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Abstract The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been studied to advance the treatment of neurodegenerative disorders. Here, we explored the transplantation efficacy of different cell subsets and delivery routes with the goal of favoring the establishment of a stable and exclusive engraftment of HSPCs and their progeny in the CNS of female mice. In this setting, we show that the CNS environment drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype. Intra-CNS transplantation of HSPCs engineered to overexpress TREM2 decreased neuroinflammation, Aβ aggregation and improved memory in 5xFAD female mice. Our proof of concept study demonstrates the therapeutic potential of HSPC gene therapy for Alzheimer’s disease.

The aim of this paper is to analyze the current and long-term effects of the European Commission Bioeconomy Strategy in order to outline possible scenarios for rural areas and evaluate their sustainability. The focus is on the main economic sectors, with particular reference to employment and turnover, in order to understand what kind of economy and jobs are intended for rural areas, as well as their territorial impacts. For this purpose, we have analyzed the main European Commission documents and datasets concerning the bioeconomy and long-term planning for rural areas, as well as the recent scientific data to verify the impact on forests. The result is that European rural areas are intended to be converted initially into large-scale biomass producers for energy and bio-based industry, according to the digitization process, and subsequently into biorefinery sites, with severe damage to landscape, environment, biodiversity, land use and local economy. Scenarios for rural areas don’t seem neither sustainable nor profitable, particularly for the peripheral countries (Southern and Eastern countries of the European Union).

The SARS-CoV-2 helicase, non-structural protein 13 (Nsp13), plays an essential role in viral replication, translocating in the 5′ → 3′ direction as it unwinds double-stranded RNA/DNA. We investigated the impact of structurally distinct DNA lesions on DNA unwinding catalyzed by Nsp13. The selected lesions include two benzo[a]pyrene (B[a]P)-derived dG adducts, the UV-induced cyclobutane pyrimidine dimer (CPD), and the pyrimidine (6–4) pyrimidone (6–4PP) photolesion. The experimentally observed unwinding rate constants (kobs) and processivities (P) were examined. Relative to undamaged DNA, the kobs values were diminished by factors of up to ~15 for B[a]P adducts but only by factors of ~2–5 for photolesions. A minor-groove-oriented B[a]P adduct showed the smallest impact on P, which decreased by ~11% compared to unmodified DNA, while an intercalated one reduced P by ~67%. However, the photolesions showed a greater impact on the processivities; notably, the CPD, with the highest kobs value, exhibited the lowest P, which was reduced by ~90%. Our findings thus show that DNA unwinding efficiencies are lesion-dependent and most strongly inhibited by the CPD, leading to the conclusion that processivity is a better measure of DNA lesions’ inhibitory effects than unwinding rate constants.

Biostimulant products are recognized for their ability to improve the agronomic parameters of plants and the qualitative and nutraceutical parameters of fruits and confer greater resistance to plants under abiotic and biotic stress conditions. In our study, we tested three different biostimulants on cultivar “Lady Cot” apricot plants: animal-derived protein hydrolysate, plant-derived protein hydrolysate, and one based on algae to evaluate their effects on improving the agronomic parameters of plants and fruit quality. The product that stood out for providing positive effects was the protein hydrolysate-based product, which increased plant production by 53.80% and yield efficiency by 56.38%. At the same time, it also increased the fruit’s diameter growth by approximately 8.3%, showing positive effects on fruit weight as well. The animal-derived protein hydrolysate also reduced acidity by 13.8% and showed a significant increase compared to the control in terms of total polyphenols. Additional research is scheduled to validate these results and ascertain which categories of biostimulant products are most effective in enhancing the agronomic, qualitative, and sensory characteristics of other apricot cultivars.

The abandonment of inland areas has become a major demographical challenge, causing a condition of local fragility in terms of spatial marginalization. To deal with this issue in Italy, a number of policy actions have been implemented over the time, namely the National Strategy for Inland Areas, established a decade ago, and more recently the Next Generation EU (NGEU) to foster local economic recovery and employment. In this context, RI.P.R.O.VA.RE., a project funded by the former Italian Ministry of the Environment and Protection of Land and Sea (MATTM), was aimed at strengthening the resilience features of communities and territories, focusing on areas within the Matese and Ufita in the Campania region and the Medio Agri in the Basilicata region (southern Italy). Besides the ability to respond to different pressure factors (e.g., of demographic and economic origin), the project also addressed issues concerning seismic and flood risks. This paper synthesizes the methods and tools provided for their analysis and mitigation as a prerequisite for regenerating inland areas. After presenting the developed methods and tools, the results obtained for the Matese study area are presented and discussed. While, on the one hand, the retrieved risk zoning maps allow individuating those municipalities requiring priority structural interventions, on the other hand, the latter are properly individuated based on the peculiar characteristics of urban fabrics.

IntroductionProcesses of redefinition of work, already in place in the pre-pandemic era, with the advent of COVID-19, have become widely required. A “model of work” that uses new technologies and the development of existing ones to improve workers’ performance and satisfaction has emerged. Smart working has changed how people work and, as a result, spaces must also change to support them. The use of prefabricated movable buildings (PMB) could represent an opportunity to create smart (and co-) working spaces in a regenerative contest. Small villages with historical, architectural, and naturalistic elements and slow-life features are potential platforms where vacation and work could merge easily. This paper aims to establish if working in movable offices, like the PMBs, which provide a high level of visual and acoustics interaction with the surroundings, and which is positioned in small villages’ squares, can affect workers’ sense of restoration and working performance.MethodsIn a laboratory setting, in the SENS i-Lab, a videowall and a 3D spatial audio system were used to compare, in terms of restorativeness and self-reported cognitive performance, the effects of a high-rise building context of a City Business District (CBD), i.e. the control scenario, and of two typical squares of small Italian villages with historic buildings, without (HIS) and with water elements (HIS-W).ResultsThe findings of the experimental sessions showed that when working in close contact (visual and auditory) with historical or water elements, where life flows slowly, workers perceived a higher sense of restoration while job performance was unchanged.DiscussionImplementing smart working policies in small villages that encourage the use of energy-efficient prefabricated movable buildings and that offer a high level of visual and acoustic interaction with the surrounding environment may represent a promising strategy to foster the development of the local economy and contrast the depopulation of small villages, improving the worker well-being and the reducing the impact of their activities of the environment.

Abstract Background Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the absence of a specific combination antiretroviral treatment (ART). Integrase strand transfer inhibitors (INSTIs) are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs. Methods Phylogenetic analysis of lentiviral integrase (IN) sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD) was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD). Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR. Results The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810. Conclusion We report a drug class (other than nucleosidic reverse transcriptase inhibitors) that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound successfully tested in human clinical trials, as one of the most potent anti-FIV agents ever tested in vitro. This finding may provide new avenues for treating FIV infection and contribute to the development of a small animal model mimicking the effects of ART in humans.

Abstract Background The genome of Bacillus anthracis, the etiological agent of anthrax, is highly monomorphic which makes differentiation between strains difficult. A Multiple Locus Variable-number tandem repeats (VNTR) Analysis (MLVA) assay based on 20 markers was previously described. It has considerable discrimination power, reproducibility, and low cost, especially since the markers proposed can be typed by agarose-gel electrophoresis. However in an emergency situation, faster genotyping and access to representative databases is necessary. Results Genotyping of B. anthracis reference strains and isolates from France and Italy was done using a 25 loci MLVA assay combining 21 previously described loci and 4 new ones. DNA was amplified in 4 multiplex PCR reactions and the length of the resulting 25 amplicons was estimated by automated capillary electrophoresis. The results were reproducible and the data were consistent with other gel based methods once differences in mobility patterns were taken into account. Some alleles previously unresolved by agarose gel electrophoresis could be resolved by capillary electrophoresis, thus further increasing the assay resolution. One particular locus, Bams30, is the result of a recombination between a 27 bp tandem repeat and a 9 bp tandem repeat. The analysis of the array illustrates the evolution process of tandem repeats. Conclusion In a crisis situation of suspected bioterrorism, standardization, speed and accuracy, together with the availability of reference typing data are important issues, as illustrated by the 2001 anthrax letters event. In this report we describe an upgrade of the previously published MLVA method for genotyping of B. anthracis and apply the method to the typing of French and Italian B. anthracis strain collections. The increased number of markers studied compared to reports using only 8 loci greatly improves the discrimination power of the technique. An Italian strain belonging to the B branch was described, and two new branches, D and E, are proposed. Owing to the upgrading achieved here, precise genotyping can now be produced either by automated capillary electrophoresis, or by the more accessible but slower and for some markers slightly less accurate agarose gel methodology.

Automated Fault Detection and Diagnosis (AFDD) algorithms could represent one of the most effective solutions in order to reduce energy demand, greenhouse gas emissions and running costs of Heating, Ventilation and Air-Conditioning (HVAC) systems equipped with Air-Handling Units (AHUs). In particular, data-driven AFDD tools are recognized as easier to be developed and able to provide a higher accuracy with respect to other AFDD tools. However, they are still in the early stage of adoption stock-wide mainly due to the facts that data-driven AFDD models (i) require labeled and reliable experimental faulty data that are time-consuming and expensive to be obtained under different operating scenarios, and (ii) cannot operate beyond the training data. In this paper the most significant scientific papers focusing on experimental analyses of AHUs aiming at the development of data-driven AFDD algorithms have been systematically reviewed and categorized in order to highlight the most important research gaps to be still covered. In particular, the AHU operating schemes, fault types, faults severities and climatic conditions requiring further studies have been identified with the main aim of supporting and guide the future development of new and accurate data-driven AFDD systems.

The SARS-CoV-2 helicase, non-structural protein 13 (Nsp13), plays an essential role in viral replication, translocating in the 5′ → 3′ direction as it unwinds double-stranded RNA/DNA. We investigated the impact of structurally distinct DNA lesions on DNA unwinding catalyzed by Nsp13. The selected lesions include two benzo[a]pyrene (B[a]P)-derived dG adducts, the UV-induced cyclobutane pyrimidine dimer (CPD), and the pyrimidine (6–4) pyrimidone (6–4PP) photolesion. The experimentally observed unwinding rate constants (kobs) and processivities (P) were examined. Relative to undamaged DNA, the kobs values were diminished by factors of up to ~15 for B[a]P adducts but only by factors of ~2–5 for photolesions. A minor-groove-oriented B[a]P adduct showed the smallest impact on P, which decreased by ~11% compared to unmodified DNA, while an intercalated one reduced P by ~67%. However, the photolesions showed a greater impact on the processivities; notably, the CPD, with the highest kobs value, exhibited the lowest P, which was reduced by ~90%. Our findings thus show that DNA unwinding efficiencies are lesion-dependent and most strongly inhibited by the CPD, leading to the conclusion that processivity is a better measure of DNA lesions' inhibitory effects than unwinding rate constants. [ABSTRACT FROM AUTHOR]

IntroductionIn hospitalized patients with COVID-19, bloodstream infections (BSI) are associated with high mortality and high antibiotic resistance rates. The aim of this study was to describe BSI etiology, antimicrobial resistance profile and risk factors in a sample of patients deceased with COVID-19 from the Italian National COVID-19 surveillance.MethodsHospital charts of patients who developed BSI during hospitalization were reviewed to describe the causative microorganisms and their antimicrobial susceptibility profiles. Risk factors were analyzed in univariate and multivariate analyses.ResultsThe study included 73 patients (71.2% male, median age 70): 40 of them (54.8%) received antibiotics and 30 (41.1%) systemic steroids within 48 h after admission; 53 (72.6%) were admitted to intensive care unit. Early steroid use was associated with a significantly shorter interval between admission and BSI occurrence. Among 107 isolated microorganisms, the most frequent were Enterococcus spp., Candida spp., Acinetobacter baumannii, and Klebsiella pneumoniae. Median time from admission to BSI was shorter for Staphylococcus aureus compared to all other bacteria (8 vs. 24 days, p = 0.003), and longer for Enterococcus spp., compared to all other bacteria (26 vs. 18 days, p = 0.009). Susceptibility tests showed a high rate of resistance, with 37.6% of the bacterial isolates resistant to key antibiotics. Resistance was associated with geographical area [adjusted odds ratio (AOR) for Central/South Italy compared to North Italy: 6.775, p = 0.002], and with early use of systemic steroids (AOR 6.971, p = 0.018).ConclusionsIn patients deceased with COVID-19, a large proportion of BSI are caused by antibiotic-resistant bacteria. Early steroid use may facilitate this occurrence.

BackgroundInjection drug use (IDU) is the leading risk factor for hepatitis C virus (HCV) transmission in the U.S. While the general risk factors for HCV transmission are known, there is limited work on how these factors interact and impact young people who inject drugs (YPWID).MethodsProject data were drawn from a study of 539 New York City (NYC) residents ages 18-29 who were recruited via Respondent-Driven Sampling and, reported past-month non-medical use of prescription opioids and/or heroin. Analyses are based on a subsample of 337 (62%) who reported injecting any drug in the past 12 months. All variables were assessed via self-report, except HCV status, which was established via rapid antibody testing. Integrating the observed statistical associations with extant literature on HCV risk, we also developed a qualitative system dynamics (SD) model to use as a supplemental data visualization tool to explore plausible pathways and interactions among key risk and protective factors for HCV.ResultsResults showed a 31% HCV antibody prevalence with an overall incidence of 10 per 100 person-years. HCV status was independently correlated with having shared cookers with two or more people (AOR = 2.17); injected drugs 4–6 years (AOR = 2.49) and 7 or more years (AOR = 4.95); lifetime homelessness (AOR = 2.52); and having been incarcerated two or more times (AOR = 1.99). These outcomes along with the extant literature on HCV risk were used to develop the qualitative SD model, which describes a causal hypothesis around non-linearities and feedback loop structures underlying the spread of HCV among YPWID.ConclusionsDespite ongoing harm reduction efforts, close to a third of YPWID in the community sample have been exposed to HCV, have risks for injection drug use, and face challenges with structural factors that may be preventing adequate intervention. The qualitative SD model explores these issues and contributes to a better understanding of how these various risk factors interact and what policies could potentially be effective in reducing HCV infections.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which new therapeutic options are urgently needed. We injected GFP+ adipose-derived stem cells (EGFP-ADSCs) directly into the cerebrospinal fluid (CSF) of transgenic SOD1G93A mice, a well-characterized model of familial ALS. Despite short-term survival of the injected cells and limited engraftment efficiency, EGFP-ADSCs improved motor function and delayed disease onset by promoting motor neuron (MN) survival and reducing glial activation. We then tested the in vitro neuroprotective potential of mouse ADSCs in astrocyte/MN co-cultures where ALS astrocytes show neurotoxicity. ADSCs were able to rescue MN death caused by ALS astrocytes derived from symptomatic SOD1G93A mice. Further, ADSCs were found to reduce the inflammatory signature of ALS astrocytes by inhibiting the release of pro-inflammatory mediators and inducing the secretion of neuroprotective factors. Finally, mouse ADSCs were able to protect MNs from the neurotoxicity mediated by human induced astrocytes (iAstrocytes) derived from patients with either sporadic or familial ALS, thus for the first time showing the potential therapeutic translation of ADSCs across the spectrum of human ALS. These data in two translational models of ALS show that, through paracrine mechanisms, ADSCs support MN survival and modulate the toxic microenvironment that contributes to neurodegeneration in ALS.

Biostimulant products are recognized for their ability to improve the agronomic parameters of plants and the qualitative and nutraceutical parameters of fruits and confer greater resistance to plants under abiotic and biotic stress conditions. In our study, we tested three different biostimulants on cultivar "Lady Cot" apricot plants: animal-derived protein hydrolysate, plant-derived protein hydrolysate, and one based on algae to evaluate their effects on improving the agronomic parameters of plants and fruit quality. The product that stood out for providing positive effects was the protein hydrolysate-based product, which increased plant production by 53.80% and yield efficiency by 56.38%. At the same time, it also increased the fruit's diameter growth by approximately 8.3%, showing positive effects on fruit weight as well. The animal-derived protein hydrolysate also reduced acidity by 13.8% and showed a significant increase compared to the control in terms of total polyphenols. Additional research is scheduled to validate these results and ascertain which categories of biostimulant products are most effective in enhancing the agronomic, qualitative, and sensory characteristics of other apricot cultivars. [ABSTRACT FROM AUTHOR]

The abandonment of inland areas has become a major demographical challenge, causing a condition of local fragility in terms of spatial marginalization. To deal with this issue in Italy, a number of policy actions have been implemented over the time, namely the National Strategy for Inland Areas, established a decade ago, and more recently the Next Generation EU (NGEU) to foster local economic recovery and employment. In this context, RI.P.R.O.VA.RE., a project funded by the former Italian Ministry of the Environment and Protection of Land and Sea (MATTM), was aimed at strengthening the resilience features of communities and territories, focusing on areas within the Matese and Ufita in the Campania region and the Medio Agri in the Basilicata region (southern Italy). Besides the ability to respond to different pressure factors (e.g., of demographic and economic origin), the project also addressed issues concerning seismic and flood risks. This paper synthesizes the methods and tools provided for their analysis and mitigation as a prerequisite for regenerating inland areas. After presenting the developed methods and tools, the results obtained for the Matese study area are presented and discussed. While, on the one hand, the retrieved risk zoning maps allow individuating those municipalities requiring priority structural interventions, on the other hand, the latter are properly individuated based on the peculiar characteristics of urban fabrics. [ABSTRACT FROM AUTHOR]

Abstract An elderly patient with head injury was registered to the emergency room. Because the patient arrived to the hospital unconscious, her cranial, cerebrovascular, and cardiac function was studied. The cardiac function measurements were (i) heart rate, (ii) blood pressure, (iii) oxygen saturation level, (iv) electrocardiogram (ECG), (v) coronary angiogram, (vi) chest computerized tomography (CT), and (vii) echocardiogram. The head damage was studied by cerebral CT and magnetic resonance imaging (MRI). The serum ischemia and inflammatory biomarkers were analysed. For the immediate treatment, the patient received cardiovascular system supporting medication. The cardiac diagnostic results were (i) the ECG suggested an elevation in the left ventricular systolic function, (ii) the blood test showed neutrophilia, increased creatine and increased troponin I kinase values, and (iii) the coronary angiogram and ECG analysis demonstrated a lack of a myocardial infarction but identified apical akinesia. The patient did not have previous symptoms of cardiovascular disease. The brain imaging demonstrated (iv) an acute ischemia in the left occipital area and (v) increased intracranial pressure. Brain MRI indicated (vi) aqueductal stenosis and (vii) multiple gliomatotic foci demonstrating hydrocephalus caused by gliomatosis cerebri. A chest CT indicated (viii) chronic obstructive pulmonary disease (COPD). One week later, the patient died because of cardiac arrest. The diagnosis was Takotsubo syndrome enforced by gliomatosis cerebri and COPD. To our knowledge, this is the first reported case in which the cardiac dysfunction of the patient is associated with gliomatosis cerebri‐derived hydrocephalus and increased intracranial pressure that together with COPD may have enhanced the negative clinical outcome.

ABSTRACTThe RNA purification is the gold standard for the detection of SARS-CoV-2 in swab samples, but it is dependent on the availability of chemical reagents. In this study, we evaluated the heat treatment method without RNA extraction as a reliable option to nucleic acid purification.

Abstract Background Idiopathic Pulmonary Fibrosis (IPF) is an aggressive interstitial lung disease with an unpredictable course. Occupational dust exposure may contribute to IPF onset, but its impact on antifibrotic treatment and disease prognosis is still unknown. We evaluated clinical characteristics, respiratory function and prognostic predictors at diagnosis and at 12 month treatment of pirfenidone or nintedanib in IPF patients according to occupational dust exposure. Methods A total of 115 IPF patients were recruited. At diagnosis, we collected demographic, clinical characteristics, occupational history. Pulmonary function tests were performed and two prognostic indices [Gender, Age, Physiology (GAP) and Composite Physiologic Index (CPI)] calculated, both at diagnosis and after the 12 month treatment. The date of long-term oxygen therapy (LTOT) initiation was recorded during the entire follow-up (mean = 37.85, range 12–60 months). Results At baseline, patients exposed to occupational dust [≥ 10 years (n = 62)] showed a lower percentage of graduates (19.3% vs 54.7%; p = 0.04) and a higher percentage of asbestos exposure (46.8% vs 18.9%; p 0.002) than patients not exposed [

Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed.