PHARMACOLOGICAL APPROACHES TO SARS-CoV-2 INFECTION: FROM DRUG REPOSITIONING FOR COVID-19 TREATMENT TO DISEASE ARREST/PREVENTION WITH MoAbs AND NOVEL ANTIVIRALS

COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the major emergencies that have affected health care systems and society in recent decades. At the end of winter 2021-2022, the number of patients infected with SARS-CoV-2 and especially those suffering from severe COVID-19 is decreasing in Europe. This is due to the protective effect of anti-SARS-CoV-2 vaccines and the increasing number of people who had COVID-19, thus developing a certain immunity. However, vaccines to prevent the disease did not appear until more than one year after the emergence of SARS-CoV-2, so the initial medical approaches to control the disease focused on the existing drugs that were considered suitable for controlling the pathological events caused by the virus as far as was known at the time. Unfortunately, due in part to the limited initial knowledge of the molecular details of the pathology of COVID-19, many of the proposed drugs fell short of expectations and were abandoned. Over time, the challenge of understanding the mechanisms behind COVID-19 has generated a large body of knowledge about how this beta-coronavirus gains control of the host during infection, a knowledge that has been used to redefine treatment strategies by repurposing existing drugs and to explore new drugs. Here, we draw a picture of the major strategies and groups of drugs studied and provide a critical overview of their efficacy and safety based on the available literature data. The main topics covered are repurposed drugs, anticoagulants, anti-cytokine agents, monoclonal antibodies against SARS-CoV-2, and small antiviral molecules

Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain and provide a potential new target for the treatment of nicotine addictio

Tectonic setting of the kenya rift in the nakuru area, based on geophysical prospecting

In this paper, we present results of tectonic and geophysical investigations in the Kenya Rift valley, in the Nakuru area. We compiled a detailed geological map of the area based on published earlier works, well data and satellite imagery. The map was then integrated with original fieldwork and cross sections were constructed. In key areas, we then performed geophysical survey using Electrical Resistivity Tomography (ERT), Hybrid Source AudioMagnetoTelluric (HSAMT), and single station passive seismic measurements (HVSR). In the study area, a volcano-sedimentary succession of the Neogene-Quaternary age characterized by basalts, trachytes, pyroclastic rocks, and tephra with intercalated lacustrine and fluvial deposits crops out. Faulting linked with rift development is evident and occurs throughout the area crosscutting all rock units. We show a rotation of the extension in this portion of the Kenya rift with the NE-SW extension direction of a Neogene-Middle Pleistocene age, followed by the E-Wextension direction of anUpper Pleistocene-Present age. Geophysical investigations allowed to outline main lithostratigraphic units and tectonic features at depth and were also useful to infer main cataclasites and fractured rock bodies, the primary paths for water flow in rocks. These investigations are integrated in a larger EU H2020 Programme aimed to produce a geological and hydrogeological model of the area to develop a sustainable water management system

Preoperative assessment of cardiovascular risk in patients undergoing noncardiac surgery: The Orion study

In patients undergoing noncardiac surgery risk indices can estimate patients' perioperative risk of major cardiovascular complications. The indexes currently in use were derived from observational studies that are now outdated with respect to the current clinical context. We undertook a prospective, observational, cohort study to derive, validate, and compare a new risk index with established risk indices. We evaluated 7335 patients (mean age 63±13 years) who underwent noncardiac surgery. Based on prospective data analysis of 4600 patients (derivation cohort) we developed an Updated Cardiac Risk Score (UCRS), and validated the risk score on 2735 patients (validation cohort). Four variables (i.e. the UCRS) were significantly associated with the risk of a major perioperative cardiovascular events: high-risk surgery, preoperative estimate glomerular filtration rate <30 ml/min/1.73 m2, age ≥75 years, and history of heart failure. Based on the UCRS we created risk classes 1,2,3 and 4 and their corresponding 30-day risk of a major cardiovascular complication was 0.8% (95% confidence interval [CI] 0.5-1.7), 2.5 (95% CI 1.6-5.6), 8.7 (95% CI 5.2-18.9) and 27.2 (95% CI 11.8-50.3), respectively. No significant differences were found between the derivation and validation cohorts. Receiver operating characteristic (ROC) curves demonstrate a high predictive performance of the new index, with greater power to discriminate between the various classes of risk than the indexes currently used. The high predictive performance and simplicity of the UCRS make it suitable for wide-scale use in preoperative cardiac risk assessment of patients undergoing noncardiac surgery

Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in sardinian alcohol-preferring rats

The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intak

Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts.

Studies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23, p = 0.004), 0.77 (SE = 0.37, p = 0.036), and 1.11 (SE = 0.39, p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings

Prevalence and correlates of DSM-5 major depressive and related disorders in the community.

Although the DSM-5 has suggested the two new categories of Persistent Depressive Disorders (PDD) and Other Specified Depressive Disorders (OSDD), no study so far has applied the DSM-5 criteria throughout the range of depressive disorders. The aims of the present study were to 1) establish the lifetime prevalence of specific depressive disorders according to the new DSM-5 definitions in a community sample, and 2) determine their clinical relevance in terms of socio-demographic characteristics, comorbidity, course and treatment patterns. The semi-structured Diagnostic Interview for Genetic Studies was administered by masters-level psychologists to a random sample of an urban area (n=3720). The lifetime prevalence was 15.2% for PDD with persistent major depressive episode (MDE), 3.3% for PDD with pure dysthymia, 28.2% for Major Depressive Disorder (MDD) and 9.1% for OSDD. Subjects with PDD with persistent MDE were the most severely affected, followed by those with recurrent MDD, single episode MDD, PDD with pure dysthymia and OSDD and finally those without depressive disorders. Our data provide further evidence for the clinical significance of mild depressive disorders (OSDD), but cast doubt on the pertinence of lumping together PDD with persistent MDE and the former DSM-IV dysthymic disorder within the new PDD category

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p =.02) and ln CES-D score (p =.001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p =.02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p =.03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs

Decoding the IRX-\beta\ dust attenuation relation in star-forming galaxies at intermediate redshift

We aim to understand what drives the IRX-\beta dust attenuation relation at intermediate redshift (0.5 < z < 0.8) in star-forming galaxies. We investigate the role of various galaxy properties in shaping this observed relation. We use robust [O ii] {\lambda}3727, [O iii] {\lambda}{\lambda}4959, 5007, and H\beta line detections of our statistical sample of 1049 galaxies to estimate the gas-phase metallicities. We derive key physical properties that are necessary to study galaxy evolution, such as the stellar masses and the star formation rates, using the spectral energy distribution fitting tool CIGALE. Equivalently, we study the effect of galaxy morphology (mainly the S\'ersic index n and galaxy inclination) on the observed IRX-\beta scatter. We also investigate the role of the environment in shaping dust attenuation in our sample. We find a strong correlation of the IRX-\beta relation on gas-phase metallicity in our sample, and also strong correlation with galaxy compactness characterized by the S\'ersic indexes. Correlations are also seen with stellar masses, specific star formation rates and the stellar ages of our sources. Metallicity strongly correlates with the IRX-\beta scatter, this also results from the older stars and higher masses at higher beta values. Galaxies with higher metallicities show higher IRX and higher beta values. The correlation with specific dust mass strongly shifts the galaxies away from the IRX-\beta relation towards lower \b{eta} values. We find that more compact galaxies witness a larger amount of attenuation than less compact galaxies. There is a subtle variation in the dust attenuation scatter between edge-on and face-on galaxies, but the difference is not statistically significant. Galaxy environments do not significantly affect dust attenuation in our sample of star-forming galaxies at intermediate redshift.Comment: 14 pages, 13 figures, accepted for publication in A&