Effects of Stride Length on Lower Limb Stiffness when Running with Body Borne Load

Introduction: During military activities, soldiers are often required to run at a fixed cadence with body borne load, but these loads purportedly increase leg stiffness, leading to increased risk of musculoskeletal injury. Yet, to date, it is unknown how altering stride length when running with body borne load affects lower limb stiffness for males and females. Purpose: To quantify leg stiffness, and lower limb joint (hip, knee and ankle) stiffness for males and females using different stride lengths to run with body borne loads of 20 kg, 25 kg, 30 kg, and 35 kg. Methods: Twenty-seven (17 males and 10 females) participants (age: 21.2 ± 2.3 years, height: 1.7 ± 0.1 m, and weight: 75.5 ± 11.3 kg) had leg and joint stiffness quantified while running at 4 m/s with four load conditions (20, 25, 30, and 35 kg). With each load condition, participants performed three run trials using either: their preferred stride length (PSL) and strides that are 15% longer (LSL) and shorter (SSL) than their PSL. Statistical Analysis: Leg and hip, knee, and ankle stiffness were submitted to a RM ANOVA to test the main effect and interaction of load (20, 25, 30, and 35 kg), stride length (PSL, PSL+15%, and PSL-15%), and sex (male vs female). Results: Body borne load increased leg stiffness (P=0.006). Male participants decreased leg stiffness as stride lengthened from SSL to PSL and PSL to LSL (P=0.026; P0.05). Body borne load increased peak vGRF (PP=0.010; P=0.011), while females only increased peak vGRF between PSL and LSL (PPP=0.013) stiffness increased with the addition of body borne load, but load had no significant effect on hip stiffness (P=0.723). Increasing stride length significant decreased ankle stiffness (P=0.003), but had no effect on hip (P=0.661) or knee (P=0.170) stiffness. Sex had no significant effect on hip (P=0.880), knee (P=0.234), or ankle (P=0.081) stiffness. Conclusion: Running with body borne load increased leg stiffness and potential risk of musculoskeletal injury. But, only male participants decreased leg stiffness and injury risk with longer strides. Both the knee and ankle increased joint stiffness, and risk of musculoskeletal injury with the addition of body borne load. The ankle, however, decreased joint stiffness with longer strides

Stride Length, but Not Body Borne Load Impacts Gait Stability

Military personnel are required to alter their stride length to run with heavy body borne loads during training. This may compromise their gait stability and increase the risk of suffering fall related musculoskeletal injury. This study quantified how running with body borne loads impact gait stability and whether it differed with stride length. Twelve male participants had medial-lateral (ML) gait stability quantified while running 4.0 m/s with four borne loads (20, 25, 30, and 35 kg). Each participant had ML margin of stability (MoS) calculated when using a normal stride (NS), short (SS, -15% of NS), and long stride (LS, +15 of NS) to run. The MoS measures were submitted to RM ANOVA to test main and interactions effects of load (20,25,30, and 35 kg) and stride (NS, SS, LS) with alpha level at

Load and Sex Impact Active Lower Limb Muscle Volume During Running

Military training requires personnel to safely dissipate large ground reaction forces to avert musculoskeletal injury. Training often requires running with heavy body borne loads, but it is currently unknown if active lower limb muscle volume increases when running with load, and whether muscle volume differs between sexes. Thirty-six (20 Male, 16 Female) participants had lower limb muscle volume quantified when running 4.0 m/s with four body borne loads (20, 25, 30, 35 kg). Custom Matlab code calculated hip, knee, and ankle muscle force (Fm=Mjoint/r) and volume (Vm= L×Fm/σ), using moment arm (r), fascicle length (L) and isometric muscle force per unit of cross-sectional area (σ=20N/cm2) data obtained from published work. Muscle volume was submitted to an RM ANOVA to test the main effect and interaction between sex (male, female) and load (20, 25, 30, 35 kg). Alpha was p \u3c 0.05. Females used greater knee muscle volume than males to run with the 20 (p=0.019) and 35 kg (p=0.017), but not 25 (p=0.280) or 30 kg (p=0.534) loads. Load increased active muscle volume increased at the ankle (p=0.012), but not hip (p=0.112) or knee (p=0.887). Sex had no effect on active muscle volume (p\u3e0.05)

Sex Impacts Leg Stiffness When Increasing Stride Length to Run with Body Borne Load

Military personnel routinely run at a fixed cadence with body borne load, which may increase leg stiffness and potential injury risk - particularly for females. Seventeen males and ten females had leg stiffness quantified when running with four loads (20, 25, 30, and 35 kg) and three stride lengths (preferred, and ±15% of preferred). Participants increased leg stiffness (P=0.006), and potentially injury risk when running with load. But, a sex dimorphism in stiffness was evident with changes in stride length. Males exhibited reduced leg stiffness with longer strides (P\u3e0.05)

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

Military Body Borne Load, but Not Sex Impact on Postural Stability

Postural stability is necessary to prevent the musculoskeletal injuries suffered by military personnel during occupational activities. During these activities, military personnel don body borne loads greater than 20 kg, that increase injury risk. Yet it is largely unknown if these body borne load impacts dynamic postural stability, particularly for females. Twenty-six (15 male and 11 female) participants (ht: 1.75±0.1m, wt: 76.98±11.57kg) had dynamic postural stability index (DPSI) quantified during a forward jump with four body borne loads (20, 25, 30 and 35 kg). With each load, participants jumped three times over a of box (16.5 cm) and landed with their dominant limb on a force platform. DPSI, which is a composite indices of Medial-Lateral (MLSI), Anterior-Posterior (APSI) and Vertical (VSI) stability, was quantified for 3 seconds following landing. Each DPSI measure was submitted to a RM ANOVA to examine the main effects and interaction of load and sex. Body borne load significantly decreased DPSI (p\u3c0.001), MLSI p\u3c0.001), and VSI (p\u3c0.001), but not APSI (Insert p-value). However, sex had no significant effect on any measure of DPSI. The reduction of postural stability with body borne load may contribute to the high rate of musculoskeletal injury during occupational military activities