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Although maximal force increases following short-term isometric strength training, the rate of force development (RFD) may remain relatively unaffected. The underlying neural and muscular mechanisms during rapid contractions after strength training are largely unknown. Since strength training increases the neural drive to muscles, it may be hypothesized that there are distinct neural or muscular adaptations determining the change in RFD independently of an increase in maximal force. Therefore, we examined motor unit population data acquired from surface electromyography during the rapid generation of force before and after 4 wk of strength training. We observed that strength training did not change the RFD because it did not influence the number of motor units recruited per second or their initial discharge rate during rapid contractions. Although strength training did not change motoneuron behavior in the force increase phase of rapid contractions, it increased the discharge rate of motoneurons (by ∼4 spikes/s) when reaching the plateau phase (∼150 ms) of the rapid contractions, determining an increase in maximal force production. Computer simulations with a motor unit model that included neural and muscular properties, closely matched the experimental observations and demonstrated that the lack of change in RFD following training is primarily mediated by an unchanged maximal recruitment speed of motoneurons. These results demonstrate that maximal force and contraction speed are determined by different adaptations in motoneuron behavior following strength training and indicate that increases in the recruitment speed of motoneurons are required to evoke training-induced increases in RFD.NEW & NOTEWORTHY Although maximal force increases with strength training, the rate of force development may remain unaffected. For the first time, we associated motor unit population behavior during rapid force contractions before and after a 4-wk isometric strength training intervention. We found that strength training combined with slow and rapid contractions does not change rate of force development. The specific mechanisms include similar discharge rate during the initial phase of contraction and similar recruitment speed of motoneurons.

Thermotoga maritima Arginine Binding Protein has been extensively characterized because of its peculiar features and its possible use as a biosensor. In this characterization, deletion of the C-terminal helix to obtain the monomeric protein TmArgBP20–233 and dissection of the monomer in its two domains, D1 and D2, have been performed. In the present study the stability of these three forms against guanidinium chloride is investigated by means of circular dichroism and differential scanning calorimetry measurements. All three proteins show a high conformational stability; moreover, D1 shows an unusual behavior in the presence of low concentrations of guanidinium chloride. This finding has led us to investigate a possible binding interaction by means of isothermal titration calorimetry and X-ray crystallography; the results indicate that D1 is able to bind the guanidinium ion (GuH+), due to its similarity with the arginine terminal moiety. The analysis of the structural and dynamic properties of the D1-GuH+ complex indicates that the protein binds the ligand through multiple and diversified interactions. An exhaustive survey of the binding modes of GuH+ to proteins indicates that this is a rather common feature. These observations provide interesting insights into the effects that GuH+ is able to induce in protein structures.

Background: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3–8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. Methods: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. Results: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. Conclusions: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

Treatment for hallux valgus (HV) remains challenging. Third-generation percutaneous procedures try to reproduce chevron-type osteotomies to replicate their benefits, such as intrinsic stability and reproducibility. We report the first results using a percutaneous, intra-articular, chevron osteotomy (PeICO) technique that mimics the classic intra-articular open chevron procedure, associated with a percutaneous adductor tendon release (PATR) for the treatment of mild-to-moderate HV. From May 2015 to October 2018, a total of consecutive 114 feet (74 patients) were included. Primary outcome measures included radiographic (hallux valgus and intermetatarsal angles) and clinical parameters such as visual analog scale (VAS), FAAM Activities of Daily Living (ADL), and FAAM Sport, AOFAS Score, and MOXFQ, preoperatively and at final follow-up (Minimum 18 months). A patient satisfaction survey was also performed. Pronation and length of the first metatarsal were also assessed. Secondary outcomes included fluoroscopic time, length of surgery, complications, recurrence, and re-operation rates. At 24.09 months on average, the AOFAS score improved from 52.1 points preoperatively to 91.1 (p

In February and March 2020, two mass swab testing campaigns were conducted in Vo’, Italy. In May 2020, we tested 86% of the Vo’ population with three immuno-assays detecting antibodies against the spike and nucleocapsid antigens, a neutralisation assay and Polymerase Chain Reaction (PCR). Subjects testing positive to PCR in February/March or a serological assay in May were tested again in November. Here we report on the results of the analysis of the May and November surveys. We estimate a seroprevalence of 3.5% (95% Credible Interval (CrI): 2.8–4.3%) in May. In November, 98.8% (95% Confidence Interval (CI): 93.7–100.0%) of sera which tested positive in May still reacted against at least one antigen; 18.6% (95% CI: 11.0–28.5%) showed an increase of antibody or neutralisation reactivity from May. Analysis of the serostatus of the members of 1,118 households indicates a 26.0% (95% CrI: 17.2–36.9%) Susceptible-Infectious Transmission Probability. Contact tracing had limited impact on epidemic suppression., Vo’, Italy, is a unique setting for studying SARS-CoV-2 antibody dynamics because mass testing was conducted there early in the pandemic. Here, the authors perform two follow-up serological surveys and estimate seroprevalence, the extent of within-household transmission, and the impact of contact tracing.

Initiation of protein-primed (−) strand DNA synthesis in hepatitis B virus (HBV) requires interaction of the viral polymerase with a cis-acting regulatory signal, designated epsilon ([Formula: see text]), located at the 5′-end of its pre-genomic RNA (pgRNA). Binding of polymerase to [Formula: see text] is also necessary for pgRNA encapsidation. While the mechanistic basis of this interaction remains elusive, mutagenesis studies suggest its internal 6-nt “priming loop” provides an important structural contribution. [Formula: see text] might therefore be considered a promising target for small molecule interventions to complement current nucleoside-analog based anti-HBV therapies. An ideal prerequisite to any RNA-directed small molecule strategy would be a detailed structural description of this important element. Herein, we present a solution NMR structure for HBV [Formula: see text] which, in combination with molecular dynamics and docking simulations, reports on a flexible ligand “pocket”, reminiscent of those observed in proteins. We also demonstrate the binding of the selective estrogen receptor modulators (SERMs) Raloxifene, Bazedoxifene, and a de novo derivative to the priming loop.

Background: In this cross-sectional, international study, we aimed to analyze vector-borne and zoonotic infections (VBZI), which are significant global threats. Method: VBZIs’ data between May 20–28, 2018 was collected. The 24 Participatingcountries were classified as lower-middle, upper-middle, and high-income. Results: 382 patients were included. 175(45.8%) were hospitalized, most commonly in Croatia, Egypt, and Romania(P = 0.001). There was a significant difference between distributions of VBZIs according to geographical regions(P < 0.001). Amebiasis, Ancylostomiasis, Blastocystosis, Cryptosporidiosis, Giardiasis, Toxoplasmosis were significantly more common in the Middle-East while Bartonellosis, Borreliosis, Cat Scratch Disease, Hantavirus syndrome, Rickettsiosis, Campylobacteriosis, Salmonellosis in Central/East/South-East Europe; Brucellosis and Echinococcosis in Central/West Asia; Campylobacteriosis, Chikungunya, Tick-borne encephalitis, Visceral Leishmaniasis, Salmonellosis, Toxoplasmosis in the North-Mediterranean; CCHF, Cutaneous Leishmaniasis, Dengue, Malaria, Taeniasis, Salmonellosis in Indian Subcontinent; Lassa Fever in West Africa. There were significant regional differences for viral hemorrhagic fevers(P < 0.001) and tick-borne infections(P < 0.001), and according to economic status for VBZIs(P < 0.001). The prevalences of VBZIs were significantly higher in lower-middle income countries(P = 0.001). The most similar regions were the Indian Subcontinent and the Middle-East, the Indian Subcontinent and the North-Mediterranean, and the Middle-East and North-Mediterranean regions. Conclusions: Regional and socioeconomic heterogeneity still exists for VBZIs. Control and eradication of VBZIs require evidence-based surveillance data, and multidisciplinary efforts.

Background: Previous research highlighted positive musculoskeletal adaptations resulting from mechanical forces and loadings distinctive to impacts and movements with sports participation. However, little is known about these adaptations in combat athletes. The aim of this study was to quantify bone mineral density, lean muscle mass and punching and kicking power in amateur male combat athletes. Methods: Thirteen male combat athletes (lightweight and middleweight) volunteered all physiological tests including dual energy X-ray absorptiometry for bone mineral density (BMD) segmental body composition (lean muscle mass, LMM), muscle strength and striking power, sedentary controls (n = 15) were used for selected DXA outcome variables. Results: There were significant differences (p p versus non-dominant) were significantly different between combat groups (p versus 7.3%). There were no differences in punch/kick power (absolute or relative) between combat groups. 5RM strength (bench and squat) correlated significantly with upper limb striking power (r = 0.57), dominant and non-dominant leg BMD (r = 0.67, r = 0.70, respectively) and total body BMD (r = 0.59). Conclusion: BMD and LMM appear to be particularly important to discriminate between dominant and non-dominant upper limbs and less so for lower limb dominance in recreational combat athletes.

There is a paucity of information on the clinical course and outcome of young cats with polyneuropathy. The aim of the study was to describe the clinical features, diagnostic investigations, and outcome of a large cohort of cats with inflammatory polyneuropathy from several European countries. Seventy cats with inflammatory infiltrates in intramuscular nerves and/or peripheral nerve biopsies were retrospectively included. Information from medical records and follow up were acquired via questionnaires filled by veterinary neurologists who had submitted muscle and nerve biopsies (2011–2019). Median age at onset was 10 months (range: 4–120 months). The most common breed was British short hair (25.7%), followed by Domestic short hair (24.3%), Bengal cat (11.4%), Maine Coon (8.6%) and Persian cat (5.7%), and 14 other breeds. Male cats were predominantly affected (64.3%). Clinical signs were weakness (98.6%) and tetraparesis (75.7%) in association with decreased withdrawal reflexes (83.6%) and, less commonly, cranial nerve signs (17.1%), spinal pain/hyperesthesia (12.9%), and micturition/defecation problems (14.3%). Onset was sudden (30.1%) or insidious (69.1%), and an initial progressive phase was reported in 74.3%. Characteristic findings on electrodiagnostic examination were presence of generalized spontaneous electric muscle activity (89.6%), decreased motor nerve conduction velocity (52.3%), abnormal F-wave studies (72.4%), pattern of temporal dispersion (26.1%) and unremarkable sensory tests. The clinical course was mainly described as remittent (49.2%) or remittent-relapsing (34.9%), while stagnation, progressive course or waxing and waning were less frequently reported. Relapses were common and occurred in 35.7% of the cats' population. An overall favorable outcome was reported in 79.4% of patients. In conclusion, young age at the time of diagnosis and sudden onset of clinical signs were significantly associated with recovery (p < 0.05). Clinical and electrodiagnostic features and the remittent-relapsing clinical course resembles juvenile chronic inflammatory demyelinating polyneuropathy (CIDP), as seen in human (children/adolescents), in many aspects.

Evaluating trends in antibiotic resistance is a requisite. The study aimed to analyze the profile of multidrug-resistant organisms (MDROs) among hospitalized patients with bacteremia in intensive care units (ICUs) in a large geographical area. This is a 1-month cross-sectional survey for blood-borne pathogens in 57 ICUs from 24 countries with different income levels: lower-middle-income (LMI), upper-middle-income (UMI), and high-income (HI) countries. Multidrug-resistant (MDR), extensively drug-resistant (XDR), or pan-drug-resistant isolates were searched. Logistic regression analysis determined resistance predictors among MDROs. Community-acquired infections were comparable to hospital-acquired infections particularly in LMI (94/202; 46.5% vs 108/202; 53.5%). Although MDR (65.1%; 502/771) and XDR (4.9%; 38/771) were common, no pan-drug-resistant isolate was recovered. In total, 32.1% of MDR were Klebsiella pneumoniae, and 55.3% of XDR were Acinetobacter baumannii. The highest MDR and XDR rates were in UMI and LMI, respectively, with no XDR revealed from HI. Predictors of MDR acquisition were male gender (OR, 12.11; 95% CI, 3.025-15.585) and the hospital-acquired origin of bacteremia (OR, 2.643; 95%CI, 1.462-3.894), and XDR acquisition was due to bacteremia in UMI (OR, 3.344; 95%CI, 1.189-5.626) and admission to medical-surgical ICUs (OR, 1.481; 95% CI, 1.076-2.037). We confirm the urgent need to expand stewardship activities to community settings especially in LMI, with more paid attention to the drugs with a higher potential for resistance. Empowering microbiology laboratories and reports to direct prescribing decisions should be prioritized. Supporting stewardship in ICUs, the mixed medical-surgical ones in particular, is warranted.

Food intake is a vital process that supplies necessary energy and essential nutrients to the body. Information regarding luminal composition in the gastrointestinal tract (GIT) collected through mechanical and nutrient sensing mechanisms are generally conveyed, in both mammals and fish, to the hypothalamic neurocircuits. In this context, ghrelin, the only known hormone with an orexigenic action, and the intestinal peptide transporters 1 and 2, involved in absorption of dietary di- and tripeptides, exert important and also integrated roles for the nutrient uptake. Together, both are potentially involved in signaling pathways that control food intake originating from different segments of the GIT. However, little is known about the role of different paralogs and their response to fasting. Therefore, after 3 weeks of acclimatization, 12 Atlantic salmon (Salmo salar) post-smolt were fasted for 4 days to explore the gastrointestinal response in comparison with fed control (n = 12). The analysis covered morphometric (weight, length, condition factor, and wet content/weight fish %), molecular (gene expression variations), and correlation analyses. Such short-term fasting is a common and recommended practice used prior to any handling in commercial culture of the species. There were no statistical differences in length and weight but a significant lower condition factor in the fasted group. Transcriptional analysis along the gastrointestinal segments revealed a tendency of downregulation for both paralogous genes slc15a1a and slc15a1b and with significant lowered levels in the pyloric ceca for slc15a1a and in the pyloric ceca and midgut for slc15a1b. No differences were found for slc15a2a and slc15a2b (except a higher expression of the fasted group in the anterior midgut), supporting different roles for slc15 paralogs. This represents the first report on the effects of fasting on slc15a2 expressed in GIT in teleosts. Transcriptional analysis of ghrelin splicing variants (ghrl-1 and ghrl-2) showed no difference between treatments. However, correlation analysis showed that the mRNA expression for all genes (restricted to segment with the highest levels) were affected by the residual luminal content. Overall, the results show minimal effects of 4 days of induced fasting in Atlantic salmon, suggesting that more time is needed to initiate a large GIT response.

Skull base osteomyelitis (SBO) is an invasive infection refractory to therapy, closely linked with malignant otitis externa (MOE). It is characterized by a mild clinical presentation that can delay cross-sectional imaging considered as the key to revealing it. Skull base osteomyelitis typically affects elderly diabetics and immunocompromised patients (>70 years). It most commonly has an otogenic origin due to an extension of MOE. The prognosis can be very poor without the administration of adequate and timely therapy at an early disease stage. Nowadays, Pseudomonas aeruginosa remains the most common pathogen associated with SBO. Fungi are a rare cause of MOE. This report documents a rare case of otogenic SBO caused by Candida parapsilosis in a diabetic patient, with persistent otologic symptoms as clinical onset and resistance to medical treatment. Fungal MOE has more subtle symptoms and is more aggressive than its bacterial counterpart. When MOE is resistant to antibacterial drugs, this should raise the suspicion of a fungal etiology of MOE. The current guidelines do not exhaustively describe the diagnosis, antifungal drugs of choice, and optimum duration of treatment. The description of these rare clinical cases should help with the multidisciplinary management of this disease in order to optimize the diagnosis and therapeutic protocol.

Long non-coding RNAs (lncRNAs) are emerging as fundamental players in cancer biology. Indeed, they are deregulated in several neoplasias and have been associated with cancer progression, tumor recurrence, and resistance to treatment, thus representing potential biomarkers for cancer diagnosis, prognosis, and therapy. In this study, we aimed to identify lncRNAs associated with pituitary tumorigenesis. We have analyzed the lncRNA expression profile of a panel of gonadotroph pituitary adenomas in comparison with normal pituitaries. Then, we focused on RPSAP52, a novel lncRNA antisense for the HMGA2 gene, whose overexpression plays a critical role in the development of pituitary adenomas. We report that RPSAP52 expression is highly upregulated in gonadotroph and prolactin-secreting pituitary adenomas, where it correlates with that of HMGA2, compared with normal pituitary tissues. Conversely, its expression showed a variable behavior in somatotroph adenomas. We also demonstrate that RPSAP52 enhances HMGA2 protein expression in a ceRNA-dependent way acting as sponge for miR-15a, miR-15b, and miR-16, which have been already described to be able to target HMGA2. Interestingly, RPSAP52 also positively modulates HMGA1, the other member of the High-Mobility Group A family. Moreover, functional studies indicate that RPSAP52 promotes cell growth by enhancing the G1-S transition of the cell cycle. The results reported here reveal a novel mechanism, based on the overexpression of the lncRNA RPSAP52, which contributes to pituitary tumorigenesis, and propose this lncRNA as a novel player in the development of these tumors. KEY MESSAGES: RPSAP52 is overexpressed in pituitary adenomas. RPSAP52 increases HMGA protein levels. A ceRNA mechanism is proposed for the increased HMGA1/2 expression.

Antimicrobial peptides (AMPs) are membrane-active peptides with a broad spectrum of activity against different pathogenic organisms and they represent promising new drugs to overcome the emergence of resistance to antibiotics in bacteria. (P)GKY20 is an antimicrobial peptide with a low hemolytic effect on eukaryotic cells and a strong antimicrobial activity especially against Gram-negative bacteria. However, its mechanism of action is still unknown. Here, we use fluorescence spectroscopy and differential scanning calorimetry combined with atomic force microscopy to characterise the binding of (P)GKY20 with model biomembranes and its effect on the membrane's microstructure and thermotropic properties. We found that (P)GKY20 selectively perturbs the bacterial-like membrane via a carpet-like mechanism employing peptide conformational changes, lipid segregation and domain formation as key steps in promoting membrane disruption. These results shed a first light on the action mechanism of (P)GKY20 and could represent an important contribution to the development of new peptides serving as antimicrobial agents.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder often showing elevated serum IgG4 concentrations, dense T and B lymphocyte infiltration, and IgG4-positive plasma cells and storiform fibrosis. We prospectively evaluated for 4 years 5 patients with histologically proven IgG4-RD of whom 3 had tubulointerstitial nephritis (TIN) and 2 had retroperitoneal fibrosis (RPF). They received an intensive B depletion therapy with rituximab. The estimated glomerular filtration rate of TIN patients after 1 year increased from 9 to 24 ml/min per 1.73 m2. IgG/IgG4 dropped from 3236/665 to 706/51 mg/dl, C3/C4 went up from 49/6 to 99/27 mg/dl, and the IgG4-RD responder index fell from 10 to 1. CD20+ B cells decreased from 8.7 to 0.5%. A striking drop in interstitial plasma cell infiltrate as well as normalization of IgG4/IgG-positive plasma cells was observed at repeat biopsy. Both clinical and immunological improvement persisted over a 4-year follow-up. Treating these patients who were affected by aggressive IgG4-RD with renal involvement in an effort to induce a prolonged B cells depletion with IgG4 and cytokine production decrease resulted in a considerable rise in eGFR, with IgG4-RD RI normalization and a noteworthy improvement in clinical and histological features. Furthermore, the TIN subgroup was shown not to need for any maintenance therapy.

In the last decade, minimally invasive or percutaneous surgery has evolved rapidly through the development of novel techniques. Treatment of hallux valgus deformity is one of the indications for percutaneous surgery, both for bony and soft tissue correction. The release of the structures on the lateral part of the first metatarsophalangeal joint (lateral release) is one of the best indications for percutaneous surgery in the forefoot. In this article, a detailed description of the anatomy of the metatarsophalangeal joint is provided, along with the indications and tips to perform a safe percutaneous lateral release.

Background: Lateral release (LR) for the treatment of hallux valgus is a routinely performed technique, either by means of open or minimally invasive (MI) surgery. Despite this, there is no available evidence of the efficacy and safety of MI lateral release. Our aim was to study 2 popular techniques for MI LR in cadavers by subsequently dissecting the released anatomical structures. Methods: Twenty-two cadaveric feet were included in the study and allocated into 2 groups, 1 for each procedure: 1 group underwent a MI adductor tendon release (AR), and in the other group, an extensive percutaneous lateral release (EPLR) (adductor tendon, suspensory ligament, phalanx-sesamoid ligament, lateral head of flexor hallucis brevis, and deep transverse metatarsal ligament) was performed. Anatomical dissection was performed to identify neurovascular injuries and to verify the released structures. Results: Both techniques demonstrated to be effective in reproducing a MI LR. A satisfactory release of the adductor tendon was achieved equally in both techniques ( P = .85), being partial in most EPLR cases and full in the majority of AR cases. The EPLR was successful in releasing the intended additional structures ( P < .05). One case of inadvertent complete section of the flexor hallucis longus was identified in the percutaneous adductor tendon release group. No cases of dorsolateral nerve injury were seen with either of the techniques. Conclusion: Percutaneous lateral release was a reliable and accurate technique in this cadaveric model. The MI AR proved to be more effective in fully releasing the adductor tendon while the ER was intended and able to release a number of other structures. Clinical Relevance: MI LR is a safe procedure that could obviate the need for open surgery to achieve the same surgical goal. It can be associated to either open or MI osteotomies in the correction of hallux valgus.

Vasconcelos, BB, Protzen, GV, Galliano, LM, Kirk, C, and Del Vecchio, FB. Effects of high-intensity interval training in combat sports: A systematic review with meta-analysis. J Strength Cond Res 34(3): 888-900, 2020-Combat sports (CS) are intermittent by nature and high-intensity interval training (HIIT) has been used as a tool to maintain and improve physical fitness among CS athletes. The aim of this study was to perform a systematic review and meta-analysis about chronic effects of HIIT in CS athletes. An electronic search was performed in PubMed, Science Direct, and Google Scholar using the following Boolean criteria: ("CS" OR "martial arts" OR "judo" OR "taekwondo" OR "jiu jitsu" OR "boxing" OR "karate" OR "wrestling" OR "wushu" OR "kung fu") AND ("HIIT" OR "intermittent exercise" OR "sprint interval training" OR "repeated sprint training [RST]"). To be included, the studies needed to be original, involve CS athletes, present HIIT intervention protocol (HIIT, sprint interval training [SIT] or RST), and analyze chronic physiological outcomes. From 2,211 identified studies, after screening and eligibility evaluation, 12 studies were included in this review with meta-analysis. Aerobic (aerobic capacity, heart rate, and maximum oxygen uptake), anaerobic (peak and mean power in single and successive Wingate tests, and blood lactate concentration), and anthropometric outcomes (body mass and body fat percentage) were evaluated. Data of 255 subjects from 12 studies were assessed. Regarding methodological quality, 7 studies obtained 9-10/12 on the TESTEX scale. For the interventions, 5 studies used HIIT, 4 studies used RST protocols, one used SIT protocols, and one used an intermittent protocol that could not be classified. Relating to aerobic power, was found an increase in V[Combining Dot Above]O2max, with a mean difference (MD) of 2.83 ml·kg·min (CI 95% = 0.40-5.25; p < 0.001) for striking and 2.36 ml·kg·min (CI 95% = 1.05-3.66; p < 0.001) for grappling athletes. No differences on anaerobic peak power for striking (MD = 0.67 W; CI 95% = -0.43 to 1.77; p = 0.23) were found, and a statistical improvement for grappling athletes, (MD = 0.51 W; CI 95% = 0.03-0.98; p = 0.04) was found. Seven studies analyzed anthropometric variables, with differences for body mass in striking (MD = -0.93 kg; CI 95% = -1.68 to -0.19; p = 0.01) and no differences for grappling (MD = -0.09 kg; CI 95% = -2.80 to 2.62; p = 0.95). Differences in body fat percentage in striking (MD = 0.50%; CI 95% = 0.30-0.70; p < 0.001) and no differences in grappling (MD = -0.87%; CI 95% = -1.77 to 0.03; p = 0.06) were found. It was concluded that HIIT positively influences maximum oxygen uptake and anaerobic power in combat sport athletes, with a minor impact on body composition.

Breast cancer (BC) is the most common type of cancer diagnosed in women. Among female cancer deaths, BC is the second leading cause of death worldwide. For estrogen receptor-positive (ER-positive) breast cancers, endocrine therapy is an effective therapeutic approach. However, in many cases, an ER-positive tumor becomes unresponsive to endocrine therapy, and tumor regrowth occurs after treatment. While some genetic mutations contribute to resistance in some patients, the underlying causes of resistance to endocrine therapy are mostly undetermined. In this study, we utilized a recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of endocrine resistance and identified a novel group of genes whose time course expression significantly change during cell modelling of endocrine resistant BC development. Expression of a subset of these genes was also differentially expressed in microarray analysis of endocrine-resistant and endocrine-sensitive tumor samples. Surprisingly, a subset of those genes was also differentially genes expressed in triple-negative breast cancer (TNBC) as compared with ER-positive BC. The findings suggest shared genetic mechanisms may underlie the development of endocrine resistant BC and TNBC. Our findings identify 34 novel genes for further study as potential therapeutic targets for treatment of endocrine-resistant BC and TNBC.

Inflammatory polyradiculoneuropathy (IMPN) is one of the causes of sudden onset of neuromuscular signs such as para-/tetraparesis in young cats. Even though most cases have a favorable outcome, persistent deficits, relapses, and progressive courses are occasionally seen. As clinical presentation does not always appear to predict outcome and risk of recurrence, this study was initiated to screen for prognostic biopsy findings in a large cohort of histologically confirmed IMPN cases with clinical follow-up. In total, nerve and muscle specimens of 107 cats with biopsy diagnosis of presumed autoreactive inflammatory polyneuropathy and 22 control cases were reviewed by two blinded raters for a set of 36 histological parameters. To identify patterns and subtypes of IMPN, hierarchical k-means clustering of 33 histologic variables was performed. Then, the impact of histological parameters on IMPN outcome was evaluated via an univariate analysis to identify variables for the final multivariate model. The data on immediate outcome and follow-up were collected from submitting neurologists using a purpose-designed questionnaire. Hierarchical k-means clustering sorted the tissues into 4 main categories: cluster 1 (44/129) represents a purely inflammatory IMPN picture, whereas cluster 2 (47/129) was accompanied by demyelinating features and cluster 3 (16/129) by Wallerian degeneration. Cluster 4 (22/129) reflects normal tissues from non-neuropathic control cats. Returned questionnaires provided detailed information on outcome in 63 animals. They were categorized into recovered and non-recovered. Thereby, fiber-invasive infiltrates by mononuclear cells and mild fiber loss in intramuscular nerve branches correlated with higher probabilities of recovery. Remyelination in semithin sections, on the other hand, is correlated with a less favorable outcome. Animals grouping in cluster 1 had a tendency to a higher probability of recovery compared to other clusters. In conclusion, diagnosis of feline IMPN from nerve and muscle biopsies allowed for the identification of histologic features that were positively or negatively correlated with outcome.

Extracellular vesicles (EVs) mediate the cross‐talk between cancer cells and the cells of the surrounding Tumour Microenvironment (TME). Professional killer cells include Natural Killer (NK) cells and CD8+ Cytotoxic T‐lymphocytes (CTLs), which represent some of the most effective immune defense mechanisms against cancer cells. Recent evidence supports the role of EVs released by NK cells and CTLs in killing cancer cells, paving the road to a possible therapeutic role for such EVs. This review article provides the state‐of‐the‐art knowledge on the role of NK‐ and CTL‐derived EVs as anticancer agents, focusing on the different functions of different sub‐types of EVs. We also reviewed the current knowledge on the effects of cancer‐derived EVs on NK cells and CTLs, identifying areas for future investigation in the emerging new field of EV‐mediated immunotherapy of cancer.

Extracellular vesicles (EVs) have emerged as important players in all aspects of cancer biology. Their function is mediated by their cargo and surface molecules including proteins, lipids, sugars and nucleic acids. RNA in particular is a key mediator of EV function both in normal and cancer cells. This statement is supported by several lines of evidence. First, cells do not always randomly load RNA in EVs, there seems to be a specific manner in which cells populate their EVs with certain RNA molecules. Moreover, cellular uptake of EV-RNA and the secondary compartmentalization of EV-RNA in recipient cells is widely reported, and these RNAs have an impact on all aspects of cancer growth and the anti-tumoral immune response. Additionally, EV-RNA seems to work through various mechanisms of action, highlighting the intricacies of EVs and their RNA cargo as prominent means of inter-cellular communication.

Next generation sequencing (NGS) has changed our approach to diagnosis of genetic disorders. Nowadays, the most comprehensive application of NGS is whole genome sequencing (WGS) that is able to detect virtually all DNA variations. However, even after accurate WGS, many genetic conditions remain unsolved. This may be due to the current NGS protocols, based on DNA fragmentation and short reads. To overcome these limitations, we applied a linked-read sequencing technology that combines single-molecule barcoding with short-read WGS. We were able to assemble haplotypes and distinguish between alleles along the genome. As an exemplary case, we studied the case of a female carrier of X-linked muscular dystrophy with an unsolved genetic status. A deletion of exons 16&ndash, 29 in DMD gene was responsible for the disease in her family, but she showed a normal dosage of these exons by Multiplex Ligation-dependent Probe Amplification (MLPA) and array CGH. This situation is usually considered compatible with a &ldquo, non-carrier&rdquo, status. Unexpectedly, the girl also showed an increased dosage of flanking exons 1&ndash, 15 and 30&ndash, 34. Using linked-read WGS, we were able to distinguish between the two X chromosomes. In the first allele, we found the 16&ndash, 29 deletion, while the second allele showed a 1&ndash, 34 duplication: in both cases, linked-read WGS correctly mapped the borders at single-nucleotide resolution. This duplication in trans apparently restored the normal dosage of exons 16&ndash, 29 seen by quantitative assays. This had a dramatic impact in genetic counselling, by converting a non-carrier into a double carrier status prediction. We conclude that linked-read WGS should be considered as a valuable option to improve our understanding of unsolved genetic conditions.

Crimean-Congo hemorrhagic fever (CCHF) is a severe disease of humans caused by CCHF virus (CCHFV), a biosafety level (BSL)-4 pathogen. Ticks of the genus Hyalomma are the viral reservoir, and they represent the main vector transmitting the virus to its hosts during blood feeding. We have previously shown that CCHFV can persistently infect Hyalomma-derived tick cell lines. However, the mechanism allowing the establishment of persistent viral infections in ticks is still unknown. Hazara virus (HAZV) can be used as a BSL-2 model virus instead of CCHFV to study virus/vector interactions. To investigate the mechanism behind the establishment of a persistent infection, we developed an in vitro model with Hyalomma-derived tick cell lines and HAZV. As expected, HAZV, like CCHFV, persistently infects tick cells without any sign of cytopathic effect, and the infected cells can be cultured for more than 3 years. Most interestingly, we demonstrated the presence of short viral-derived DNA forms (vDNAs) after HAZV infection. Furthermore, we demonstrated that the antiretroviral drug azidothymine triphosphate could inhibit the production of vDNAs, suggesting that vDNAs are produced by an endogenous retrotranscriptase activity in tick cells. Moreover, we collected evidence that vDNAs are continuously synthesized, thereby downregulating viral replication to promote cell survival. Finally, vDNAs were also detected in CCHFV-infected tick cells. In conclusion, vDNA synthesis might represent a strategy to control the replication of RNA viruses in ticks allowing their persistent infection. IMPORTANCE Crimean-Congo hemorrhagic fever (CCHF) is an emerging tick-borne viral disease caused by CCHF virus (CCHFV). Ticks of the genus Hyalomma can be persistently infected with CCHFV representing the viral reservoir, and the main vector for viral transmission. Here we showed that tick cells infected with Hazara virus, a nonpathogenic model virus closely related to CCHFV, contained short viral-derived DNA forms (vDNAs) produced by endogenous retrotranscriptase activity. vDNAs are transitory molecules requiring viral RNA replication for their continuous synthesis. Interestingly, vDNA synthesis seemed to be correlated with downregulation of viral replication and promotion of tick cell viability. We also detected vDNAs in CCHFV-infected tick cells suggesting that they could represent a key element in the cell response to nairovirus infection and might represent a more general mechanism of innate immunity against RNA viral infection.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Movements are reportedly controlled through the combination of synergies that generate specific motor outputs by imposing an activation pattern on a group of muscles. To date, the smallest unit of analysis has been the muscle. In this human study, we decoded the spiking activities of spinal motor neurons innervating six lower limb muscles during an isometric multi-joint task. We identified their common low-frequency components, from which networks of common synaptic inputs to the motor neurons were derived. The vast majority of the identified motor neurons shared common inputs with other motor neuron(s). In addition, groups of motor neurons were partly decoupled from their innervated muscle, such that motor neurons innervating the same muscle did not necessarily receive common inputs. Conversely, some motor neurons from different muscles – including distant muscles – received common inputs. Our results provide evidence of a synergistic control of a multi-joint motor task at the spinal motor-neuron level.TeaserThe generation of movement involves the activation of many spinal motor neurons from multiple muscles. A central and unresolved question is how these motor neurons are controlled to allow flexibility for adaptation to various mechanical constraints. Since the computational load of controlling each motor neuron independently would be extremely large, the central nervous system presumably adopts dimensionality reduction. We identified networks of functional connectivity between spinal motor neurons based on the common synaptic inputs they receive during a multi-joint task. Our findings revealed functional groupings of motor neurons in a low dimensional space. These groups did not necessarily overlap with the muscle anatomy. We provide a new neural framework for a deeper understanding of movement control in health and disease.

Objectives To describe a unique case of acute vertigo presenting with spontaneous horizontal nystagmus (SHN) and a clinical picture consistent with right acute peripheral vestibular loss (APVL) in which an isolated hypofunction of a horizontal semicircular canal (HSC) permitted to detect a spontaneous canalith jam and treat the patient accordingly. Methods Case report and literature review. Results A 74-year old woman presented with acute vertigo, left-beating SHN and a clinical picture consistent with right APVL. Nevertheless, vestibular evoked myogenic potentials were normal with symmetrical amplitudes and the video head impulse test (vHIT) revealed an isolated hypofunction of the right HSC. After repeated head shakings, the supine roll test evoked bilaterally a positioning paroxysmal geotropic horizontal nystagmus suggesting benign paroxysmal positional vertigo involving the non-ampullated arm of the right HSC. vHIT and caloric testing confirmed restitution of HSC function after repositioning maneuvers. Conclusions In case of acute vertigo with SHN, a complete functional assessment of vestibular receptors and afferents should always be given in order to avoid misdiagnosis. Canalith jam should be considered in case of spontaneous nystagmus and isolated canal hypofunction.

Background Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. This study aimed to explore global DNA methylation dynamic of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) from donors and their respective recipients affected by acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and Hodgkin lymphoma (HL) during the first year after transplant. Methods We measured DNA methylation profile by Illumina HumanMethylationEPIC in BM HSPC of 10 donors (t0) and their matched recipients at different time points after AHSCT, at day + 30 (t1), + 60 (t2), + 120 (t3), + 180 (t4), and + 365 (t5). Differential methylation analysis was performed by using R software and CRAN/Bioconductor packages. Gene set enrichment analysis was carried out on promoter area of significantly differentially methylated genes by clusterProfiler package and the mSigDB genes sets. Results Results show significant differences in the global methylation profile between HL and acute leukemias, and between patients with mixed and complete chimerism, with a strong methylation change, with prevailing hyper-methylation, occurring 30 days after AHSCT. Functional analysis of promoter methylation changes identified genes involved in hematopoietic cell activation, differentiation, shaping, and movement. This could be a consequence of donor cell “adaptation” in recipient BM niche. Interestingly, this epigenetic remodeling was reversible, since methylation returns similar to that of donor HSPCs after 1 year. Only for a pool of genes, mainly involved in dynamic shaping and trafficking, the DNA methylation changes acquired after 30 days were maintained for up to 1 year post-transplant. Finally, preliminary data suggest that the methylation profile could be used as predictor of relapse in ALL. Conclusions Overall, these data provide insights into the DNA methylation changes of HSPCs after transplantation and a new framework to investigate epigenetics of AHSCT and its outcomes. Electronic supplementary material The online version of this article (10.1186/s13287-019-1245-6) contains supplementary material, which is available to authorized users.

Embryonic stem cells (ESCs) are derived from inner cell mass (ICM) of the blastocyst. In serum/LIF culture condition, they show variable expression of pluripotency genes that mark cell fluctuation between pluripotency and differentiation metastate. The ESCs subpopulation marked by zygotic genome activation gene (ZGA) signature, including Zscan4, retains a wider differentiation potency than epiblast-derived ESCs. We have recently shown that retinoic acid (RA) significantly enhances Zscan4 cell population. However, it remains unexplored how RA initiates the ESCs to 2-cell like reprogramming. Here we found that RA is decisive for ESCs to 2C-like cell transition, and reconstructed the gene network surrounding Zscan4. We revealed that RA regulates 2C-like population co-activating Dux and Duxbl1. We provided novel evidence that RA dependent ESCs to 2C-like cell transition is regulated by Dux, and antagonized by Duxbl1. Our suggested mechanism could shed light on the role of RA on ESC reprogramming.

Aims The early phases in the life cycle of a plant are the bottleneck for successful species establishment thereby affecting population dynamics and distribution. In coastal environments, the spatial pattern of plant communities (i.e. vegetation zonation) follows the ecological gradient of abiotic stress changing with the distance from the sea. This pattern has been mainly explained based on the adaptation and tolerance to the abiotic stress of adult plants. However, the adult niche may considerably differ from the germination niche of a plant species. The aim of this work was to investigate to what extent abiotic factors (specifically salinity, temperature, nitrogen and their interactions) constrain seed germination along the sea–inland gradient. Location Latium coast (Central Italy). Methods Germination tests were performed on seeds of focal species of three different plant communities which establish at increasing distances from the coastline: Cakile maritima subsp. maritima, Elymus farctus, Crucianella maritima. We tested increasing concentrations of NaCl (one of the main abiotic factors which decrease across the sea–inland gradient), and their interactions with temperature and KNO3, to consider other factors which drive germination processes. Results The tolerance to salinity significantly decreased in relation to the position of species along the coastal zonation. Crucianella maritima was shown to be the least tolerant species, having a decrease in germination >80% across all conditions. KNO3 significantly (although slightly) increased the germination percentage in Cakile maritima subsp. maritima and Elymus farctus. When combined with NaCl, KNO3 alleviated the negative effects of salinity only in Cakile maritima subsp. maritima. Conclusions The germination responses to the interaction among the tested factors suggest that the germination niche may explain vegetation zonation filtering species at their early stages. Quantifying environmental niches in different phases of the life cycle of plants may provide important insights into community assembly processes.

In this work, zebrafish (Danio rerio) embryos were subjected to different physical stresses, consisting of a static and two low frequency magnetic fields, and two radio frequencies. Specifically, embryos were exposed to static (Bo, 0 Hz), very low frequency (VLF, 0.2 Hz), low frequency (LF, 270 kHz), very high frequency (VHF, 100 MHz) and ultra-high frequency (UHF, 900 MHz) magnetic field irradiations for up to 5 days. The field intensities were 40 mT, 40 mT, 470 μT, 240 nT and 240 nT, respectively. Untreated embryos were used as control (n = 10 for each condition).

Coeliac disease (CD) is a multifactorial autoimmune disorder and gut dysbiosis contributes to its pathogenesis. We previously profiled by 16S rRNA sequencing duodenal and oropharyngeal microbiomes in active CD (a-CD), gluten-free diet (GFD) patients, and controls (CO) and found significantly higher levels of Neisseria spp., with pro-inflammatory activities, in a-CD patients than in the other two groups. In this study, we developed a fast and simple qPCR-based method to evaluate the abundance of the oral Neisseria spp. and the diagnostic performances of the test in CD diagnosis. The Neisseria spp. abundances detected by quantitative PCR (qPCR) were: CO = 0.14, GFD = 0.15, a-CD = 2.08, showing a similar trend to those previously measured by next generation sequencing (NGS). In particular, Neisseria spp. values obtained by both methods were significantly higher (p < 0.001) in a-CD than in the other two groups GFD and CO—the latter almost overlapping. We calculated by ROC curve analysis the threshold of 1.12 ng/μL of Neisseria spp. to discriminate between CO+GFD and a-CD patients with 100% and 96.7% of diagnostic sensitivity and specificity, respectively. In conclusion, our data, if confirmed in other cohorts, suggest the q-PCR evaluation of oral Neisseria spp. could be a fast and simple method to assess CD-associated dysbiosis for diagnostic purposes.

Previously, we described the design and synthesis of three nine-residue AMPs, P9Nal(SS), P9Trp(SS), and P9Nal(SR), showing high stability in serum and broad spectrum antimicrobial activity. The peptides P9Trp(SS) and P9Nal(SR) differ from P9Nal(SS) for the replacement of the two 2Nal residues with Trp residues and for the replacement of the two Cys (StBu) with Cys (tBu) residues, respectively. These changes led to peptides with a lower hydrophobicity respect to the P9Nal(SS). Interestingly, the three peptides have very similar activity against Gram-negative bacteria. Instead, they exhibit a significant difference towards Gram-positive bacteria, being P9Nal(SS) the most active. In order to evaluate the impact of amino acids substitution on membranotropic activity and rationalize the observed effects in vivo, here, we report the detailed biophysical characterization of the interaction between P9Nal(SR) and P9Trp(SS) and liposomes by combining differential scanning calorimetry, circular dichroism, and fluorescence spectroscopy. The comparison with the results for the previously characterized P9Nal(SS) peptide reveals similarities and differences on the interaction process and perturbation activities. It was found that the three peptides can penetrate at different extent inside the bilayer upon changing their conformation and inducing lipid domains formation, revealing that the formation of lipid domains is fundamental for the activity against Gram-negative bacteria. On the contrary, the dissimilar activity against Gram-positive bacteria well correlate with the different affinity of peptides for the lipoteichoic acid, a component selectively present in the cell wall of Gram-positive bacteria.

A nonsense mutation adds a premature stop signal that hinders any further translation of a protein-coding gene, usually resulting in a null allele. To investigate the possible exceptions, we used theDMDgene as an ideal model. First, because dystrophin absence causes Duchenne muscular dystrophy (DMD), while its reduction causes Becker muscular dystrophy (BMD). Second, theDMDgene is X-linked and there is no second allele that can interfere in males. Third, databases are accumulating reports on many mutations and phenotypic data. Finally, becauseDMDmutations may have important therapeutic implications. For our study, we analyzed large databases (LOVD, HGMD and ClinVar) and literature and revised critically all data, together with data from our internal patients. We totally collected 2593 patients. Positioning these mutations along the dystrophin transcript, we observed a nonrandom distribution of BMD-associated mutations within selected exons and concluded that the position can be predictive of the phenotype. Nonsense mutations always cause DMD when occurring at any point in fifty-one exons. In the remaining exons, we found milder BMD cases due to early 5' nonsense mutations, if reinitiation can occur, or due to late 3' nonsense when the shortened product retains functionality. In the central part of the gene, all mutations in some in-frame exons, such as in exons 25, 31, 37 and 38 cause BMD, while mutations in exons 30, 32, 34 and 36 cause DMD. This may have important implication in predicting the natural history and the efficacy of therapeutic use of drug-stimulated translational readthrough of premature termination codons, also considering the action of internal natural rescuers. More in general, our survey confirm that a nonsense mutation should be not necessarily classified as a null allele and this should be considered in genetic counselling.

Background Peptide transporter 1 (PepT1, alias Slc15a1) mediates the uptake of dietary di/tripeptides in all vertebrates. However, in teleost fish, more than one PepT1-type transporter might function, due to specific whole genome duplication event(s) that occurred during their evolution leading to a more complex paralogue gene repertoire than in higher vertebrates (tetrapods). Results Here, we describe a novel di/tripeptide transporter in the zebrafish (Danio rerio), i.e., the zebrafish peptide transporter 1a (PepT1a; also known as Solute carrier family 15 member a1, Slc15a1a), which is a paralogue (78% similarity, 62% identity at the amino acid level) of the previously described zebrafish peptide transporter 1b (PepT1b, alias PepT1; also known as Solute carrier family 15 member 1b, Slc15a1b). Also, we report a basic analysis of the pept1a (slc15a1a) mRNA expression levels in zebrafish adult tissues/organs and embryonic/early larval developmental stages. As assessed by expression in Xenopus laevis oocytes and two-electrode voltage clamp measurements, zebrafish PepT1a, as PepT1b, is electrogenic, Na+-independent, and pH-dependent and functions as a low-affinity system, with K0.5 values for Gly-Gln at − 60 mV of 6.92 mmol/L at pH 7.6 and 0.24 mmol/L at pH 6.5 and at − 120 mV of 3.61 mmol/L at pH 7.6 and 0.45 mmol/L at pH 6.5. Zebrafish pept1a mRNA is highly expressed in the intestine and ovary of the adult fish, while its expression in early development undergoes a complex trend over time, with pept1a mRNA being detected 1 and 2 days post-fertilization (dpf), possibly due to its occurrence in the RNA maternal pool, decreasing at 3 dpf (~ 0.5-fold) and increasing above the 1–2 dpf levels at 4 to 7 dpf, with a peak (~ 7-fold) at 6 dpf. Conclusions We show that the zebrafish PepT1a-type transporter is functional and co-expressed with pept1b (slc15a1b) in the adult fish intestine. Its expression is also confirmed during the early phases of development when the yolk syncytial layer is present and yolk protein resorption processes are active. While completing the missing information on PepT1-type transporters function in the zebrafish, these results open to future investigations on the similar/differential role(s) of PepT1a/PepT1b in zebrafish and teleost fish physiology.

Nutritional imbalance and metabolic alterations associated with maternal obesity during pregnancy predispose offspring to obesity and/or to type 2 diabetes, but the mechanisms underlying these effects are still obscure. In this context, we evaluated whether the two main energy-producing pathways (glycolysis and mitochondrial oxidative phosphorylation) are impaired in obesity during pregnancy thus contributing to metabolic intrauterine alterations. Specifically, we studied metabolic abnormalities in the intrauterine life of newborns using stem cells isolated from amnion and umbilical cord (hA- and hUC-MSCs). We isolated, at delivery, neonatal hUC-MSCs from 13 obese (Ob) and 10 normal weight control (Co) women (prepregnancy body mass index >30 and

Lactoferrin (Lf) is a cationic glycoprotein synthetized by exocrine glands and is present in all human secretions. It is also secreted by neutrophils in infection and inflammation sites. This glycoprotein possesses antimicrobial activity due to its capability to chelate two ferric ions per molecule, as well as to interact with bacterial and viral anionic surface components. The cationic features of Lf bind to cells, protecting the host from bacterial and viral injuries. Its anti-inflammatory activity is mediated by the ability to enter inside the nucleus of host cells, thus inhibiting the synthesis of proinflammatory cytokine genes. In particular, Lf down-regulates the synthesis of IL-6, which is involved in iron homeostasis disorders and leads to intracellular iron overload, favoring viral replication and infection. The well-known antiviral activity of Lf has been demonstrated against DNA, RNA, and enveloped and naked viruses and, therefore, Lf could be efficient in counteracting also SARS-CoV-2 infection. For this purpose, we performed in vitro assays, proving that Lf exerts an antiviral activity against SARS-COV-2 through direct attachment to both SARS-CoV-2 and cell surface components. This activity varied according to concentration (100/500 μg/ml), multiplicity of infection (0.1/0.01), and cell type (Vero E6/Caco-2 cells). Interestingly, the in silico results strongly supported the hypothesis of a direct recognition between Lf and the spike S glycoprotein, which can thus hinder viral entry into the cells. These in vitro observations led us to speculate a potential supplementary role of Lf in the management of COVID-19 patients.

Invasive alien species risk assessment and adaptive management are often hindered by a lack of information for most species. This work aims at predicting the probability of successful establishment and invasion of Oenothera stucchii Soldano, a neophyte invasive species belonging to the sect. Oenothera subsect. Oenothera, in xerophilous grasslands of grey dunes. Based on fine-scale field data, we modelled O. stucchii presence/absence and abundance as a function of environmental factors, human disturbance, and attributes of the recipient community through a zero-inflated Poisson model. The invasion success of O. stucchii depended on a combination of factors which differed when considering either the patterns of occurrence (species presence/absence) or those of species abundance. While human-driven disturbance strongly influenced the probability of presence/absence of O. stucchii, patterns of abundance were mostly driven by a combination of environmental and biotic features. Attributes of the recipient community remarkably influenced both O. stucchii presence and abundance. Based on fine-scale field data, we determined the mechanisms which drive the spatial patterns of presence and abundance of O. stucchii in xerophilous grasslands and provided quantitative thresholds to identify the most susceptible areas of grey dune habitats prone to invasion, which combine human disturbance (distance from the nearest beach access), attributes of the resident community (resident vegetation cover and structure), and environmental disturbance (foredune ridge height). These results provide useful insights to be used to plan cost-effective measures to prevent O. stucchii establishment and spread in sandy coastal systems. Our model may also be applied to closely related congener species included in the subsect. Oenothera, sharing similar biological and ecological traits.

Although analysis of maternal plasma cell-free content has been employed for screening of genetic abnormalities within a pregnancy, limited attention has been paid to its use for the detection of adverse pregnancy outcomes (APOs) based on placental function. Here we investigated cell-free DNA and RNA content of 102 maternal and 25 cord plasma samples. Employing a novel deconvolution methodology, we found that during the first trimester, placenta-specific DNA increased prior to the subsequent development of gestational diabetes with no change in patients with preeclampsia while decreasing with maternal obesity. Moreover, using cell-free RNA sequencing, APOs revealed 71 differentially expressed genes early in pregnancy. We noticed the upregulation of S100A8, MS4A3, and MMP8 that have been already associated with APOs but also the upregulation of BCL2L15 and the downregulation of ALPL that have never been associated with APOs. We constructed a classifier with a positive predictive ability (AUC) of 0.91 for APOs, 0.86 for preeclampsia alone and 0.64 for GDM. We conclude that placenta-specific cell-free nucleic acids during early gestation provide the possibility of predicting APOs prior to the emergence of characteristic clinical features.

This study assessed the effect of starvation on survival and nutritional status of newborn juveniles H. erectus (

This work presents a study about the distance matrix of a family of trees called caterpillar graphs. Our purpose is to determine the multiplicity of − 2 as distance eigenvalue and the number of distinct distance eigenvalues of a caterpillar graph.

High heterogeneity of grassland communities supports a high diversity of species and represents a key point for the retention of pollinators in agricultural landscapes. In the present study, we explored whether the co-occurrence of different grassland communities has any effect on the stability of the network of pollination interactions. We monitored pollination interactions in two co-occurring grassland communities, differing in disturbance history and water and nutrient supply. The monitoring was carried out during the summer season (7 surveys). For each survey we compared the role in the pollination networks (i.e., keystone vs. peripheral species) of habitat-specialist and habitat-generalist plant and pollinator species. We found that plant and pollinator species of the two different grassland communities were highly interconnected, revealing that pollination interactions occur at a level of organization above that of the single community. The co-occurrence of the two grassland communities increased the type, number and frequency of contacts, thereby contributing to networks stability. The role of habitat-specialist and habitat-generalist plant and pollinator species in pollination networks was asymmetric, with habitat-specialist plants and habitat-generalist pollinators being keystone species, while habitat-generalist plants and habitat-specialist pollinators being peripheral in the pollination networks. Our results showed that the stability of the network does stem from the co-occurrence of different species pools having different but complementary roles in the pollination networks. From a conservation perspective, the maintenance of different grassland communities is important not only because they allow the conservation of habitat-specialist species, but specifically because plant species specialized in either grassland community are also keystone for the maintenance of the stability of the pollination networks.

We aimed to describe the nutritional and behavioral strategies for rapid weight loss (RWL), investigate the effects of RWL and weight regain in winners and losers, and verify mood state and technical–tactical/time–motion parameters in mixed martial arts. The sample consisted of mixed martial arts athletes after a single real match and was separated into two groups: winners (n = 8; age: 25.4 ± 6.1 years, height: 173.9 ± 0.2 cm, habitual body mass: 89.9 ± 17.3 kg) and losers (n = 7; age: 24.4 ± 6.8 years, height: 178.4 ± 0.9 cm, habitual body mass: 90.8 ± 19.5 kg). Both groups exhibited RWL and weight regain, verified their macronutrient intake, underwent weight and height assessments, and completed two questionnaires (Profile of Mood States and RWL) at (a) 24 hr before weigh-in, (b) weigh-in, (c) postbout, and (d) during a validated time–motion and technical–tactical analysis during the bout. Variance analysis, repeated measures, and a logistic regression analysis were used. The main results showed significant differences between the time points in terms of total caloric intake as well as carbohydrate, protein, and lipid ingestion. Statistical differences in combat analysis were observed between the winners and losers in terms of high-intensity relative time (58 [10–98] s and 32 [1–60] s, respectively), lower limb sequences (3.5 [1.0–7.5] sequences and 1.0 [0.0–1.0] sequences, respectively), and ground and pound actions (2.5 [0.0–4.5] actions and 0.0 [0.0–0.5] actions, respectively), and logistic regression confirmed the importance of high-intensity relative time and lower limb sequences on mixed martial arts performance. RWL and weight regain strategies were related to technical–tactical and time–motion patterns as well as match outcomes. Weight management should be carefully supervised by specialized professionals to reduce health risks and raise competitive performance.

SARS-CoV-2 genetic variants are emerging as a major threat to vaccination efforts worldwide as they may increase virus transmission rate and/or confer the ability to escape vaccine induced immunity with knock on effects on the level of herd immunity and vaccine efficacy respectively. These variants concern the Spike protein, which is encoded by the S gene, involved in virus entry into host cells and the major target of vaccine development. We report here that genetic variants of the N gene can impair our ability to utilize antigenic tests for both diagnosis and mass testing efforts aimed at controlling virus transmission. While conducting a large validation study on the Abbott Panbio™ COVID-19 Ag test, we noticed that some swab samples failed to generate a positive result in spite of a high viral load in Rt-PCR assays. Sequencing analysis of viruses showing discordant results in the RT-PCR and antigen assays revealed the presence of multiple disruptive amino-acid substitutions in the N antigen (the viral protein detected in the antigen test) clustered from position 229 to 374 a region known to contain an immunodominant epitope. A relevant fraction of the variants, undetected by the antigen test, contained the mutations A376T coupled to M241I. Intriguingly we found that virus sequences with this mutation were over-represented in the antigen-test-negative and PCR-positive samples and progressively increased in frequency over time in Veneto, a region of Italy that has aggressively scaled up the utilization of antigen tests, which reached nearly 68% of all the SARS-CoV-2 swab assays performed there. We speculate that mass utilization of antigen assays could create a selection pressure on the target that may favor the spread of undetectable virus variants.

While maximal force increases following short-term isometric strength training, the rate of force development (RFD) may remain relatively unaffected. The underlying neural and muscular mechanisms during rapid contractions after strength training are largely unknown. Since strength training increases the neural drive to muscles, it may be hypothesized that there are distinct neural or muscular adaptations determining the change in RFD independently of an increase in maximal force. Therefore, we examined motor unit population data during the rapid generation of force before and after four weeks of strength training. We observed that strength training did not change the RFD because it did not influence the number of motor units recruited per second or their initial discharge rate during rapid contractions. While strength training did not change motoneuron behaviour in the force increase phase of rapid contractions, it increased the discharge rate of motoneurons (by ∼4 spikes/s) when reaching the plateau phase (∼150 ms) of the rapid contractions, determining an increase in maximal force production. Computer simulations with a motor unit model that included neural and muscular properties, closely matched the experimental observations and demonstrated that the lack of change in RFD following training is primarily mediated by an unchanged maximal recruitment speed of motoneurons. These results demonstrate that maximal force and contraction speed are determined by different adaptations in motoneuron behaviour following strength training and indicate that increases in the recruitment speed of motoneurons are required to evoke training-induced increases in RFD.

Background: Hyaluronans exist in different forms, accordingly with molecular weight and degree of crosslinking. Here, we tested the capability to induce osteogenic differentiation in hDPSCs (human dental pulp stem cells) of three hyaluronans forms: linear pharmaceutical-grade hyaluronans at high and (HHA) low molecular weight (LHA) and hybrid cooperative complexes (HCC), containing both sizes. Methods: hDPSCs were treated with HHA, LHA, HCC for 7, 14 and 21 days. The effects of hyaluronans on osteogenic differentiation were evaluated by qRT-PCR and WB of osteogenic markers and by Alizarin Red S staining. To identify the involved pathway, CD44 was analyzed by immunofluorescence, and YAP/TAZ expression was measured by qRT-PCR. Moreover, YAP/TAZ inhibitor-1 was used, and the loss of function of YAP/TAZ was evaluated by qRT-PCR, WB and immunofluorescence. Results: We showed that all hyaluronans improves osteogenesis. Among these, HCC is the main inducer of osteogenesis, along with overexpression of bone related markers and upregulating CD44. We also found that this biological process is subordinate to the activation of YAP/TAZ pathway. Conclusions: We found that HA's molecular weight can have a relevant impact on HA performance for bone regeneration, and we unveil a new molecular mechanism by which HA acts on stem cells. Keywords: YAP/TAZ pathway; dental pulp stem cells; hyaluronic acid; osteogenic differentiation.

Colorectal carcinoma (CRC) is a common cause of cancer-related death worldwide. Indeed, treatment failures are triggered by cancer stem cells (CSCs) that give rise to tumor repopulation upon initial remission. Thus, the role of the heat shock protein TRAP1 in stemness was investigated in CRC cell lines and human specimens, based on its involvement in colorectal carcinogenesis, through regulation of apoptosis, protein homeostasis and bioenergetics. Strikingly, co-expression between TRAP1 and stem cell markers was observed in stem cells located at the bottom of intestinal crypts and in CSCs sorted from CRC cell lines. Noteworthy, TRAP1 knockdown reduced the expression of stem cell markers and impaired colony formation, being the CSC phenotype and the anchorage-independent growth conserved in TRAP1-rich cancer cells. Consistently, the gene expression profiling of HCT116 cells showed that TRAP1 silencing results in the loss of the stem-like signature with acquisition of a more-differentiated phenotype and the downregulation of genes encoding for activating ligands and target proteins of Wnt/beta-catenin pathway. Mechanistically, TRAP1 maintenance of stemness is mediated by the regulation of Wnt/beta-catenin signaling, through the modulation of the expression of frizzled receptor ligands and the control of beta-catenin ubiquitination/phosphorylation. Remarkably, TRAP1 is associated with higher expression of beta-catenin and several Wnt/beta-catenin target genes in human CRCs, thus supporting the relevance of TRAP1 regulation of beta-catenin in human pathology. This study is the first demonstration that TRAP1 regulates stemness and Wnt/beta-catenin pathway in CRC and provides novel landmarks in cancer biology and therapeutics.

Aims: We aimed at evaluating a standard multiplex ligation-dependent probe amplification (MLPA) probe set for the detection of aneuploidy to diagnose Turner syndrome (TS). We first fixed an MLPA ratio cutoff able to detect all cases of TS in a pilot TS group. We then tested this value on a second group of TS patients and a short-stature population to measure specificity and sensitivity. Methods: 15 TS patients with X mosaicism or X structural abnormalities (Pilot TS Group), 45 TS karyotype-assessed patients (TS Group), and 74 prepubertal female patients with apparent idiopathic short stature (Short-Stature Group) were enrolled. All subjects underwent MLPA and karyotype analysis. In the TS and Short-Stature Groups, MLPA testing was performed in blind. Results: The choice of an MLPA threshold ratio of 0.76 for at least 1 probe allowed us to detect all TS cases, including mosaicisms. Sensitivity and specificity were 100% (CI 95%, 0.92-1) and 88.89% (CI 95%, 0.79-0.94), respectively. The positive predictive value was 88.5%, and the negative predictive value was 100%. MLPA detected the presence of Y chromosome material in 2 patients. Conclusion: MLPA is an accurate and inexpensive tool to screen for TS in girls with short stature. A customized MLPA kit may be useful for the screening of an even larger population.