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ROHs are long stretches of DNA homozygous at each polymorphic position. The proportion of genome covered by ROHs and their length are indicators of the level and origin of inbreeding. Frequent commonROHs withinthe samepopulationdefineROHislandsand indicatehotspots of selection. In this work, we investigated ROHs in a total of 1131 pigs from20 European local pig breeds and in three cosmopolitan breeds, genotyped with the GGP PorcineHDGenomic Profiler. PLINK software was used to identify ROHs. Size classes and genomic inbreeding parameters were evaluated. ROH islands were defined by evaluating different thresholds of homozygous SNP frequency. A functional overview of breed-specific ROH islands was obtained via overrepresentation analyses of GO biological processes. Mora Romagnola and Turopolje breeds had the largest proportions of genome covered with ROH (~1003 and ~955 Mb respectively), whereas Nero Siciliano and Sarda breeds had the lowest proportions (~207 and 247 Mb respectively). The highest proportion of long ROH (>16 Mb) was in Apulo-Calabrese, Mora Romagnola and Casertana. The largest number of ROH islands was identified in the Italian Landrace (n=32), Cinta Senese (n=26) and LithuanianWhite Old Type (n=22) breeds. Several ROH islands were in regions encompassing genes known to affect morphological traits. Comparative ROH structure analysis among breeds indicated the similar genetic structure of local breeds across Europe. This study contributed to understanding of the genetic history of

The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumor–initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

Single-cell epigenomic assays have tremendous potential to illuminate mechanisms of transcriptional control in functionally diverse cancer cell populations. However, application of these techniques to clinical tumor specimens has been hampered by the current inability to distinguish malignant from nonmalignant cells, which potently confounds data analysis and interpretation. Here, we describe Copy-scAT, an R package that uses single-cell epigenomic data to infer copy number variants (CNVs) that define cancer cells. Copy-scAT enables studies of subclonal chromatin dynamics in complex tumors like glioblastoma. By deploying Copy-scAT, we uncovered potent influences of genetics on chromatin accessibility profiles in individual subclones. Consequently, some genetic subclones were predisposed to acquire stem-like or more differentiated molecular phenotypes, reminiscent of developmental paradigms. Copy-scAT is ideal for studies of the relationships between genetics and epigenetics in malignancies with high levels of intratumoral heterogeneity and to investigate how cancer cells interface with their microenvironment.

To date, the leading causes of mortality and morbidity worldwide include viral infections, such as Ebola, influenza virus, acquired immunodeficiency syndrome (AIDS), severe acute respiratory syndrome (SARS) and recently COVID-19 disease, caused by the SARS-CoV-2 virus. Currently, we can count on a narrow range of antiviral drugs, especially older generation ones like ribavirin and interferon which are effective against viruses in vitro but can often be ineffective in patients. In addition to these, we have antiviral agents for the treatment of herpes virus, influenza virus, HIV and hepatitis virus. Recently, drugs used in the past especially against ebolavirus, such as remdesivir and favipiravir, have been considered for the treatment of COVID-19 disease. However, even if these drugs represent important tools against viral diseases, they are certainly not sufficient to defend us from the multitude of viruses present in the environment. This represents a huge problem, especially considering the unprecedented global threat due to the advancement of COVID-19, which represents a potential risk to the health and life of millions of people. The demand, therefore, for new and effective antiviral drugs is very high. This review focuses on three fundamental points: (1) presents the main threats to human health, reviewing the most widespread viral diseases in the world, thus describing the scenario caused by the disease in question each time and evaluating the specific therapeutic remedies currently available. (2) It comprehensively describes main phytochemical classes, in particular from plant foods, with proven antiviral activities, the viruses potentially treated with the described phytochemicals. (3) Consideration of the various applications of drug delivery systems in order to improve the bioavailability of these compounds or extracts. A PRISMA flow diagram was used for the inclusion of the works. Taking into consideration the recent dramatic events caused by COVID-19 pa

In this paper we consider the fractional nonlinear Schrödinger equation $$ \eps^{2s}(- \Delta)^s v+ V(x) v= f(v), \quad x \in \R^N$$ where $s \in (0,1)$, $N \geq 2$, $V \in C(\R^N,\R)$ is a positive potential and $f$ is a nonlinearity satisfying Berestycki-Lions type conditions. For $\eps>0$ small, we prove the existence of at least $\cupl(K)+1$ positive solutions, where $K$ is a set of local minima in a bounded potential well and $\cupl(K)$ denotes the cup-length of $K$. By means of a variational approach, we analyze the topological difference between two levels of an indefinite functional in a neighborhood of expected solutions. Since the nonlocality comes in the decomposition of the space directly, we introduce a new fractional center of mass, via a suitable seminorm. Some other delicate aspects arise strictly related to the presence of the nonlocal operator. By using regularity results based on fractional De Giorgi classes, we show that the found solutions decay polynomially and concentrate around some point of $K$ for $\eps$ small.

Due to an oversight in the production process, the following errors were introduced into the article. On page 4019, the list (g1)1, g(1)2 and g(1)3 has been corrected to read (g1), (g2), and (g3). Similarly, on page 4022, the list (f1)1, f(1)2 and f(1)3 has been corrected to read (f1), (f2), and (f3).

We study existence of solutions for the fractional problem \begin{equation*} (P_m) \quad \parag{ (-\Delta)^{s} u + \mu u &=g(u) & \; \text{in $\mathbb{R}^N$}, \cr \int_{\mathbb{R}^N} u^2 dx &= m, & \cr u \in H^s_r&(\mathbb{R}^N), & } \end{equation*} where $N\geq 2$, $s\in (0,1)$, $m>0$, $\mu$ is an unknown Lagrange multiplier and $g \in C(\mathbb{R}, \mathbb{R})$ satisfies Berestycki-Lions type conditions. Using a Lagrangian formulation of the problem $(P_m)$, we prove the existence of a weak solution with prescribed mass when $g$ has $L^2$ subcritical growth. The approach relies on the construction of a minimax structure, by means of a \emph{Pohozaev's mountain} in a product space and some deformation arguments under a new version of the Palais-Smale condition introduced in \cite{HT0,IT0}. A multiplicity result of infinitely many normalized solutions is also obtained if $g$ is odd.

We prove the existence of a spherically symmetric solution for a Schr\"odinger equation with a nonlocal nonlinearity of Choquard type, i.e. $$ (- \Delta)^s u + \mu u = (I_\alpha*F(u))f(u) \quad \hbox{in $\mathbb{R}^N$}, $$ where $N\geq 2$, $s \in (0,1)$, $\alpha\in (0,N)$, $I_\alpha(x)=\frac{A_{N,\alpha}}{|x|^{N-\alpha}}$ is the Riesz potential, $\mu>0$ is part of the unknowns, and $F\in C^1(\mathbb{R},\mathbb{R})$, $F' = f$ is assumed to be subcritical and to satisfy almost optimal assumptions. The mass of of the solution, described by its norm in the $L^2$-space, is prescribed in advance by $\int_{\mathbb{R}^N} u^2 \, dx = c$ for some $c>0$. The approach to this constrained problem relies on a Lagrange formulation and new deformation arguments. In addition, we prove that the obtained solution is also a ground state, which means that it realizes minimal energy among all the possible solutions to the problem.

Goal of this paper is to study the following singularly perturbed nonlinear Schr\"odinger equation $$ \varepsilon^{2s}(- \Delta)^s v+ V(x) v= f(v), \quad x \in \mathbb{R}^N,$$ where $s \in (0,1)$, $N \geq 2$, $V \in C(\mathbb{R}^N,\mathbb{R})$ is a positive potential and $f$ is assumed critical and satisfying general Berestycki-Lions type conditions. When $\eps>0$ is small, we obtain existence and multiplicity of semiclassical solutions, relating the number of solutions to the cup-length of a set of local minima of $V$; in particular we improve the result in \cite{HeZo}. Furthermore, these solutions are proved to concentrate in the potential well, exhibiting a polynomial decay. Finally, we prove the previous results also in the limiting local setting $s=1$ and $N\geq 3$, with an exponential decay of the solutions.

As the COVID-19 outbreak traveled through various Italian regions, all national and local administrations issued measures to counter the spread of the contagion and organize healthcare. The Italian healthcare system is, indeed, a decentralized system with 21 regional health systems (RHSs), with different models of healthcare service delivery and organization. This study investigates whether a different organization of RHSs would have led to different management of the COVID-19 epidemic, and evaluates the effect of different approaches in epidemic management on the COVID-19 epidemiological trend. A set of indicators is identified by conducting an online synchronous Focus Group, involving an experts panel. A Pearson's correlation test was performed on the values assumed by the historical series of indicators investigate correlations among the trends represented by the indicators or between them and external factors. The comparison between the experiences of the different Italian regions, regarding the management of the epidemic, has helped to confirm and emphasize the importance of a community-based approach in health care—integrated with the hospital’s functions for the care of complex conditions and the need for specialized assistance.

Aim: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). Data synthesis: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH–OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH–OR 0.58 [0.23, 1.45]). Conclusions: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.

Aim: Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM. Data synthesis: A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients’ adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH–OR), with 95% Confidence Interval (CI), were calculated. We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89; 0.09] mmol/mol, p = 0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education. Conclusions: In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients’ knowledge. Prospero and OSF registration: ID243149.

Aims: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i. Data synthesis: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel–Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure. Conclusions: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure.