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Pearson, J, Wadhi, T, Barakat, C, Aube, D, Schoenfeld, BJ, Andersen, JC, Barroso, R, Ugrinowitsch, C, and De Souza, EO. Does varying repetition tempo in a single-joint lower body exercise augment muscle size and strength in resistance-trained men? J Strength Cond Res36(8): 2162–2168, 2022—This study compared the effects of FAST and SLOW eccentric repetition tempo in a single exercise volume-matched intervention on muscle thickness (MT) and strength in resistance-trained men. Using a within-subject design, 13 subjects had each leg randomly assigned to SLOW (1-0-3) or FAST (1-0-1) repetition tempo. Subjects underwent an 8-week strength-training (ST) intervention performed twice weekly. Unilateral leg-extension one repetition-maximum (1RM) and anterior thigh MT at the proximal (MTP) and distal (MTD) portions were assessed via ultrasound imaging at baseline and after 8 weeks of RT. Rating of perceived exertion (RPE) assessments of the training sessions (i.e., 16 per leg) were averaged for further analysis. Both legs similarly increased MTP (estimated differences: FAST: 0.24 cm, 3.6%; SLOW: 0.20 cm, 3.1%). However, for MTD, analysis of covariance analysis showed a leg effect (p= 0.02) in which absolute pre-to-post change was greater in FAST compared with SLOW (estimated differences: FAST 0.23 cm, 5.5%; SLOW: 0.13 cm, 2.2%). For 1RM, both legs similarly increased maximum strength (estimated differences: FAST: 9.1 kg, 17.0%; SLOW: 10.4 kg, 22.1%, p≤ 0.0001). The SLOW group had a higher RPE than FAST (8.59 vs. 7.98, p= 0.002). Despite differences in RPE, our results indicate that both repetition tempos produced similar muscular adaptations. However, they also suggest that the FAST tempo may provide a small hypertrophic advantage at the distal quadriceps. From a practical standpoint, strength and conditioning professionals may implement a FAST tempo at least in one single-joint exercise during an 8-week training period to enhance regional hypertrophic adaptations in trained individuals.

Individuals can exhibit differences in metabolism that are caused by the interplay of genetic background, nutritional input, microbiota and other environmental factors1–4. It is difficult to connect differences in metabolism to genomic variation and derive underlying molecular mechanisms in humans, owing to differences in diet and lifestyle, among others. Here we use the nematode Caenorhabditis elegansas a model to study inter-individual variation in metabolism. By comparing three wild strains and the commonly used N2 laboratory strain, we find differences in the abundances of both known metabolites and those that have not to our knowledge been previously described. The latter metabolites include conjugates between 3-hydroxypropionate (3HP) and several amino acids (3HP-AAs), which are much higher in abundance in one of the wild strains. 3HP is an intermediate in the propionate shunt pathway, which is activated when flux through the canonical, vitamin-B12-dependent propionate breakdown pathway is perturbed5. We show that increased accumulation of 3HP-AAs is caused by genetic variation in HPHD-1, for which 3HP is a substrate. Our results suggest that the production of 3HP-AAs represents a ‘shunt-within-a-shunt’ pathway to accommodate a reduction-of-function allele in hphd-1. This study provides a step towards the development of metabolic network models that capture individual-specific differences of metabolism and more closely represent the diversity that is found in entire species.

Midbrain dopaminergic neurons (DANs) are subject to extensive metabotropic regulation, but the repertoire of G protein-coupled receptors (GPCRs) present in these neurons has not been mapped. Here, we isolate DANs from Dat-eGFP mice to generate a GPCR atlas by unbiased qPCR array expression analysis of 377 GPCRs. Combined with data mining of scRNA-seq databases, we identify multiple receptors in DAN subpopulations with 38 of these receptors representing the majority of transcripts. We identify 41 receptors expressed in midbrain DANs but not in non-DAN midbrain cells, including the free fatty acid receptor 4 (FFAR4). Functional expression of FFAR4 is validated by ex vivoCa2+imaging, and in vivoexperiments support that FFAR4 negatively regulates food and water intake and bodyweight. In addition to providing a critical framework for understanding metabotropic DAN regulation, our data suggest fatty acid sensing by FFAR4 as a mechanism linking high-energy intake to the dopamine-reward pathway.

Gene duplication is an important substrate for the evolution of new gene functions, but the impacts of gene duplicates on their own activities and on the developmental networks in which they act are poorly understood. Here, we use a natural experiment of lin-12/Notchgene duplication within the nematode genus Caenorhabditis, combined with characterization of loss- and gain-of-function mutations, to uncover functional distinctions between the duplicate genes in 1 species (Caenorhabditis briggsae) and their single-copy ortholog in Caenorhabditis elegans. First, using improved genomic sequence and gene model characterization, we confirm that the C. briggsaegenome includes 2 complete lin-12genes, whereas most other genes encoding proteins that participate in the LIN-12signaling pathway retain a one-to-one orthology with C. elegans. We use CRISPR-mediated genome editing to introduce alleles predicted to cause gain-of-function (gf) or loss-of-function (lf) into each C. briggsaegene and find that the gfmutations uncover functional distinctions not apparent from the lfalleles. Specifically, Cbr-lin-12.1(gf), but not Cbr-lin-12.2(gf), causes developmental defects similar to those observed in Cel-lin-12(gf). In contrast to Cel-lin-12(gf), however, the Cbr-lin-12.1(gf)alleles do not cause dominant phenotypes as compared to the wild type, and the mutant phenotype is observed only when 2 gfalleles are present. Our results demonstrate that gene duplicates can exhibit differential capacities to compensate for each other and to interfere with normal development, and uncover coincident gene duplication and evolution of developmental sensitivity to LIN-12/Notch activity.

The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system has been validated to predict wound healing among patients with critical limb threatening ischemia (CLTI). Our goal was to analyze the use of a previously reported conservative wound care approach to non-infected (foot infection score of zero), diabetic foot ulcers with mild-moderate peripheral arterial disease enrolled in a conservative tier of a multidisciplinary limb preservation program.

Short tandem repeats (STRs) represent an important class of genetic variation that can contribute to phenotypic differences. Although millions of single nucleotide variants (SNVs) and short indels have been identified among wild Caenorhabditis elegansstrains, the natural diversity in STRs remains unknown. Here, we characterized the distribution of 31,991 STRs with motif lengths of 1–6 bp in the reference genome of C. elegans. Of these STRs, 27,667 harbored polymorphisms across 540 wild strains and only 9691 polymorphic STRs (pSTRs) had complete genotype data for more than 90% of the strains. Compared with the reference genome, the pSTRs showed more contraction than expansion. We found that STRs with different motif lengths were enriched in different genomic features, among which coding regions showed the lowest STR diversity and constrained STR mutations. STR diversity also showed similar genetic divergence and selection signatures among wild strains as in previous studies using SNVs. We further identified STR variation in two mutation accumulation line panels that were derived from two wild strains and found background-dependent and fitness-dependent STR mutations. We also performed the first genome-wide association analyses between natural variation in STRs and organismal phenotypic variation among wild C. elegansstrains. Overall, our results delineate the first large-scale characterization of STR variation in wild C. elegansstrains and highlight the effects of selection on STR mutations.

Introduction Major lower extremity amputation (LEA) results in significant morbidity and mortality. This study identifies factors contributing to adverse long-term outcomes after major LEA.Study Design Amputations in the Vascular Quality Initiative (VQI) long-term follow-up database from 2012 to 2017 were included. Multivariable logistic regression determined which significant patient factors were associated with 1-year mortality, long-term functional status, and progression to higher level amputation within 1 year.Results 3440 major LEAs were performed and a mortality rate of 19.9% was seen at 1 year. Logistic regression demonstrated that 1-year mortality was associated with post-op myocardial infarction (MI) (odds ratio (OR) 1.7, CI 1.02-2.97, P= .04), congestive heart failure (CHF) (OR 1.9, confidence interval (CI) 1.56-2.38, P< .001), hypertension (HTN) (OR 1.31, CI 1.00-1.72, P= .05), chronic obstructive pulmonary disease (COPD) (OR 1.36, CI 1.13-1.63, P< .001), and dependent functional status (OR 2.01, CI 1.67-2.41, P< .001). A decline in ambulatory status was associated with COPD (OR 1.36, CI 1.09-1.68, P= .006). Dependent functional status was protective against revision to higher level amputation (OR .18, CI .07-.45, P< .001).Conclusion In the VQI, 1-year mortality after major LEA is nearly 20% and associated with HTN, CHF, COPD, dependent functional status, and post-op MI. Decreased functional status at 1 year was associated with COPD, and progression to higher level amputation was less likely in patients with dependent functional status.

ABSTRACTActive learning strategies engage students in instruction by making them an integral part of the teaching process. Gamification is one type of active learning approach that incentivises student participation by incorporating gaming elements into the learning experience. Although gamification might be an effective strategy for the introduction of new material, adding gaming elements to a review activity can motivate students to study, help them organise material, and identify material that they should review further before an exam. Escape rooms are collaborative problem-solving challenges and aspects of escape-room experiences can be applied to active learning. Here, we describe an escape room inspired review game for an advanced genetic analysis class at Northwestern University. We provide a detailed account of each puzzle within the review game and assess the impact of the game on learning outcomes.

Important clues about natural selection can be gleaned from discrepancies between the properties of segregating genetic variants and of mutations accumulated experimentally under minimal selection, provided the mutational process is the same in the laboratory as in nature. The base-substitution spectrum differs between C. eleganslaboratory mutation accumulation (MA) experiments and the standing site-frequency spectrum, which has been argued to be in part owing to increased oxidative stress in the laboratory environment. Using genome sequence data from C. elegansMA lines carrying a mutation (mev-1) that increases the cellular titer of reactive oxygen species (ROS), leading to increased oxidative stress, we find the base-substitution spectrum is similar between mev-1, its wild-type progenitor (N2), and another set of MA lines derived from a different wild strain (PB306). Conversely, the rate of short insertions is greater in mev-1, consistent with studies in other organisms in which environmental stress increased the rate of insertion–deletion mutations. Further, the mutational properties of mononucleotide repeats in all strains are different from those of nonmononucleotide sequence, both for indels and base-substitutions, and whereas the nonmononucleotide spectra are fairly similar between MA lines and wild isolates, the mononucleotide spectra are very different, with a greater frequency of A:T → T:A transversions and an increased proportion of ±1-bp indels. The discrepancy in mutational spectra between laboratory MA experiments and natural variation is likely owing to a consistent (but unknown) effect of the laboratory environment that manifests itself via different modes of mutability and/or repair at mononucleotide loci.

Patient frailty indices are increasingly being utilized to anticipate post-operative complications. This study explores whether a 5-factor modified frailty index (mFI-5) is associated with outcomes following below-knee amputation (BKA). All BKAs in the vascular quality initiative (VQI) amputation registry from 2012-2017 were reviewed. Preoperative frailty status was determined with the mFI-5 which assigns one point each for history of diabetes, chronic obstructive pulmonary disease or active pneumonia, congestive heart failure, hypertension, and nonindependent functional status. Outcomes included 30-day mortality, unplanned return to odds ratio (OR), post-op myocardial infarction (MI), post-op SSI, all-cause complication, revision to higher level amputation, disposition status, and prosthetic use. 2040 BKAs were performed. Logistic regression showed an increasing mFI-5 score that was associated with higher risk of combined complications (OR 1.22, confidence interval [CI] 1.07-1.38, P< .05), 30-day mortality (OR 1.60, CI 1.19-2.16, P< .05), post-op MI (OR 1.79, CI 1.30-2.45, P< .05), and failure of long-term prosthetic use (OR 1.17, CI 1.03-1.32, P< .05). In the VQI, every one-point increase in mFI-5 is associated with an increased risk of 22% for combined complications, 60% for 30-day mortality, nearly 80% for post-op MI, and 17% for failure of prosthetic use in BKA patients. The mFI-5 frailty index should be incorporated into preoperative planning and risk stratification.

Guidelines recommend that patients with carotid artery stenosis ≥50% (Sx-CAS) undergo carotid endarterectomy (CEA) within 14 days of symptoms. However, perioperative risks, especially stroke, may be increased when CEA is performed within 48 hours. This study seeks to more fully evaluate the effect of timing of surgery on outcomes for Sx-CAS.

Antenatal corticosteroids given to women before preterm birth improve infant survival and health. However, whether dexamethasone or betamethasone have better maternal, neonatal, and childhood health outcomes remains unclear. We therefore aimed to assess whether administration of antenatal dexamethasone to women at risk of preterm birth reduced the risk of death or neurosensory disability in their children at age 2 years compared with betamethasone. We also aimed to assess whether dexamethasone reduced neonatal morbidity, had benefits for the mother, or affected childhood body size, blood pressure, behaviour, or general health compared with betamethasone.