Higher PLIN5 but not PLIN3 content in isolated skeletal muscle mitochondria following acute in vivo contraction in rat hindlimb

Contraction-mediated lipolysis increases the association of lipid droplets and mitochondria, indicating an important role in the passage of fatty acids from lipid droplets to mitochondria in skeletal muscle. PLIN3 and PLIN5 are of particular interest to the lipid droplet–mitochondria interaction because PLIN3 is able to move about within cells and PLIN5 associates with skeletal muscle mitochondria. This study primarily investigated: 1) if PLIN3 is detected in skeletal muscle mitochondrial fraction; and 2) if mitochondrial protein content of PLIN3 and/or PLIN5 changes following stimulated contraction. A secondary aim was to determine if PLIN3 and PLIN5 associate and whether this changes following contraction. Male Long Evans rats (n = 21;age, 52 days; weight = 317 6 g) underwent 30 min of hindlimb stimulation (10 msec impulses, 100 Hz/3 sec at 10–20 V; train duration 100 msec). Contraction induced a ~50% reduction in intramuscular lipid content measured by oil red-O staining of red gastrocnemius muscle. Mitochondria were isolated from red gastrocnemius muscle by differential centrifugation and proteins were detected by western blotting. Mitochondrial PLIN5 content was ~1.6-fold higher following 30 min of contraction and PLIN3 content was detected in the mitochondrial fraction, and unchanged following contraction. An association between PLIN3 and PLIN5 was observed and remained unaltered following contraction. PLIN5 may play a role in mitochondria during lipolysis, which is consistent with a role in facilitating/regulating mitochondrial fatty acid oxidation. PLIN3 and PLIN5 may be working together on the lipid droplet and mitochondria during contraction-induced lipolysis

Cusp Catastrophe Models for Cognitive Workload and Fatigue in a Verbally Cued Pictorial Memory Task

Objective: The aim of this study was to evaluate two cusp catastrophe models for cognitive workload and fatigue. They share similar cubic polynomial structures but derive from different underlying processes and contain variables that contribute to flexibility with respect to load and the ability to compensate for fatigue. Background: Cognitive workload and fatigue both have a negative impact on performance and have been difficult to separate. Extended time on task can produce fatigue, but it can also produce a positive effect from learning or automaticity. Method: In this two-part experiment, 129 undergraduates performed tasks involving spelling, arithmetic, memory, and visual search. Results: The fatigue cusp for the central memory task was supported with the quantity of work performed and performance on an episodic memory task acting as the control parameters. There was a strong linear effect, however. The load manipulations for the central task were competition with another participant for rewards, incentive conditions, and time pressure. Results supported the workload cusp in which trait anxiety and the incentive manipulation acted as the control parameters. Conclusion: The cusps are generally better than linear models for analyzing workload and fatigue phenomena; practice effects can override fatigue. Future research should investigate multitasking and task sequencing issues, physical-cognitive task combinations, and a broader range of variables that contribute to flexibility with respect to load or compensate for fatigue. Applications: The new experimental medium and analytic strategy can be generalized to virtually any realworld cognitively demanding tasks. The particular results are generalizable to tasks involving visual search

Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD

Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Correction: Volume13, Issue1 Article Number1122 DOI 10.1038/s41467-022-28863-y Published FEB 25 2022Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genomewide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.Peer reviewe

PD-1T TILs as a predictive biomarker for clinical benefit to PD-1 blockade in patients with advanced NSCLC

PURPOSE Durable clinical benefit to PD-1 blockade in NSCLC is currently limited to a small fraction of patients, underlining the need for predictive biomarkers. We recently identified a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, termed PD-1T TILs, with predictive potential in NSCLC. Here, we examined PD-1T TILs as biomarker in NSCLC. EXPERIMENTAL DESIGN PD-1T TILs were digitally quantified in120 baseline samples from advanced NSCLC patients treated with PD-1 blockade. Primary outcome was Disease Control (DC) at 6 months. Secondary outcomes were DC at 12 months and survival. Exploratory analyses addressed the impact of lesion-specific responses, tissue sample properties and combination with other biomarkers on the predictive value of PD-1T TILs. RESULTS PD-1T TILs as a biomarker reached 77% sensitivity and 67% specificity at 6 months, and 93% and 65% at 12 months, respectively. Particularly, a patient group without clinical benefit was reliably identified, indicated by a high negative predictive value (NPV) (88% at 6 months, 98% at 12 months). High PD-1T TILs related to significantly longer progression-free (HR 0.39, 95% CI: 0.24-0.63, p<0.0001) and overall survival (HR 0.46, 95% CI: 0.28-0.76, p<0.01). Predictive performance was increased when lesion-specific responses and samples obtained immediately before treatment were assessed. Notably, the predictive performance of PD-1TTILs was superior to PD-L1 and TLS in the same cohort. CONCLUSIONS This study established PD-1T TILs as predictive biomarker for clinical benefit to PD-1 blockade in advanced NSCLC patients. Most importantly, the high NPV demonstrates an accurate identification of a patient group without benefit

Manifestation allergischer Krankheiten bei jungen Erwachsenen in Zusammenhang mit dem Eintritt in das Berufsleben - Untersuchungen zur Abhängigkeit von arbeitsbedingten Faktoren unter Berücksichtigung von Vorerkrankungen, Disposition und außerberuflichen Umweltfaktoren und Ableitung von Vorschlägen zur verbesserten Prävention: Studie in Ost- und Westdeutschland zu beruflichen Allergierisiken - SOLAR II -; Abschlussbericht

SOLAR II ist das zweite Follow-up einer bevölkerungsbezogenenden Kohorten-Studie. Diese Studie basiert auf einer Kohorte, die 1995/1996 aus damals 9-11jährigen Kindern aus Dresden und München zusammengestellt wurde. Die inzwischen erwachsenen Teilnehmer wurden nun erneut mit dem Ziel untersucht, Zusammenhänge zwischen beruflichen Expositionen und Allergien und Atemwegserkrankungen zu ermitteln. Ein Schwerpunkt der Auswertung galt der Frage, wie sich aus Risikofaktoren, die bereits in der Kindheit erkennbar sind, vorhersagen lässt, dass sich bei Tätigkeitsbeginn in Berufen mit hoher Exposition eine Allergie oder eine Atemwegserkrankung entwickeln wird. Mit den Ergebnissen der Studie kann nicht begründet werden, Jugendlichen mit Risikofaktoren für allergische Atemwegserkrankungen grundsätzlich von Tätigkeiten mit hohem Expositions-Potenzial abzuraten. Die Autoren sprechen sich aber für eine engmaschige arbeitsmedizinische Betreuung junger Erwachsener aus, die am Beginn einer solchen Tätigkeit stehen

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Phylogeography of the second plague pandemic revealed through analysis of historical Yersinia pestis genomes

The second plague pandemic, caused by Yersinia pestis, devastated Europe and the nearby regions between the 14th and 18th centuries AD. Here we analyse human remains from ten European archaeological sites spanning this period and reconstruct 34 ancient Y. pestis genomes. Our data support an initial entry of the bacterium through eastern Europe, the absence of genetic diversity during the Black Death, and low within-outbreak diversity thereafter. Analysis of post-Black Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct clades that may have given rise to more than one disease reservoir in, or close to, Europe. In addition, we show the loss of a genomic region that includes virulence-related genes in strains associated with late stages of the pandemic. The deletion was also identified in genomes connected with the first plague pandemic (541–750 AD), suggesting a comparable evolutionary trajectory of Y. pestis during both events

Collective writing: An inquiry into praxis

This is the second text in the series collectively written by members of the Editors' Collective, which comprises a series of individual and collaborative reflections upon the experience of contributing to the previous and first text written by the Editors' Collective: 'Towards a Philosophy of Academic Publishing.' In the article, contributors reflect upon their experience of collective writing and summarize the main themes and challenges. They show that the act of collective writing disturbs the existing systems of academic knowledge creation, and link these disturbances to the age of the digital reason. They conclude that the collaborative and collective action is a thing of learning-by-doing, and that collective writing seems to offer a possible way forward from the co-opting of academic activities by economics. Through detaching knowledge creation from economy, collaborative and collective writing address the problem of forming new collective intelligences