COVID-19 and individual genetic susceptibility/receptivity: Role of ACE1/ACE2 genes, immunity, inflammation and coagulation. might the double x-chromosome in females be protective against SARS-COV-2 compared to the single x-chromosome in males?

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex-or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection

Dynamical response of the "GGG" rotor to test the Equivalence Principle: theory, simulation and experiment. Part I: the normal modes

Recent theoretical work suggests that violation of the Equivalence Principle might be revealed in a measurement of the fractional differential acceleration $\eta$ between two test bodies -of different composition, falling in the gravitational field of a source mass- if the measurement is made to the level of $\eta\simeq 10^{-13}$ or better. This being within the reach of ground based experiments, gives them a new impetus. However, while slowly rotating torsion balances in ground laboratories are close to reaching this level, only an experiment performed in low orbit around the Earth is likely to provide a much better accuracy. We report on the progress made with the "Galileo Galilei on the Ground" (GGG) experiment, which aims to compete with torsion balances using an instrument design also capable of being converted into a much higher sensitivity space test. In the present and following paper (Part I and Part II), we demonstrate that the dynamical response of the GGG differential accelerometer set into supercritical rotation -in particular its normal modes (Part I) and rejection of common mode effects (Part II)- can be predicted by means of a simple but effective model that embodies all the relevant physics. Analytical solutions are obtained under special limits, which provide the theoretical understanding. A simulation environment is set up, obtaining quantitative agreement with the available experimental data on the frequencies of the normal modes, and on the whirling behavior. This is a needed and reliable tool for controlling and separating perturbative effects from the expected signal, as well as for planning the optimization of the apparatus.Comment: Accepted for publication by "Review of Scientific Instruments" on Jan 16, 2006. 16 2-column pages, 9 figure

Human ectoparasites and the spread of plague in Europe during the Second Pandemic

Plague, caused by the bacterium Yersinia pestis, can spread through human populations by multiple transmission pathways. Today, most human plague cases are bubonic, caused by spillover of infected fleas from rodent epizootics, or pneumonic, caused by inhalation of infectious droplets. However, little is known about the historical spread of plague in Europe during the Second Pandemic (14-19th centuries), including the Black Death, which led to high mortality and recurrent epidemics for hundreds of years. Several studies have suggested that human ectoparasite vectors, such as human fleas (Pulex irritans) or body lice (Pediculus humanus humanus), caused the rapidly spreading epidemics. Here, we describe a compartmental model for plague transmission by a human ectoparasite vector. Using Bayesian inference, we found that this model fits mortality curves from nine outbreaks in Europe better than models for pneumonic or rodent transmission. Our results support that human ectoparasites were primary vectors for plague during the Second Pandemic, including the Black Death (1346-1353), ultimately challenging the assumption that plague in Europe was predominantly spread by rats

A kinetic study of gamma-glutamyltransferase (GGT)-mediated S-nitrosoglutathione catabolism.

S-Nitrosoglutathione (GSNO) is a nitric oxide (NO) donor compound which has been postulated to be involved in transport of NO in vivo. It is known that c-glutamyl transpeptidase (GGT) is one of the enzymes involved in the enzyme-mediated decomposition of GSNO, but no kinetics studies of the reaction GSNO-GGT are reported in literature. In this study we directly investigated the kinetics of GGT with respect to GSNO as a substrate and glycyl- glycine (GG) as acceptor co-substrate by spectrophotometry at 334 nm. GGT hydrolyses the c-glutamyl moiety of GSNO to give S-nitroso-cysteinylglycine (CGNO) and c-glutamyl-GG. However, as both the substrate GSNO and the first product CGNO absorb at 334 nm, we optimized an ancillary reaction coupled to the enzymatic reaction, based on the copper-mediated decomposition of CGNO yielding oxidized cysteinyl-glycine and NO. The ancillary reaction allowed us to study directly the GSNO/GGT kinetics by following the decrease of the characteristic absorbance of nitrosothiols at 334 nm. A Km of GGT for GSNO of 0.398 ± 31 mM was thus found, comparable with Km values reported for other c-glutamyl substrates of GGT

Climate-driven introduction of the Black Death and successive plague reintroductions into Europe

The Black Death, originating in Asia, arrived in the Mediterranean harbors of Europe in 1347 CE, via the land and sea trade routes of the ancient Silk Road system. This epidemic marked the start of the second plague pandemic, which lasted in Europe until the early 19th century. This pandemic is generally understood as the consequence of a singular introduction of Yersinia pestis, after which the disease established itself in European rodents over four centuries. To locate these putative plague reservoirs, we studied the climate fluctuations that preceded regional plague epidemics, based on a dataset of 7,711 georeferenced historical plague outbreaks and 15 annually resolved tree-ring records from Europe and Asia. We provide evidence for repeated climate-driven reintroductions of the bacterium into European harbors from reservoirs in Asia, with a delay of 15 ± 1 y. Our analysis finds no support for the existence of permanent plague reservoirs in medieval Europe

Nano-scaled Biomolecular Field-Effect Transistors: Prototypes and Evaluations

As modern electronics rapidly approach the ultimate level of integration (typically thought to be at the nanoscale level), the fascinating world of biomolecules provides new opportunities and directions for further miniaturization. In this work we review our results in the field of biomolecular electronics, starting from the fabrication of nanojunctions up to the implementation of hybrid devices

The Cerebellar Dopaminergic System

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments

Gravitational ultrarelativistic spin-orbit interaction and the weak equivalence principle

It is shown that the gravitational ultrarelativistic spin-orbit interaction violates the weak equivalence principle in the traditional sense. This fact is a direct consequence of the Mathisson-Papapetrou equations in the frame of reference comoving with a spinning test particle. The widely held assumption that the deviation of a spinning test body from a geodesic trajectory is caused by tidal forces is not correctComment: 12 page

The role of fundamental solution in Potential and Regularity Theory for subelliptic PDE

In this survey we consider a general Hormander type operator, represented as a sum of squares of vector fields plus a drift and we outline the central role of the fundamental solution in developing Potential and Regularity Theory for solutions of related PDEs. After recalling the Gaussian behavior at infinity of the kernel, we show some mean value formulas on the level sets of the fundamental solution, which are the starting point to obtain a comprehensive parallel of the classical Potential Theory. Then we show that a precise knowledge of the fundamental solution leads to global regularity results, namely estimates at the boundary or on the whole space. Finally in the problem of regularity of non linear differential equations we need an ad hoc modification of the parametrix method, based on the properties of the fundamental solution of an approximating problem

Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively