Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report.

Prokineticin 2 (Prok2) or prokineticin-receptor2 (Prok-R2) gene mutations are associated with Kallmann syndrome (KS). We describe a new homozygous mutation of Prok-R2 gene in a man displaying KS with an apparent reversal of hypogonadism. The proband, offspring of consanguineous parents, presented at age 19 years with absent puberty, no sense of smell, low testosterone and gonadotrophin levels. Magnetic resonance imaging showed olfactory bulb absence. The patient achieved virilization and spermatogenesis with gonadotrophin administration. Two years after discontinuing hormonal therapy, he maintained moderate oligozoospermia and normal testosterone levels. Prok2 and Prok- R2 gene sequence analyses were performed. The proband had a homozygous mutation in Prok-R2 exon 2 that harbours the c.T820>A base substitution, causing the introduction of an aspartic acid in place of valine at position 274 (Val274Asp). His mother had the same mutation in heterozygous state. This report describes a novel homozygous mutation of Prok-R2 gene in a man with variant KS, underlying the role of Prok-R2 gene in the olfactory and reproductive system development in humans. Present findings indicate that markedly delayed activation of gonadotrophin secretion may occur in some KS cases with definite gene defects, and that oligozoospermia might result from a variant form of reversible hypogonadotrophic hypogonadism

Cross-validated Bagged Learning

Many applications aim to learn a high dimensional parameter of a data generating distribution based on a sample of independent and identically distributed observations. For example, the goal might be to estimate the conditional mean of an outcome given a list of input variables. In this prediction context, Breiman (1996a) introduced bootstrap aggregating (bagging) as a method to reduce the variance of a given estimator at little cost to bias. Bagging involves applying the estimator to multiple bootstrap samples, and averaging the result across bootstrap samples. In order to deal with the curse of dimensionality, typical practice has been to apply bagging to estimators which themselves use cross-validation, thereby using cross-validation within a bootstrap sample to select fine-tuning parameters trading off bias and variance of the bootstrap sample-specific candidate estimators. In this article we point out that in order to achieve the correct bias variance trade-off for the parameter of interest, one should apply the cross-validation selector externally to candidate bagged estimators indexed by these fine-tuning parameters. In addition we define variable importance as a summary measure of the parameter of interest, and present a novel bootstrap method to achieve statistical inference and p-values based on the (externally) cross-validated bagged estimator. We illustrate the new cross-validated bagging method with a data analysis and investigate the performance of the variable importance measures in a small simulation study

Super Learning: An Application to Prediction of HIV-1 Drug Susceptibility

Many statistical methods exist that can be used to learn a predictor based on observed data. Examples include decision trees, neural networks, support vector regression, least angle regression, Logic Regression, and the Deletion/Substitution/Addition algorithm. The optimal algorithm for prediction will vary depending on the underlying data-generating distribution. In this article, we introduce a super learner, a prediction algorithm that applies any set of candidate learners and uses cross-validation to select among them. Theory shows that asymptotically the super learner performs essentially as well or better than any of the candidate learners. We briefly present the theory behind the super learner, before providing an example based on research aimed at predicting the in vitro phenotypic susceptibility of the HIV virus to antiretroviral drugs based on viral mutations. We apply the super learner to predict susceptibility to one protease inhibitor, nelfinavir, using a set of database-derived nonpolymorphic treatment-selected protease mutations

Going Conservative or Conventional? Investigating Farm Management Strategies in between Economic and Environmental Sustainability in Southern Italy

The European “Green Deal” strategy is aimed at making Europe the first climate-neutral continent by 2050 through integrated actions relying on healthier agricultural systems grounded in (environmental and economic) sustainable practices, including soil carbon management and biodiversity enhancement. In this vein, the present study contrasts the economic-environmental performances of conventional (deep tillage) and conservative (no-tillage and soil ripping) practices for two varieties of durum wheat (Triticum turgidum spp. durum), namely a modern (Anco Marzio) and an ancient landrace (Saragolla Lucana) variety in the Basilicata region (Southern Italy). Field and laboratory analysis (granulometry, mineralogy, and geochemistry) as well as satellite data (RapidEye) were used to characterize the soil and vegetation patterns. The empirical results indicate a higher biomass production and vegetative potential together with higher grain yields in soils managed with conventional deep tillage compared with soil managed with conservative practices. Similarly, the modern wheat variety exhibited better performance with respect to the old landrace. The soils managed with conventional practices had a distribution of exchangeable macro-nutrients characterized by a reduction in Ca+ and an increase in Mg2+ and K+ between pre-sowing and post-harvesting. Such a distribution was also genotype-dependent, with a higher variability for Saragolla Lucana than Anco Marzio, showing a diverging adsorption of macro-elements between the modern and ancient landrace varieties

Irrational beliefs about COVID-19: A scoping review

Since the emergence of the recent Coronavirus Disease of 2019 (COVID-19) and its spread as a pandemic, there has been a parallel spread of false and misleading information, known as an infodemic. The COVID-19 infodemic has induced distrust in scientific communities, governments, institutions and the population, and a confidence crisis that has led to harmful health behaviours, also impacting on mental health. The aim of this study is to provide a scoping review of the scientific literature about COVID-19-related misinformation and conspiracy theories, focusing on the construction of a conceptual framework which is useful for the interpretation of the conspiracy theory phenomenon surrounding COVID-19, and its consequences. Particular socio-environmental conditions (i.e., low educational level, younger age), psychological processes and attitudes (such as low levels of epistemic trust, the avoidance of uncertainty, extraversion, collective narcissism, and a conspiracy-prone mindset), and contextual factors (e.g., high levels of self-perceived risk and anxiety) seem to underpin the adherence to beliefs that are not solely the domain of paranoids and extremists but a widespread phenomenon that has caused important health, social and political consequences

Compact solid-state CMOS single-photon detector array for in vivo NIR fluorescence lifetime oncology measurements

In near infrared fluorescence-guided surgical oncology, it is challenging to distinguish healthy from cancerous tissue. One promising research avenue consists in the analysis of the exogenous fluorophores’ lifetime, which are however in the (sub-)nanosecond range. We have integrated a single-photon pixel array, based on standard CMOS SPADs (single-photon avalanche diodes), in a compact, time-gated measurement system, named FluoCam. In vivo measurements were carried out with indocyanine green (ICG)-modified derivatives targeting the avb3 integrin, initially on a genetically engineered mouse model of melanoma injected with ICG conjugated with tetrameric cyclic pentapeptide (ICG􀀀E[c(RGDfK)4]), then on mice carrying tumour xenografts of U87-MG (a human primary glioblastoma cell line) injected with monomeric ICG􀀀c(RGDfK). Measurements on tumor, muscle and tail locations allowed us to demonstrate the feasibility of in vivo lifetime measurements with the FluoCam, to determine the characteristic lifetimes (around 500 ps) and subtle lifetime differences between bound and unbound ICG-modified fluorophores (10% level), as well as to estimate the available photon fluxes under realistic conditions

Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies

Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

Purpose: Recently we showed that a number of carboxylated near-infrared fluorescent (NIRF) cyanine dyes possess strong necrosis avid properties in vitro as well as in different mouse models of spontaneous and therapy-induced tumor necrosis, indicating their potential use for cancer diagnostic- and prognostic purposes. In the previous study, the detection of the cyanines was achieved by whole body optical imaging, a technique that, due to the limited penetration of near-infrared light, is not suitable for investigations deeper than 1 cm within the human body. Therefore, in order to facilitate clinical translation, the purpose of the present study was to generate a necrosis avid cyanine-based NIRF probe that could also be used for single photon emission computed tomography (SPECT). For this, the necrosis avid NIRF cyanine HQ4 was radiolabeled with 111indium, via the chelate diethylene triamine pentaacetic acid (DTPA). Procedures: The necrosis avid properties of the radiotracer [111In]DTPA-HQ4 were examined in vitro and in vivo in different breast tumor models in mice using SPECT and optical imaging. Moreover, biodistribution studies were performed to examine the pharmacokinetics of the probe in vivo. Results: Using optical imaging and radioactivity measurements, in vitro, we showed selective accumulation of [111In]DTPA-HQ4 in dead cells. Using SPECT and in biodistribution studies, the necrosis avidity of the radiotracer was confirmed in a 4T1 mouse breast cancer model of spontaneous tumor necrosis and in a MCF-7 human breast cancer model of chemotherapy-induced tumor necrosis. Conclusions: The radiotracer [111In]DTPA-HQ4 possessed strong and selective necrosis avidity in vitro and in various mouse models of tumor necrosis in vivo, indicating its potential to be clinically applied for diagnostic purposes and to monitor anti-cancer treatment efficacy

Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria.

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.)