Sub-millisecond time-resolved SAXS using a continuous-flow mixer and X-ray micro-beam

Small-angle X-ray scattering (SAXS) is a well established technique to probe the nanoscale structure and interactions in soft matter. It allows one to study the structure of native particles in near physiological environments and to analyze structural changes in response to variations in external conditions. The combination of microfluidics and SAXS provides a powerful tool to investigate dynamic processes on a molecular level with sub-millisecond time resolution. Reaction kinetics in the sub-millisecond time range has been achieved using continuous-flow mixers manufactured using micromachining techniques. The time resolution of these devices has previously been limited, in part, by the X-ray beam sizes delivered by typical SAXS beamlines. These limitations can be overcome using optics to focus X-rays to the micrometer size range providing that beam divergence and photon flux suitable for performing SAXS experiments can be maintained. Such micro-SAXS in combination with microfluidic devices would be an attractive probe for time-resolved studies. Here, the development of a high-duty-cycle scanning microsecond-timeresolution SAXS capability, built around the Kirkpatrick–Baez mirror-based microbeam system at the Biophysics Collaborative Access Team (BioCAT) beamline 18ID at the Advanced Photon Source, Argonne National Laboratory, is reported. A detailed description of the microbeam small-angle-scattering instrument, the turbulent flow mixer, as well as the data acquisition and control and analysis software is provided. Results are presented where this apparatus was used to study the folding of cytochrome c. Future prospects for this technique are discussed

Eating habits and lifestyle changes during COVID-19 lockdown : An Italian survey

Background: On December 12th 2019, a new coronavirus (SARS-Cov2) emerged in Wuhan, China, sparking a pandemic of acute respiratory syndrome in humans (COVID-19). On the 24th of April 2020, the number of COVID-19 deaths in the world, according to the COVID-Case Tracker by Johns Hopkins University, was 195,313, and the number of COVID-19 confirmed cases was 2,783,512. The COVID-19 pandemic represents a massive impact on human health, causing sudden lifestyle changes, through social distancing and isolation at home, with social and economic consequences. Optimizing public health during this pandemic requires not only knowledge from the medical and biological sciences, but also of all human sciences related to lifestyle, social and behavioural studies, including dietary habits and lifestyle. Methods: Our study aimed to investigate the immediate impact of the COVID-19 pandemic on eating habits and lifestyle changes among the Italian population aged 65 12 years. The study comprised a structured questionnaire packet that inquired demographic information (age, gender, place of residence, current employment); anthropometric data (reported weight and height); dietary habits information (adherence to the Mediterranean diet, daily intake of certain foods, food frequency, and number of meals/day); lifestyle habits information (grocery shopping, habit of smoking, sleep quality and physical activity). The survey was conducted from the 5th to the 24th of April 2020. Results: A total of 3533 respondents have been included in the study, aged between 12 and 86 years (76.1% females). The perception of weight gain was observed in 48.6% of the population; 3.3% of smokers decided to quit smoking; a slight increased physical activity has been reported, especially for bodyweight training, in 38.3% of respondents; the population group aged 18-30 years resulted in having a higher adherence to the Mediterranean diet when compared to the younger and the elderly population (p < 0.001; p < 0.001, respectively); 15% of respondents turned to farmers or organic, purchasing fruits and vegetables, especially in the North and Center of Italy, where BMI values were lower. Conclusions: In this study, we have provided for the first time data on the Italian population lifestyle, eating habits and adherence to the Mediterranean Diet pattern during the COVID-19 lockdown. However, as the COVID-19 pandemic is ongoing, our data need to be confirmed and investigated in future more extensive population studies

Modulation of frustration in folding by sequence permutation

Folding of globular proteins can be envisioned as the contraction of a random coil unfolded state toward the native state on an energy surface rough with local minima trapping frustrated species. These substructures impede productive folding and can serve as nucleation sites for aggregation reactions. However, little is known about the relationship between frustration and its underlying sequence determinants. Chemotaxis response regulator Y (CheY), a 129-amino acid bacterial protein, has been shown previously to populate an off-pathway kinetic trap in the microsecond time range. The frustration has been ascribed to premature docking of the N- and C-terminal subdomains or, alternatively, to the formation of an unproductive local-in-sequence cluster of branched aliphatic side chains, isoleucine, leucine, and valine (ILV). The roles of the subdomains and ILV clusters in frustration were tested by altering the sequence connectivity using circular permutations. Surprisingly, the stability and buried surface area of the intermediate could be increased or decreased depending on the location of the termini. Comparison with the results of small-angle X-ray-scattering experiments and simulations points to the accelerated formation of a more compact, on-pathway species for the more stable intermediate. The effect of chain connectivity in modulating the structures and stabilities of the early kinetic traps in CheY is better understood in terms of the ILV cluster model. However, the subdomain model captures the requirement for an intact N-terminal domain to access the native conformation. Chain entropy and aliphatic-rich sequences play crucial roles in biasing the early events leading to frustration in the folding of CheY

The ITGAV rs3738919-C allele is associated with rheumatoid arthritis in the European Caucasian population: a family-based study

The integrin αvβ3, whose αv subunit is encoded by the ITGAV gene, plays a key role in angiogenesis. Hyperangiogenesis is involved in rheumatoid arthritis (RA) and the ITGAV gene is located in 2q31, one of the suggested RA susceptibility loci. Our aim was to test the ITGAV gene for association and linkage to RA in a family-based study from the European Caucasian population

Emerging therapies in pheochromocytoma and paraganglioma: Immune checkpoint inhibitors in the starting blocks

Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respec-tively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progres-sive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

“Es fundamental que la información que se transmita sea confiable”

El flamante Doctor Honoris Causa de la UNLP, Emilio Luque Fadón, de la Universidad Autónoma de Barcelona, fue uno de los conferencistas de CACIC 2017. Durante su estadía por la ciudad de La Plata, el español habló acerca de las nuevas tecnologías, su tolerancia a los fallos y el consumo energético.Facultad de Informátic

Anti-TNF therapy and plasma HDL cholesterol concentration.

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