Biophysical insights into the high pressure sensitivity of biomolecules

Accurate folding and dynamics of biomolecules are substantially important for the functionality of living systems. As life can also be found in the realm of environmental extremes, biomolecules as well as their homo- and heterotypic interactions must withstand different environmental stresses including a wide range of temperature, pressure and salinity. For example, extreme conditions including high temperature, high hydrostatic pressure and high salinity can be found close to marine hydrothermal vents. Hence, adaptation strategies must exist to ensure life of extremophiles. Notably, globular proteins and double-stranded nucleic acids have been reported to be very pressure stable, whereas initial studies have shown that quaternary interactions of proteins and non-canonical structures of nucleic acids, being essential components of cellular entities, are rather pressure-sensitive. The present work shed light on the origin of the pressure sensitivity of the eukaryotic cytoskeleton by focusing on the components actin filaments and microtubules. More importantly, it addressed the issue of molecular strategies for pressure resistance. In particular, it focused on the role of accessory proteins of the cytoskeleton as well as the effects of macromolecular crowding and osmolytes, phenomena easily encountered inside cells. Further, the latter aspect was also investigated for a functional and temperature-sensitive ribonucleic acid hairpin known to regulate the gene expression in bacteria. To fundamentally understand the pressure effect on nucleic acids, the self-assembly reaction of guanosine-monophosphate as a single nucleotide was focus of the present work as well

NUMERICAL SIMULATION OF LIQUID SLOSHING IN RECTANGULAR TANKS USING CONSISTENT PARTICLE METHOD AND EXPERIMENTAL VERIFICATION

Ph.DDOCTOR OF PHILOSOPH

Exploring the relationship between welfare participation in childhood and depression in adulthood in the United States

OBJECTIVE: Depression is a serious mental health disorder, and untangling its causal agents is a major public health priority in the United States. This study examines the relationship between participating in welfare programs during childhood and experiencing depression during young adulthood. METHOD: This study used wave I and IV data from the Add Health (N = 15,701). Multiple imputation is used to deal with missing data. Propensity score matching is used to reduce the selection bias, and then multiple regressions were used to examine the welfare participation and depression relationships. RESULTS: Overall, young adults from welfare-recipient families reported significantly higher depression scores, rather than the clinical diagnosis of depression. Subgroup analyses showed only the poor group had significantly higher depression scores, whereas only the near-poor group had a significantly diagnosed depression outcome. Additionally, significantly higher depression scores were found for female youth from welfare-recipient families. However, no significant differences were found between the gender groups regarding diagnosed depression. DISCUSSION: Using welfare participation as an economic marker, the subgroup analyses help to identify target populations for future intervention. Implications of this study will be of interest to policy makers and have value for informing policy decisions

Individual vs. Group Delivery of Acupuncture Therapy for Chronic Musculoskeletal Pain in Urban Primary Care-a Randomized Trial

BACKGROUND: Acupuncture has been shown to be effective for the treatment of chronic musculoskeletal back, neck, and osteoarthritis pain. However, access to acupuncture treatment has been limited in medically underserved and low-income populations. OBJECTIVE: Acupuncture therapy delivered in groups could reduce cost and expand access. We compared the effectiveness of group versus individual acupuncture for pain and function among ethnically diverse, low-income primary care patients with chronic musculoskeletal pain. DESIGN: This was a randomized comparative effectiveness non-inferiority trial in 6 Bronx primary care community health centers. Participants with chronic ( \u3e 3 months) back, neck, or osteoarthritis pain were randomly assigned to individual or group acupuncture therapy for 12 weeks. PARTICIPANTS: Seven hundred seventy-nine participants were randomized. Mean age was 54.8 years. 35.3% of participants identified as black and 56.9% identified as Latino. Seventy-six percent were Medicaid insured, 60% reported poor/fair health, and 37% were unable to work due to disability. INTERVENTIONS: Participants received weekly acupuncture treatment in either group or individual setting for 12 weeks. MAIN MEASURES: Primary outcome was pain interference on the Brief Pain Inventory at 12 weeks; secondary outcomes were pain severity (BPI), physical and mental well-being (PROMIS-10), and opiate use. Outcome measures were collected at baseline, 12 and 24 weeks. KEY RESULTS: 37.5% of individual arm and 30.3% in group had \u3e 30% improvement in pain interference (d = 7.2%, 95% CI - 0.6%, 15.1%). Non-inferiority of group acupuncture was not demonstrated for the primary outcome assuming a margin of 10%. In the responder analysis of physical well-being, 63.1% of individual participants and 59.5% of group had clinically important improvement at 12 weeks (d = 3.6%, 95% CI - 4.2%, 11.4%). CONCLUSIONS: Both individual and group acupuncture therapy delivered in primary care settings reduced chronic pain and improved physical function at 12 weeks; non-inferiority of group was not shown. TRIAL REGISTRATION: Clinicaltrials.gov # NCT02456727

LIBRETTO-531: A Phase III Study of Selpercatinib in Multikinase Inhibitor-Naïve

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib

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

The Effects of Lipid Membranes, Crowding and Osmolytes on the Aggregation, and Fibrillation Propensity of Human IAPP

Type 2 diabetes mellitus (T2DM) is an age-related and metabolic disease. Its development is hallmarked, among others, by the dysfunction and degeneration of β-cells of the pancreatic islets of Langerhans. The major pathological characteristic thereby is the formation of extracellular amyloid deposits consisting of the islet amyloid polypeptide (IAPP). The process of human IAPP (hIAPP) self-association, and the intermediate structures formed as well as the interaction of hIAPP with membrane systems seem to be, at least to a major extent, responsible for the cytotoxicity. Here we present a summary and comparison of the amyloidogenic propensities of hIAPP in bulk solution and in the presence of various neutral and charged lipid bilayer systems as well as biological membranes. We also discuss the cellular effects of macromolecular crowding and osmolytes on the aggregation pathway of hIAPP. Understanding the influence of different cellular factors on hIAPP aggregation will provide more insight into the onset of T2DM and help to develop novel therapeutic strategies

Further Study on the Effects of Wind Turbine Yaw Operation for Aiding Active Wake Management

Active wake management (AWM) via yaw control has been discussed in recent years as a potential way to improve the power production of a wind farm. In such a technique, the wind turbines will be required to work frequently at misaligned yaw angles in order to reduce the vortices in the wake area behind the turbines. However, today, it is still not very clear about how yaw operation affects the dynamics and power generation performance of the wind turbines. To further understand the effects of yaw operation, numerical research is conducted in this paper. In the study, the optimal size of the flow field used in the computational fluid dynamics (CFD) calculation was specifically discussed in order to obtain an efficient numerical model to quickly and accurately predict the dynamics and the performance of the turbines. Through this research, the correlation between the blade loads during yaw and non-yaw operations is established for aiding yaw control, and the blade loads and power generation performances of the wind turbine during yaw operation under different wind shear and blade deflection conditions are analyzed for understanding the effects of yaw operation. It is found that the optimal size of the flow field for performing efficient and accurate CFD calculations does exist. The misaligned yaw operation generally tends to decrease the loads acting on the blade. However, the aerodynamic energy captured by the turbine rotor and blade loads during yaw operation is not only dependent on the yaw angle of the rotor but is also affected by wind speed, rotor speed, the pitch angle of the blades, blade deflection, and wind shear. Particularly, it is interestingly found that wind shear can cause undesirable fluctuation of the power, which will challenge the power quality of the wind farm if no measures are taken

Effects of exogenous GABA on physiological characteristics of licorice seedlings under saline-alkali stress

Licorice is widespread in arid and semi-arid areas, but high soil salinity has always been a limiting factor for vegetation growth in these areas. Gamma-aminobutyric acid (GABA) is a signaling molecule that can regulate tolerance in plant. However, the mechanism by which exogenous GABA regulates the response of licorice to saline-alkali stress is not yet clear. In this study, we investigated the effects of exogenous GABA on growth parameters, oxidative damage, hormone levels and photosynthetic indices of licorice seedlings under different combinations of saline and alkali stress conditions. The experiment involved eight treatments: CK, distilled water (control); CK + GABA, 0.1 mM GABA; salt stress (SS), 150 mM NaCl; SS + GABA, 150 mM NaCl + 0.1 mM GABA; alkali stress (AS), 10 mM Na2CO3; AS + GABA, 10 mM Na2CO3 + 0.1 mM GABA; mixed saline-alkali stress (MAS), 150 mM NaCl + 10 mM Na2CO3; MAS + GABA, 150 mM NaCl + 10 mM Na2CO3 + 0.1 mM GABA. Our results showed that the inhibitory effects of SS and MAS on the seedling height, root length and root-shoot ratio were significantly alleviated by exogenous GABA. Although soluble sugars, chlorophyll a, total chlorophyll, and superoxide dismutase (SOD) activity were lower in the leaves of the seedlings in the SS treatment compared with the control, these physiological parameters increased significantly after GABA application. Exogenous GABA improved glutathione (GSH) activity in both the leaves and roots of the seedlings during the AS treatment. Additionally, take advantage of GABA led to an increase in ABA, GA and IAA contents in leaves under SS, AS and MAS treatments. Furthermore, the photosynthetic parameters, including Pn, gs, Tr, ETR and qP, significantly increased following the utilization of GABA in both the SS and MAS treatments. Therefore, the application of exogenous GABA can reduce the accumulation of harmful substances, preserve cell morphology, and enhance cell function under saline, alkali, and saline-alkali stress. This enhances the resistance of licorice seedlings to stress conditions and reduces physiological damage