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This study investigated the synergistic difference in the effect of stretching on electromechanical delay (EMD) and its components, using a simultaneous recording of electromyographic, mechanomyographic, and force signals. Twenty-six healthy men underwent plantar flexors passive stretching. Before and after stretching, the electrochemical and mechanical components of the EMD and the relaxation EMD (R-EMD) were calculated in gastrocnemius medialis (GM), lateralis (GL) and soleus (SOL) during a supramaximal motor point stimulation. Additionally, joint passive stiffness was assessed. At baseline, the mechanical components of EMD and R-EMD were longer in GM and GL than SOL (Cohen's d from 1.78 to 3.67). Stretching decreased joint passive stiffness [-22(8)%, d = -1.96] while overall lengthened the electrochemical and mechanical EMD. The mechanical R-EMD components were affected more in GM [21(2)%] and GL [22(2)%] than SOL [12(1)%], with d ranging from 0.63 to 1.81. Negative correlations between joint passive stiffness with EMD and R-EMD mechanical components were found before and after stretching in all muscles (r from -0.477 to -0.926; P from 0.007 to <0.001). These results suggest that stretching plantar flexors affected GM and GL more than SOL. Future research should calculate EMD and R-EMD to further investigate the mechanical adaptations induced by passive stretching in synergistic muscles., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Toninelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: As COVID-19 roared through the world, governments worldwide enforced containment measures that affected various treatment pathways, including those for hip fractures (HFs). This study aimed to measure process and outcome indicators related to the quality of care provided to non-COVID-19 elderly patients affected by HF in Emilia-Romagna, a region of Italy severely hit by the pandemic., Methods: We collected the hospital discharge records of all patients admitted to the hospitals of Emilia-Romagna with a diagnosis of HF from January to May in the years 2019 (pre-pandemic period) and 2020 (pandemic period). We analyzed surgery rate, surgery delays, length of hospital stay, timely rehabilitation, and 30-day mortality for each HF patient. We evaluated monthly data (2020 vs. 2019) with the chi-square and t-test, where appropriate. Logistic regression was used to investigate the differences in 30-day mortality., Results: Our study included 5379 patients with HF. In April and May 2020, there was a significant increase in the proportion of HF patients that did not undergo timely surgery. In March 2020, we found a significant increase in mortality (OR = 2.22). Male sex (OR = 1.92), age ≥90 years (OR = 4.33), surgery after 48 hours (OR = 3.08) and not receiving surgery (OR = 6.19) were significantly associated with increased mortality. After adjusting for the aforementioned factors, patients hospitalized in March 2020 still suffered higher mortality (OR = 2.21)., Conclusions: There was a reduction in the overall quality of care provided to non-COVID-19 elderly patients affected by HF, whose mortality increased in March 2020. Patients' characteristics and variations in processes of care partially explained this increase. Policymakers and professionals involved in the management of COVID-19 patients should be aware of the needs of patients with other health needs, which should be carefully investigated and included in future emergency preparedness and response plans., Competing Interests: The authors have declared that no competing interests exist.

The current study aimed to verify whether or not passive static stretching affects balance control capacity. Thirty-eight participants (19 women and 19 men) underwent a passive static stretching session, involving the knee extensor/flexor and dorsi/plantarflexor muscles, and a control session (no stretching, CTRL). Before (PRE), immediately after (POST), after 15 (POST15) and 30 min (POST30) from stretching (or rest in CTRL), balance control was evaluated under static and dynamic conditions, with open/closed eyes, and with/without somatosensory perturbation (foam under the feet). During tests, centre of pressure (CoP) sway area and perimeter and antero-posterior and medio-lateral sway mean speed were computed. Surface electromyography root mean square (sEMG RMS) was calculated from the vastus lateralis, biceps femoris, gastrocnemius medialis, and tibialis anterior muscles during MVC and during the balance tests. Hip flexion/extension and dorsi/plantarflexion range of motion (ROM), maximum voluntary contraction (MVC) and sEMG RMS during MVC were measured at the same time points. After stretching, ROM increased (≈6.5%; P<0.05), while MVC and sEMG RMS decreased (≈9% and ≈7.5%, respectively; P<0.05). Regardless of the testing condition, CoP sway area and the perimeter remained similar, while antero-posterior and medio-lateral sway mean speed decreased by ≈8% and ≈12%, respectively (P<0.05). sEMG RMS during the balance tests increased in all muscles in POST (≈7%, P<0.05). All variables recovered in POST30. No changes occurred in CTRL. Passive static stretching did not affect the overall balance control ability. However, greater muscle activation was required to maintain similar CoP sway, thus suggesting a decrease in muscle efficiency., Competing Interests: The authors have declared that no competing interests exist

The current study determined the area-per-player during small- or large-sided games with or without goalkeeper that replicates the relative (m·min-1) total distance, high-intensity running distance, sprint distance and metabolic power covered during official matches. Time-motion analysis was performed on twenty-five elite soccer-players during 26 home-matches. A total of 2565 individual samples for SSGs using different pitch sizes and different number of players were collected and classified as SSGs with (SSG-G) or without goalkeeper (SSG-P). A between-position comparison was also performed. The area-per-player needed to replicate the official match demands was largely higher in SSG-G vs SSG-P for total distance [187±53 vs 115±35 m2, effect size (ES): 1.60 95%CI 0.94/2.21], high-intensity running distance [262±72 vs 166±39 m2, ES: 1.66(0.99/2.27)] and metabolic power [177±42 vs 94±40, ES: 1.99(1.31/2.67)], but similar for sprint distance [(316±75 vs 295±99 m2, ES: 0.24(-0.32/0.79)] with direction of larger area-per-player for sprint distance > high-intensity running > total distance ≌ metabolic power for both SSG-G and SSG-P. In SSG-G, forwards required higher area-per-player than central-defenders [ES: 2.96(1.07/4.35)], wide-midfielders [ES: 2.45(0.64/3.78)] and wide-defenders [ES: 3.45(1.13/4.99)]. Central-midfielders required higher area-per-player than central-defenders [ES: 1.69(0.20/2.90)] and wide-midfielders [ES: 1.35(-0.13/2.57)]. In SSG-P, central defenders need lower area-per-player (ES: -6.01/-0.92) to overall replicate the match demands compared to all other positions. The current results may be used to gain knowledge of the SSGs relative to the match demands. This imply manipulating SSGs using higher or lower ApP, the presence of the goalkeeper or design specific rules to increase or decrease the position-specific demands with respect to the desired external load outcomes., Competing Interests: The authors have declared that no competing interests exist

Objective: To examine health outcomes in Australian Aboriginal and Torres Strait Islander children experiencing perinatal risk and identify protective factors in the antenatal period., Methods: Baby/Child cohorts of the Longitudinal Study of Indigenous Children, born 2001-2008, across four annual surveys (aged 0-8 years, N = 1483). Children with 'mild' and 'moderate-to-high' perinatal risk were compared to children born normal weight at term for maternal-rated global health and disability, and body-mass-index measured by the interviewer., Results: Almost one third of children had experienced mild (22%) or moderate-to-high perinatal risk (8%). Perinatal risk was associated with lower body-mass-index z-scores (regression coefficients adjusted for pregnancy and environment factors: mild = -0.21, 95% CI = -0.34, -0.07; moderate-to-high = -0.42, 95% CI = -0.63, -0.21). Moderate-to-high perinatal risk was associated with poorer global health, with associations becoming less evident in models adjusted for pregnancy and environment factors; but not evident for disability. A range of protective factors, including cultural-based resilience and smoking cessation, were associated with lower risk of adverse outcomes., Conclusions: Perinatal risks are associated with Australian Aboriginal and Torres Strait children experiencing adverse health particularly lower body weight. Cultural-based resilience and smoking cessation may be two modifiable pathways to ameliorating health problems associated with perinatal risk., Competing Interests: The authors have declared that no competing interests exist.

With the goal of identifying neuroactive secondary metabolites from microalgae, a microscale in vivo zebrafish bioassay for antiseizure activity was used to evaluate bioactivities of the diatom Skeletonema marinoi, which was recently revealed as being a promising source of drug-like small molecules. A freeze-dried culture of S. marinoi was extracted by solvents with increasing polarities (hexane, dichloromethane, methanol and water) and these extracts were screened for anticonvulsant activity using a larval zebrafish epilepsy model with seizures induced by the GABAA antagonist pentylenetetrazole. The methanolic extract of S. marinoi exhibited significant anticonvulsant activity and was chosen for bioassay-guided fractionation, which associated the bioactivity with minor constituents. The key anticonvulsant constituent was identified as the nucleoside inosine, a well-known adenosine receptor agonist with previously reported antiseizure activities in mice and rat epilepsy models, but not reported to date as a bioactive constituent of microalgae. In addition, a UHPLC-HRMS metabolite profiling was used for dereplication of the other constituents of S. marinoi. Structures of the isolated compounds were elucidated by nuclear magnetic resonance and high-resolution spectrometry. These results highlight the potential of zebrafish-based screening and bioassay-guided fractionation to identify neuroactive marine natural products.

In a search for new potential multitarget anti-HIV compounds from natural products, we have identified in Hypericum scruglii, an endemic and exclusive species of Sardinia (Italy), a potent plant lead. The phytochemical study of the hydroalcoholic extract obtained from its leaves led to the isolation of its most abundant secondary metabolites, belonging to different chemical classes. In particular, three phloroglucinols derivatives were identified, confirming their significance as chemotaxonomic markers of the Hypericum genus. Among them, the 3-(13-hydroxygeranyl)-1-(2'-methylbutanoyl)phloroglucinol was reported here for the first time. All six isolated compounds have been evaluated firstly for the inhibition of both Human Immunodeficiency Virus type 1 (HIV-1) Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities, for the inhibition of HIV-1 integrase (IN) in biochemical assays, and also for their effect on viral replication. Among the isolated metabolites, three phloroglucinol derivatives and quercitrin were effective on both RT-associated RDDP and RNase H activities in biochemical assays. The same active compounds affected also HIV-1 IN strand transfer function, suggesting the involvement of the RNase H active site. Furthermore, phloroglucinols compounds, included the newly identified compound, were able to inhibit the HIV-1 replication in cell based assays.

Background: Right insular cortex is involved in taste discrimination, but its functional organization is still poorly known. In general, sensory cortices represent the spatial prevalence of relevant features for each sensory modality (visual, auditory, somatosensory) in an ordered way across the cortical space. Following this analogy, we hypothesized that primary taste cortex is organized in similar ordered way in response to six tastes with known receptorial mechanisms (sweet, bitter, sour, salt, umami, CO2)., Design: Ten normal subjects were enrolled in a pilot study. We used functional magnetic resonance imaging (fMRI), a high resolution cortical registration method, and specialized procedures of feature prevalence localization, to map fMRI responses within the right insular cortex, to water solutions of quinine hydrochloride (bitter), Acesulfamate K (sweet), sodium chloride (salt), mono potassium glutamate + inosine 5' mono phosphate (Umami), citric acid (sour) and carbonated water (CO2). During an fMRI scan delivery of the solutions was applied in pseudo-random order interleaved with cleaning water., Results: Two subjects were discarded due to excessive head movements. In the remaining subjects, statistically significant activations were detected in the fMRI responses to all tastes in the right insular cortex (p<0.05, family-wise corrected for multiple comparisons). Cortical representation of taste prevalence highlighted two spatially segregated clusters, processing two and three tastes coupled together (sweet-bitter and salt-umami-sour), with CO2 in between., Conclusions: Cortical representation of taste prevalence within the right primary taste cortex appears to follow the ecological purpose of enhancing the discrimination between safe nutrients and harmful substances.

[This corrects the article DOI: 10.1371/journal.pone.0151533.].

While it is generally acknowledged that orchid species rely on mycorrhizal fungi for completion of their life cycle, little is yet known about how mycorrhizal fungal diversity and community composition vary within and between closely related orchid taxa. In this study, we used 454 amplicon pyrosequencing to investigate variation in mycorrhizal communities between pure (allopatric) and mixed (sympatric) populations of two closely related Platanthera species (Platanthera bifolia and P. chlorantha) and putative hybrids. Consistent with previous research, the two species primarily associated primarily with members of the Ceratobasidiaceae and, to a lesser extent, with members of the Sebacinales and Tulasnellaceae. In addition, a large number of ectomycorrhizal fungi belonging to various families were observed. Although a considerable number of mycorrhizal fungi were common to both species, the fungal communities were significantly different between the two species. Individuals with intermediate morphology showed communities similar to P. bifolia, confirming previous results based on the genetic architecture and fragrance composition that putative hybrids essentially belonged to one of the parental species (P. bifolia). Differences in mycorrhizal communities between species were smaller in mixed populations than between pure populations, suggesting that variation in mycorrhizal communities was largely controlled by local environmental conditions. The small differences in mycorrhizal communities in mixed populations suggests that mycorrhizal fungi are most likely not directly involved in maintaining species boundaries between the two Platanthera species. However, seed germination experiments are needed to unambiguously assess the contribution of mycorrhizal divergence to reproductive isolation., Competing Interests: The authors have declared that no competing interests exist.

Loss in body mass (∆BM) is a common feature in patients with Alzheimer's disease (AD). However, the etiology of this phenomenon is unclear. The aim of this cohort study was to observe possible ∆BM in AD patients following a standard institutionalized diet. Secondary objective was to identify possible predictors of ∆BM. To this end, 85 AD patients (age: 76±4 yrs; stature: 165±3 cm; BM: 61.6±7.4 kg; mean±standard deviation) and 86 controls (CTRL; age: 78±5 yrs; stature: 166±4 cm; BM: 61.7±6.4 kg) were followed during one year of standard institutionalized diet (~1800 kcal/24h). BM, daily energy expenditure, albuminemia, number of medications taken, and cortisolism, were recorded PRE and POST the observation period. Potential predictors of ∆BM in women (W) and men (M) with AD were calculated with a forward stepwise regression model. After one year of standard institutionalized diet, BM decreased significantly in AD (-2.5 kg; p < 0.01), while in CTRL remained unchanged (-0.4 kg; p = 0.8). AD patients and CTRL exhibited similar levels of daily energy expenditure (~1625 kcal/24h). The combination of three factors, number of medications taken, albuminemia, and cortisolism, predicted ∆BM in W with AD. At contrary, the best predictor of ∆BM in M with AD was the cortisolism. Despite a controlled energy intake and similar energy expenditure, both W and M with AD suffered of ∆BM. Therefore, controlled diet did not prevent this phenomenon. The assessments of these variables may predict W and M with AD at risk of weight loss.

Background: Fibrin sealants are widely used in neurosurgery to seal the suture line, provide watertight closure, and prevent cerebrospinal fluid leaks. The aim of this systematic review is to summarize the current efficacy and safety literature of fibrin sealants in dura sealing and the prevention/treatment of cerebrospinal fluid leaks., Methods: A comprehensive electronic literature search was run in the following databases: Cochrane Database of Systematic Reviews, Cochrane Central Resister of Controlled Trials, clinicaltrials.gov, MEDLINE/PubMed, and EMBASE. Titles and abstracts of potential articles of interest were reviewed independently by 3 of the authors., Results: A total of 1006 database records and additional records were identified. After screening for duplicates and relevance, a total of 78 articles were assessed by the investigators for eligibility. Thirty-eight were excluded and the full-text of 40 articles were included in the qualitative synthesis. Seven of these included only safety data and were included in the safety assessment. The remaining 33 articles included findings from 32 studies that enrolled a total of 2935 patients who were exposed to fibrin sealant. Among these 33 studies there were only 3 randomized controlled trials, with the remaining being prospective cohort analysis, case controlled studies, prospective or retrospective case series. One randomized controlled trial, with 89 patients exposed to fibrin sealant, found a greater rate of intraoperative watertight dura closure in the fibrin sealant group than the control group (92.1% versus 38.0%, p<0.001); however, post-operative cerebrospinal fluid leakage occurred in more fibrin sealant than control patients (6.7% versus 2.0%, p>0.05). Other clinical trials evaluated the effect of fibrin sealant in the postoperative prevention of cerebrospinal fluid leaks. These were generally lower level evidence studies (ie, not prospective, randomized, controlled trials) that were not designed or powered to demonstrate a significant advantage to fibrin sealant use. Two small case series studies evaluated the effect of fibrin sealants in persistent cerebrospinal fluid leak treatment, but did not establish firm efficacy conclusions. Specific adverse reports where fibrin sealants were used for dura sealing were limited, with only 8 cases reported in neurosurgical procedures since 1987 and most reporting only a speculative relationship/association with fibrin sealant exposure., Conclusions: A major finding of this systematic literature review is that there is a paucity of randomized studies that have evaluated the effectiveness and safety of fibrin sealants in providing intraoperative watertight dura closure and post-operative cerebrospinal fluid leakage. Among the limited studies available, evidence from a single randomized, controlled trial indicates that fibrin sealants provide a higher rate of intraoperative watertight closure of the dura suture line than control, albeit with a higher rate of postoperative cerebrospinal fluid leakage. Evidence from non-randomized, controlled trials suggests that fibrin sealants may be effective in preventing cerebrospinal fluid leaks with an acceptable safety profile. There is a substantial need for randomized, controlled clinical trials or well-designed prospective observational trials where the conduct of a randomized trial is not feasible to fully assess the impact of fibrin sealant utilization on the rates of intraoperative dura closure, postoperative cerebrospinal leakage, and safety.

The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT.

Objective: Rathke's cleft cysts (RCCs) are quite uncommon sellar lesions that can extend or even arise in the suprasellar area. The purpose of this study is to evaluate the effectiveness of both standard and extended endoscopic endonasal approaches in the management of different located RCCs., Methods: We retrospectively analyzed a series of 29 patients (9 males, 20 females) complaining of a RCC, who underwent a standard or an extended endoscopic transsphenoidal approach at the Division of Neurosurgery, Department of Neurosciences and Reproductive and Odontostomatological Sciences, of the Università degli Studi di Napoli "Federico II". Data regarding patients' demographics, clinical evaluation, cyst characteristics, surgical treatments, complications and outcomes were extracted from our electronic database (Filemaker Pro 11, File Maker Inc., Santa Clara, California, USA)., Results: A standard transsphenoidal approach was used in 19 cases, while the extended variation of the approach in 10 cases (5 purely suprasellar and 5 intra-suprasellar RCC). Cysts contents was fully drained in all the 29 cases, whilst a gross total removal, that accounts on the complete cyst wall removal, was achieved in an overall 55,1% of patients (16/29), specifically 36,8% (7/19) that received standard approach and 90% (9/10) of those that underwent to extended approach. We reported a 56.2% of recovery from headache, 38.5% of complete recovery and 53.8% of improvement from visual field defect and an overall 46.7% of improvement of the endocrine functions. Postoperative permanent DI rate was 10.3%, overall post-operative CSF leak rate 6.9%; recurrence/regrowth occurred in 4 patients (4/29, 13.8%), but only one required a second surgery., Conclusion: The endoscopic transsphenoidal approach for the removal of a symptomatic RCC offers several advantages in terms of visualization of the surgical field during both the exposure and removal of the lesion. The "extended" variation of the endoscopic approach provides a direct access to the supradiaphragmatic space, allowing adequate view and room for the safe removal of selected supradiaphragmatic RCCs, regardless of the sellar size (even a not enlarged sella), and provides a higher likelihood of preserving normal pituitary tissue and functions.

Introduction: The default mode network and the working memory network are known to be anti-correlated during sustained cognitive processing, in a load-dependent manner. We hypothesized that functional connectivity among nodes of the two networks could be dynamically modulated by task phases across time., Methods: To address the dynamic links between default mode network and the working memory network, we used a delayed visuo-spatial working memory paradigm, which allowed us to separate three different phases of working memory (encoding, maintenance, and retrieval), and analyzed the functional connectivity during each phase within and between the default mode network and the working memory network networks., Results: We found that the two networks are anti-correlated only during the maintenance phase of working memory, i.e. when attention is focused on a memorized stimulus in the absence of external input. Conversely, during the encoding and retrieval phases, when the external stimulation is present, the default mode network is positively coupled with the working memory network, suggesting the existence of a dynamically switching of functional connectivity between "task-positive" and "task-negative" brain networks., Conclusions: Our results demonstrate that the well-established dichotomy of the human brain (anti-correlated networks during rest and balanced activation-deactivation during cognition) has a more nuanced organization than previously thought and engages in different patterns of correlation and anti-correlation during specific sub-phases of a cognitive task. This nuanced organization reinforces the hypothesis of a direct involvement of the default mode network in cognitive functions, as represented by a dynamic rather than static interaction with specific task-positive networks, such as the working memory network.

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.

Brain activity during rest is spatially coherent over functional connectivity networks called resting-state networks. In resting-state functional magnetic resonance imaging, independent component analysis yields spatially distributed network representations reflecting distinct mental processes, such as intrinsic (default) or extrinsic (executive) attention, and sensory inhibition or excitation. These aspects can be related to different treatments or subjective experiences. Among these, exhaustion is a common psychological state induced by prolonged mental performance. Using repeated functional magnetic resonance imaging sessions and spatial independent component analysis, we explored the effect of several hours of sustained cognitive performances on the resting human brain. Resting-state functional magnetic resonance imaging was performed on the same healthy volunteers in two days, with and without, and before, during and after, an intensive psychological treatment (skill training and sustained practice with a flight simulator). After each scan, subjects rated their level of exhaustion and performed an N-back task to evaluate eventual decrease in cognitive performance. Spatial maps of selected resting-state network components were statistically evaluated across time points to detect possible changes induced by the sustained mental performance. The intensive treatment had a significant effect on exhaustion and effort ratings, but no effects on N-back performances. Significant changes in the most exhausted state were observed in the early visual processing and the anterior default mode networks (enhancement) and in the fronto-parietal executive networks (suppression), suggesting that mental exhaustion is associated with a more idling brain state and that internal attention processes are facilitated to the detriment of more extrinsic processes. The described application may inspire future indicators of the level of fatigue in the neural attention system.

Previous studies by us and other groups characterized protein expression variation following long-term moderate training, whereas the effects of single bursts of exercise are less known. Making use of a proteomic approach, we investigated the effects of acute swimming exercise (ASE) on protein expression and carbonylation patterns in two hind limb muscles: the Extensor Digitorum Longus (EDL) and the Soleus, mostly composed of fast-twitch and slow-twitch fibres, respectively. Carbonylation is one of the most common oxidative modifications of proteins and a marker of oxidative stress. In fact, several studies suggest that physical activity and the consequent increase in oxygen consumption can lead to increase in reactive oxygen and nitrogen species (RONS) production, hence the interest in examining the impact of RONS on skeletal muscle proteins following ASE. Results indicate that protein expression is unaffected by ASE in both muscle types. Unexpectedly, the protein carbonylation level was reduced following ASE. In particular, the analysis found 31 and 5 spots, in Soleus and EDL muscles respectively, whose carbonylation is reduced after ASE. Lipid peroxidation levels in Soleus were markedly reduced as well. Most of the decarbonylated proteins are involved either in the regulation of muscle contractions or in the regulation of energy metabolism. A number of hypotheses may be advanced to account for such results, which will be addressed in future studies.

The intestinal mucosa is an important target of human immunodeficiency virus (HIV) infection. HIV virus induces CD4+ T cell loss and epithelial damage which results in increased intestinal permeability. The mechanisms involved in nutrient malabsorption and alterations of intestinal mucosal architecture are unknown. We previously demonstrated that HIV-1 transactivator factor (Tat) induces an enterotoxic effect on intestinal epithelial cells that could be responsible for HIV-associated diarrhea. Since oxidative stress is implicated in the pathogenesis and morbidity of HIV infection, we evaluated whether Tat induces apoptosis of human enterocytes through oxidative stress, and whether the antioxidant N-acetylcysteine (NAC) could prevent it. Caco-2 and HT29 cells or human intestinal mucosa specimens were exposed to Tat alone or combined with NAC. In an in-vitro cell model, Tat increased the generation of reactive oxygen species and decreased antioxidant defenses as judged by a reduction in catalase activity and a reduced (GSH)/oxidized (GSSG) glutathione ratio. Tat also induced cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8-hydroxy-2'-deoxyguanosine. GSH/GSSG imbalance and apoptosis occurred in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pre-treatment with NAC prevented Tat-induced apoptosis and restored the glutathione balance in both the in-vitro and the ex-vivo model. These findings indicate that oxidative stress is one of the mechanism involved in HIV-intestinal disease., (© 2011 Buccigrossi et al.)

Background: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis., Methodology/principal Findings: Immunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP(111-119)., Conclusion/significance: The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.