Functional Effects of Calcium Regulation of Thin Filaments at Single Particle Resolution

Heart disease is the leading cause of death in the United States. Understanding heart function at the molecular level is critical for developing of more effective treatments. In the cardiac muscle, the thin filament is composed by troponin (Tn), tropomyosin (Tm), and F-actin. It provides Ca2+-dependent regulation of contraction by modulating myosin attachment and force generation in a cooperative scheme. However, this mechanism remains unclear. To understand thin filament activation, we studied the binding and functional properties of Tn and Tm to F-actin at single particle resolution by employing fluorescence image colocalization, in vitro motility assays, and Förster resonance energy transfer based on fluorescence lifetime imaging (FLIM-FRET). Our results suggest that under physiologically relevant conditions, Tn and Tm binding to Factin is not cooperative and it is not affected by Ca2+. This suggests that one single type of interaction is involved in fully regulated thin filaments. Thin filament activation has been confirmed by in vitro motility assays, where phosphorylation of serine 23 and 24 in TnI, truncation of TnT C-terminal region, and incorporation of a Ca2+ desensitizer altered the Ca2+ response to filament sliding. FLIM-FRET measurements revealed an allosteric dependence on thin filament activation as a function of myosin and Ca2+. Our results provide evidence of multiple allosteric elements within thin filaments responsible for the molecular modulation of cardiac muscle activation

Multidisciplinary Conceptual Design for Reduced-Emission Rotorcraft

Python-based wrappers for OpenMDAO are used to integrate disparate software for practical conceptual design of rotorcraft. The suite of tools which are connected thus far include aircraft sizing, comprehensive analysis, and parametric geometry. The tools are exercised to design aircraft with aggressive goals for emission reductions relative to fielded state-of-the-art rotorcraft. Several advanced reduced-emission rotorcraft are designed and analyzed, demonstrating the flexibility of the tools to consider a wide variety of potentially transformative vertical flight vehicles. To explore scale effects, aircraft have been sized for 5, 24, or 76 passengers in their design missions. Aircraft types evaluated include tiltrotor, single-main-rotor, coaxial, and side-by-side helicopters. Energy and drive systems modeled include Lithium-ion battery, hydrogen fuel cell, turboelectric hybrid, and turboshaft drive systems. Observations include the complex nature of the trade space for this simple problem, with many potential aircraft design and operational solutions for achieving significant emission reductions. Also interesting is that achieving greatly reduced emissions may not require exotic component technologies, but may be achieved with a dedicated design objective of reducing emissions

Concept Vehicles for VTOL Air Taxi Operations

Concept vehicles are presented for air taxi operations, also known as urban air mobility or on-demand mobility applications. Considering the design-space dimensions of payload (passengers and pilot), range, aircraft type, and propulsion system, three aircraft are designed: a single passenger (250-lb payload), 50-nm range quadrotor with electric propulsion; a six-passenger (1200-lb payload), 4x50 = 200-nm range side-by-side helicopter with hybrid propulsion; and a fifteen-passenger (3000-lb payload), 8x50 = 400-nm range tiltwing with turbo-electric propulsion. These concept vehicles are intended to focus and guide NASA research activities in support of aircraft development for emerging aviation markets, in particular VTOL air taxi operations. Research areas are discussed, illustrated by results from the design of the concept vehicles

Heterogeneous ketonic decarboxylation of dodecanoic acid: studying reaction parameters

Ketonic decarboxylation has gained significant attention in recent years as a pathway to reduce the oxygen content within biomass-derived oils, and to produce sustainable ketones. The reaction is base catalysed, with MgO an economic, accessible and highly basic heterogeneous catalyst. Here we use MgO to catalyse the ketonic decarboxylation of dodecanoic acid to form 12-tricosanone at moderate temperatures (250 °C, 280 °C and 300 °C) with low catalyst loads of 1% (w/w), 3% (w/w) and 5% (w/w) with respect to the dodecanoic acid, with a reaction time of 1 hour under batch conditions. Three different particle sizes for the MgO were tested (50 nm, 100 nm and 44 μm). Ketone yield was found to increase with increasing reaction temperature, reaching approximately 75% yield for all the samples tested. Temperature was found to be the main control on reaction yield, rather than surface area or particle size

Analysis of NIH K99/R00 awards and the career progression of awardees

Many postdoctoral fellows and scholars who hope to secure tenure-track faculty positions in the United States apply to the National Institutes of Health (NIH) for a Pathway to Independence Award. This award has two phases (K99 and R00) and provides funding for up to 5 years. Using NIH data for the period 2006–2022, we report that ~230 K99 awards were made every year, representing up to ~$250 million annual investment. About 40% of K99 awardees were women and ~89% of K99 awardees went on to receive an R00 award annually. Institutions with the most NIH funding produced the most recipients of K99 awards and recruited the most recipients of R00 awards. The time between a researcher starting an R00 award and receiving a major NIH award (such as an R01) ranged between 4.6 and 7.4 years, and was significantly longer for women, for those who remained at their home institution, and for those hired by an institution that was not one of the 25 institutions with the most NIH funding. Shockingly, there has yet to be a K99 awardee at a historically Black college or university. We go on to show how K99 awardees flow to faculty positions, and to identify various factors that influence the future success of individual researchers and, therefore, also influence the composition of biomedical faculty at universities in the United States

Refugios transitorios en casos de emergencia post-desastre, utilizando materiales sostenibles, en el área metropolitana de Arequipa, 2020

Ante escenarios post-desastre, resulta importante la aplicación de medidas preventivas ante una eventual escasez de refugios en el ámbito local, siendo Arequipa una de las ciudades más pobladas en el territorio peruano, con una concentración mayor en su área metropolitana. En las últimas décadas, resultan mucho más evidentes las estrategias improvisadas de mitigación de desastres por parte de las autoridades competentes, siendo la principal respuesta, módulos temporales que no aseguran a los afectados el acceso a una vivienda definitiva. Ante esto, resulta necesario proponer un modelo preventivo basado en la implementación de refugios transitorios, en compañía de servicios e instalaciones de soporte, aplicables a diferentes situaciones y escalas, este enfoque, permite una construcción de viviendas gradual, aplicando módulos de refugios de primera necesidad, su evolución hacia un enfoque temporal y su culminación en refugios permanentes definiendo un modelo sostenible, que otorgue a los afectados un refugio digno, permita una organización de módulos en base a patrones y criterios de agrupación, facilite la adquisición y gestión de los recursos necesarios para cada etapa, la aplicación de materiales sostenibles y su reutilización, y fomente el desarrollo de procesos constructivos no convencionales y sistemas de autoconstrucción que posibiliten el empoderamiento de poblaciones vulnerablesTesi

Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Acknowledgements We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016. Conflict of Interest statement. None declared. Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.Peer reviewedPublisher PD

An Orphan CpG Island Drives Expression of a let-7 miRNA Precursor with an Important Role in Mouse Development.

Most human genes are associated with promoters embedded in non-methylated, G + C-rich CpG islands (CGIs). Not all CGIs are found at annotated promoters, however, raising the possibility that many serve as promoters for transcripts that do not code for proteins. To test this hypothesis, we searched for novel transcripts in embryonic stem cells (ESCs) that originate within orphan CGIs. Among several candidates, we detected a transcript that included three members of the let-7 micro-RNA family: Let-7a-1, let-7f-1, and let-7d. Deletion of the CGI prevented expression of the precursor RNA and depleted the included miRNAs. Mice homozygous for this mutation were sub-viable and showed growth and other defects. The results suggest that despite the identity of their seed sequences, members of the let-7 miRNA family exert distinct functions that cannot be complemented by other members