that can be used to assess ankle instability. Therefore, we suggest that it can be used to effectively and accurately assess chronic ankle instability in clinical settings for Chinese-speaking individuals., (© 2019 Published by Elsevier B.V. on behalf of Shanghai University of Sport.)

Context: The modified Star Excursion Balance Test (mSEBT) and Y-Balance Test (YBT) are common dynamic postural stability assessments for individuals with chronic ankle instability (CAI). However, the reach distance measurement technique and movement strategy used during the mSEBT and YBT differ. To date, no studies have compared task performance differences on these tests in CAI patients., Objective: To determine whether individuals with CAI perform the mSEBT and YBT differently., Design: Cross-sectional., Setting: Biomechanics laboratory., Participants: Of 97 consented participants, 86 (43 females, 43 males; age 21.5 [3.3] y, height 169.8 [10.3] cm, mass 69.5 [13.4] kg), who reported ≤25 on the Cumberland Ankle Instability Tool, ≥11 on the Identification of Functional Ankle Instability, and had a history of a moderate to severe ankle sprain(s) participated., Interventions: Participants were instructed to perform the mSEBT and YBT in a predetermined counterbalanced order. Three anterior, posteromedial, and posterolateral trials of each test were completed on the involved limb after 4 practice trials. Test direction order was randomized for each participant., Main Outcome Measures: Normalized (expressed in percentage) reach distance in each direction. Paired sample t tests were performed to compare each of the 3 directions between the mSEBT and YBT., Results: Significantly shorter reach distances in the anterior (58.9% [5.8%] vs 61.4% [5.4%], P = .001) and the posteromedial (98.8% [8.6%] vs 100.8% [8.1%], P = .003) directions were noted on the mSEBT relative to the YBT. No differences in the posterolateral directions were observed., Conclusions: Within those with CAI, mSEBT and YBT normalized reach distances differ in the anterior and posteriomedial directions. As a result, clinicians and researchers should not directly compare the results of these tests.