Search

Abstract The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

Numerous studies reporting on the health effects of wood dust have been published over many decades. For the clear majority of these studies, their use for setting a science-based occupational exposure level is problematic due generally to insufficient exposure measurement data, inadequate participant follow-up, and lack of control for confounding variables. However, there exists a robust data set from a large longitudinal lung function study that provides a scientifically sound basis for establishing an occupational limit of 5 mg/m 3 inhalable wood dust. The choice of this data set and its application for this purpose are presented in this review.

Motor learning involves both explicit and implicit processes that are fundamental for acquiring and adapting complex motor skills. However, stroke may damage the neural substrates underlying explicit and/or implicit learning, leading to deficits in overall motor performance. Although both learning processes are typically used in concert in daily life and rehabilitation, no gait studies have determined how these processes function together after stroke when tested during a task that elicits dissociable contributions from both. Here, we compared explicit and implicit locomotor learning in individuals with chronic stroke to age- and sex-matched neurologically intact controls. We assessed implicit learning using split-belt adaptation (where two treadmill belts move at different speeds). We assessed explicit learning (i.e., strategy-use) using visual feedback during split-belt walking to help individuals explicitly correct for step length errors created by the split-belts. After the first 40 strides of split-belt walking, we removed the visual feedback and instructed individuals to walk comfortably, a manipulation intended to minimize contributions from explicit learning. We used a multirate state-space model to characterize individual explicit and implicit process contributions to overall behavioral change. The computational and behavioral analyses revealed that, compared with controls, individuals with chronic stroke demonstrated deficits in both explicit and implicit contributions to locomotor learning, a result that runs counter to prior work testing each process individually during gait. Since poststroke locomotor rehabilitation involves interventions that rely on both explicit and implicit motor learning, future work should determine how locomotor rehabilitation interventions can be structured to optimize overall motor learning. NEW & NOTEWORTHY Motor learning involves both implicit and explicit processes, the underlying neural substrates of which could be damaged after stroke. Although both learning processes are typically used in concert in daily life and rehabilitation, no gait studies have determined how these processes function together after stroke. Using a locomotor task that elicits dissociable contributions from both processes and computational modeling, we found evidence that chronic stroke causes deficits in both explicit and implicit locomotor learning.

Background: Soccer is an intermittent team sport that demands high aerobic capacity. On field, soccer players' aerobic capacity, assessed through the maximal oxygen uptake (VO2max), is usually determined by an intermittent recovery test. The aim of this study was to obtain a construct validity of a new intermittent recovery test (IRT) with a fixed speed and a progressive decrement of rest period., Methods: Twenty-five male soccer players were recruited to perform an incremental continuous test (ICT) and the new IRT, to compare their physiological data. Fifteen male soccer players were involved to perform a test-retest of IRT to assess its reliability., Results: VEpeak, absolute VO2max, relative VO2max and VCO2peak registered during ICT and IRT correlated strongly (Pearson's correlation coefficient ranges from 0.75 to 0.80, with very large as magnitude of effects and with P<0.001). IRT showed reliability from good to excellent regarding VEpeak, absolute VO2max, relative VO2max, VCO2peak and covered distance (ICC values ranged from 0.82 to 0.95)., Conclusions: These findings and its underlying physiological and muscular demands, suggest that IRT can be considered as a valid and reliable test to assess aerobic capacity in soccer players during the competitive period.

Objective: to describe the frequency of underreporting of unfavorable outcomes of congenital syphilis in the state of São Paulo, Brazil, 2007-2018., Methods: this was a descriptive study of cases of abortion, fetal and non-fetal deaths due to congenital syphilis reported on the Notifiable Health Conditions Information System (Sistema de Informação de Agravos de Notificação - SINAN), and those of congenital syphilis registered in any line in the Death Certificate, on the Mortality Information System (Sistema de Informações sobre Mortalidade - SIM), by means of probabilistic and deterministic linkage., Results: of the 27,713 cases of congenital syphilis reported, 1,320 progressed to death (871 fetal deaths, 449 infant deaths) and were matched to the SIM; 355 deaths (259 fetal deaths, 96 infant deaths) were not included on SINAN; there was an increase in unfavorable outcomes,11.4% for infant deaths due to congenital syphilis, 3.0% for fetal deaths and 1.9% for abortions., Conclusion: the use of different relationship techniques proved to be adequate to identify the frequency of underreporting of unfavorable outcomes of congenital syphilis in the state of São Paulo.

Analog quantum simulations with Rydberg atoms in optical tweezers routinely address strongly correlated many-body problems due to the hardware-efficient implementation of the Hamiltonian. Yet, their generality is limited, and flexible Hamiltonian-design techniques are needed to widen the scope of these simulators. Here we report on the realization of spatially tunable interactions for XYZ models implemented by two-color near-resonant coupling to Rydberg pair states. Our results demonstrate the unique opportunities of Rydberg dressing for Hamiltonian design in analog quantum simulators.

The development of prophylactic agents against the SARS-CoV-2 virus is a public health priority in the search for new surrogate markers of active virus replication. Early detection markers are needed to follow disease progression and foresee patient negativization. Subgenomic RNA transcripts (with a focus on sgN) were evaluated in oro/nasopharyngeal swabs from COVID-19-affected patients with an analysis of 315 positive samples using qPCR technology. Cut-off Cq values for sgN (Cq < 33.15) and sgE (Cq < 34.06) showed correlations to high viral loads. The specific loss of sgN in home-isolated and hospitalized COVID-19-positive patients indicated negativization of patient condition, 3-7 days from the first swab, respectively. A new detection kit for sgN, gene E, gene ORF1ab, and gene RNAse P was developed recently. In addition, in vitro studies have shown that 2'- O -methyl antisense RNA (related to the sgN sequence) can impair SARS-CoV-2 N protein synthesis, viral replication, and syncytia formation in human cells (i.e., HEK-293T cells overexpressing ACE2) upon infection with VOC Alpha (B.1.1.7)-SARS-CoV-2 variant, defining the use that this procedure might have for future therapeutic actions against SARS-CoV-2.

The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development., (© 2021. The Author(s).)

To investigate how leg preference affects net efficiency ( η net ), we examined central and peripheral hemodynamics, muscle fiber type, activation and force of preferred (PL) and nonpreferred (NPL) leg. Our hypothesis was that PL greater efficiency could be explained by adaptations and interactions between central, peripheral factors, and force. Fifteen young participants performed single-leg extension exercise at absolute (35 W) and relative [50% peak power-output ( W peak )] workloads with PL and NPL. Oxygen uptake, photoplethysmography, Doppler ultrasound, near-infrared-spectroscopy deoxyhemoglobin [HHb], integrated electromyography (iEMG), maximal isometric force (MVC), rate of force development (RFD 50-100 ), and muscle biopsies of both vastus lateralis were studied to assess central and peripheral determinants of η net . During exercise executed at 35 W, η net was 17.5 ± 5.1% and 11.9 ± 2.1% ( P < 0.01) in PL and NPL respectively, whereas during exercise at the 50% of W peak was in PL = 18.1 ± 5.1% and in NPL = 12.5 ± 1.9 ( P < 0.01). The only parameter correlated with η net was iEMG, which showed an inverse correlation for absolute ( r = -0.83 and -0.69 for PL and NPL) and relative workloads ( r = -0.92 and -0.79 for PL and NPL). MVC and RFD 50-100 were higher in PL than in NPL but not correlated to η net . This study identified a critical role of leg preference in the efficiency during single-leg extension exercise. The whole spectrum of the central and peripheral, circulatory, and muscular determinants of η net did not explain the difference between PL and NPL efficiency. Therefore, the lower muscle activation exhibited by the PL is likely the primary determinant of this physiological phenomenon. NEW & NOTEWORTHY This study examined the impact of leg preference on efficiency during single-leg exercise. The results revealed lower efficiency of the nonpreferred leg during exercises performed at absolute and relative workloads. Central (cardiac output) and peripheral (fiber typing) determinants of efficiency did not explain the difference between the legs. However, the lower muscle activation of the preferred leg that was inversely correlated with efficiency is likely the primary determinant of this physiological feature.

Background and Aim of the Study: The Covid-19 pandemic has clearly impacted the Italian healthcare system. The growing number of patients in critical conditions has required a reorganization of the hospitals wards and of other healthcare structures, by changing the working routines of health professionals. The aim of the study is to explore if and how the nursing care towards Covid-19 positive patients have changed during the pandemic., Method: Qualitative study with a phenomenological approach conducted through semi-structured interviews. Interviews have been carried out during the months of October and November 2020. Our research involved 21 nursing professionals attending post-graduate courses at the Department of Medicine and Surgery of the University of Parma (academic year 2019/2020) and who have worked during the pandemic period in health services structures and organizations., Results: The interviews showed how, during the period of the pandemic emergency, the care relationship between nurses and patients has changed because of the priority given to clinical and technical practices, in some cases, "life-saving". This happened due to different factors such as the nurses' fear of being infected by the virus and the lack of a sufficient time to ensure an holistic and integrated approach towards an increasing number of patients in highly complex conditions. Thus, the dimension of caring has been consciously overshadowed., Conclusions: The health emergency that has hit Italy since the first months of 2020 has shown structural limits and gaps of public health policies, hospital settings and national health services organization that already existed in the pre-pandemic period. It also highlighted how, even before Covid-19, nursing was already in part denoted by a loss of caring, a missed nursing care.

Despite the introduction of antiretroviral (ARV) therapy (ART), approximately 30-50% of people living with human immunodeficiency virus-1 (HIV-1) will develop a spectrum of measurable neurocognitive dysfunction, collectively called HIV-associated neurocognitive disorder (HAND). While the clinical manifestations of HAND have changed with the advent of ART, certain pathological features have endured, including white matter alterations and dysfunction. The persistence of white matter alterations in the post-ART era suggests that ARV drugs themselves may contribute to HAND pathology. Our group has previously demonstrated that two ARV compounds from the protease inhibitor (PI) class, ritonavir and lopinavir, inhibit oligodendrocyte maturation and myelin protein production. We hypothesized that other members of the PI class, saquinavir and darunavir, could also negatively impact oligodendrocyte differentiation. Here we demonstrate that treating primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either ARV drug results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Furthermore, we show that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- and darunavir-induced inhibition of oligodendrocyte maturation. Moreover, our findings suggest, for the first time, an imperative role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against ARV-induced oligodendrocyte dysregulation. Graphical Abstract Treatment of primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either antiretroviral compound of the protease inhibitor class, darunavir or saquinavir, results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Additionally, in darunavir or saquinavir-treated cultures we observed a concentration-dependent decrease in the number of acidic lysosomes, via immunostaining with LysoTracker Red, compared with vehicle-treated cultures. Finally, we showed that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- or darunavir-induced inhibition of oligodendrocyte maturation. Our findings suggest, for the first time, a critical role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against antiretroviral-induced oligodendrocyte dysregulation.

Regardless of adherence to combined antiretroviral therapy, white matter and myelin pathologies persist in patients with HIV-associated neurocognitive disorders, a spectrum of cognitive, motor, and behavioral impairments. We hypothesized that antiretroviral therapy alters the maturation of oligodendrocytes which synthesize myelin. We tested whether specific frontline integrase strand transfer inhibitors would alter oligodendrocyte differentiation and myelination. To model the effect of antiretrovirals on oligodendrocytes, we stimulated primary rat oligodendrocyte precursor cells to differentiate into mature oligodendrocytes in vitro in the presence of therapeutically relevant concentrations of elvitegravir or raltegravir and then assessed differentiation with lineage specific markers. To examine the effect of antiretrovirals on myelination, we treated mice with the demyelinating compound cuprizone, for 5 weeks. This was followed by 3 weeks of recovery in absence of cuprizone, during which time some mice received a daily intrajugular injection of elvitegravir. Brains were harvested, sectioned and processed by immunohistochemistry to examine oligodendrocyte maturation and myelination. Elvitegravir inhibited oligodendrocyte differentiation in vitro in a concentration-dependent manner, while raltegravir had no effect. Following cuprizone demyelination, administration of elvitegravir to adult mice reduced remyelination compared with control animals. Elvitegravir treatment activated the integrated stress response in oligodendrocytes in vitro, an effect which was completely blocked by pretreatment with the integrated stress response inhibitor Trans-ISRIB, preventing elvitegravir-mediated inhibition of oligodendrocyte maturation. These studies demonstrate that elvitegravir impairs oligodendrocyte maturation and remyelination and that the integrated stress response mediates this effect and may be a possible therapeutic target., (© 2020 Wiley Periodicals LLC.)

Background: Chickenpox is a highly contagious airborne disease caused by the varicella zoster virus. It is generally benign and self-limiting, but it may be responsible of life-threatening complications. Acute cerebellitis (AC) is the most common neurological complication and is associated with prolonged hospitalization in the acute phase (HAP)., Aim of the Study: To estimate the costs of AC HAP in children affected by varicella., Materials and Methods: We retrospectively reviewed the medical records of a pediatric cohort hospitalized for chickenpox AC over a period of 15 years (from October 2003 to October 2018) and we analyzed acute care costs. For any patient the HAP has been calculated. The final value includes cost of hospital accommodation and management at the Pediatric and Infectious Diseases Unit. To this cost, the price of procedures (imaging, laboratory exams, medical and paramedical evaluations) and medical treatments was added., Results: In the study period, 856 children had been hospitalized for varicella. Out of them, 65 met a diagnosis of AC and were included in the study. The hospitalization length was of 10 days (range 3-20 days). The median cost of HAP for each patient was of 5366 euro, with an average annual cost of 23,252 €. The most significant part of HAP is due to the cost of hospital accommodation and management at the Pediatric Infectious Diseases Unit, which was about € 537.78 for a single day., Discussion: Although AC post-varicella is rare, its HAP cost is not negligible resulting in substantial economic burden. Vaccination would have probably prevented varicella and AC complication, avoiding hospitalization., Conclusions: Financial studies are important for evaluate the cost saving in order to influence public funding decisions. Further studies are necessary to investigate the economic burden of the disease.

Background: The aim of this study was to determine the influence of spring mass model characteristics (e.g. stiffness) and Achilles tendon properties in determining the energy cost of running in half marathon runners., Methods: Achilles tendon characteristics (i.e. cross-sectional area -ATCSA- and resting length -ATL-) were measured on 32 males by means of an ultrasound apparatus the day before a half marathon race. After these measurements the energy cost of running (C) was determined while the subjects run on a treadmill at the speed (vT) they were expected to maintain during the race (vR); the vertical (kvert) and leg (kleg) stiffness were calculated based on kinematic data., Results: No differences were observed between vT and vR. Higher values of vT were associated with larger values of kleg and kvert. The faster runners (with larger vT) were the ones with the lower C (r=-0.43, P<0.05) and the larger ATCSA (r=0.46, P<0.01). No relationship was found between C and ATCSA but C was lower in runners with longer ATL (r=-0.52, P<0.001). Finally, no relationship was found between kleg or kvert and C, but runners with larger kvert were also those with the larger ATCSA (r=0.45, P<0.01)., Conclusions: These findings underline the correlation between spring-mass model parameters and Achilles tendon characteristics in half-marathon runners; they further show how these parameters influence the half marathon pace and the energy cost of running at this pace.

Purpose: To compare the impact of two different training intensity distributions in terms of conditional and performance parameters and spent time to training in recreational athletes. Methods: Two different training intensity distribution model were performed for 8 weeks by 38 recreational runners. Runners recruited were randomly assigned to 2 different training models based on HR intensity detected with maximal test. The percentage distribution splitted in zone 1, 2, and 3 were by 77/3/20 and 40/50/10 in polarized endurance training group (PET) and focused endurance training (FOC) group, respectively. Programs were balanced for total training impulse (TRIMP). To evaluate effects of training, before and after treatment were performed a maximal exercise test to determine Maximal Oxygen Uptake (V'O 2max ), Ventilatory Threshold (VT), respiratory-compensation point (RCT) Running Economy (RE), and 2 Km performance. To investigate the effects of training on muscular performance were performed one repetition maximum (1 RM), squat jump (SJ), and counter movement jump (CMJ). Results: Both groups significantly improved their velocity at V'O 2max (3.2 and 4.0%), at VT (4.0 and 3.2%), RCT (5.7 and 3.4%), the average velocity in 2 Km performance (3.5 and 3.0%) and RE (-5.3 and -8.7%) for PET and FOC, respectively for each variable. No differences were found between the groups on any parameter investigated except about the total training time (PET = 29.9 ± 3.1 h and FOC = 24.8 ± 2.0 h). Conclusion: Focused Endurance Training obtains similar improvements than Polarized Endurance Training saving 17% of training time in recreational runners., (Copyright © 2020 Festa, Tarperi, Skroce, La Torre and Schena.)

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite effective antiretroviral therapies (ART). Evidence suggests that modern HAND is driven by subtle synaptodendritic damage in select brain regions, as ART-treated patients do not display overt neuronal death in postmortem brain studies. HAND symptoms are also aggravated by drug abuse, particularly with injection opioids. Opioid use produces region-specific synaptodendritic damage in similar brain regions, suggesting a convergent mechanism that may enhance HAND progression in opioid-using patients. Importantly, studies indicate that synaptodendritic damage and cognitive impairment in HAND may be reversible. Activation of the homeostatic chemokine receptor CXCR4 by its natural ligand CXCL12 positively regulates neuronal survival and dendritic spine density in cortical neurons, reducing functional deficits. However, the molecular mechanisms that underlie CXCR4, as well as opioid-mediated regulation of dendritic spines are not completely defined. Here, we will consolidate studies that describe the region-specific synaptodendritic damage in the cerebral cortex of patients and animal models of HAND, describe the pathways by which opioids may contribute to cortical synaptodendritic damage, and discuss the prospects of using the CXCR4 signaling pathway to identify new approaches to reverse dendritic spine deficits. Additionally, we will discuss novel research questions that have emerged from recent studies of CXCR4 and µ-opioid actions in the cortex. Understanding the pathways that underlie synaptodendritic damage and rescue are necessary for developing novel, effective therapeutics for this growing patient population., (Copyright © 2019. Published by Elsevier B.V.)

Adding nanoparticles to liquid fuel is known to promote its combustion characteristics through improving several thermo-physical properties. This study investigates the effects of adding carbon nanoparticles on thermal conductivity and evaporation rate of liquid jet fuel. Multi-walled carbon nanotubes, activated carbon nanoparticles, and graphene nanoplatelets were added to jet fuel at different concentrations to prepare colloidal suspensions. Thermal conductivity is determined by passing known amounts of heat through a very thin layer of fuel and measuring temperature difference across its thickness. A fiber-supported droplet technique is also used to evaluate evaporation rate due to force convection of a hot inert gas. It is observed that both thermal conductivity and evaporation rate increase as a result of nanoparticle addition. Since there is no radiation heat transfer mechanism, the increase in evaporation rate is concluded to be only due to enhanced thermal conductivity.

HIV-associated neurocognitive disorders (HAND) remain prevalent and are aggravated by µ-opioid use. We have previously shown that morphine and other µ-opioids may contribute to HAND by inhibiting the homeostatic and neuroprotective chemokine receptor CXCR4 in cortical neurons, and this novel mechanism depends on upregulation of the protein ferritin heavy chain (FHC). Here, we examined the cellular events and potential mechanisms involved in morphine-mediated FHC upregulation using rat cortical neurons of either sex in vitro and in vivo. Morphine dose dependently increased FHC protein levels in primary neurons through µ-opioid receptor (µOR) and Gαi-protein signaling. Cytoplasmic FHC levels were significantly elevated, but nuclear FHC levels and FHC gene expression were unchanged. Morphine-treated rats also displayed increased FHC levels in layer 2/3 neurons of the prefrontal cortex. Importantly, both in vitro and in vivo FHC upregulation was accompanied by loss of mature dendritic spines, which was also dependent on µOR and Gαi-protein signaling. Moreover, morphine upregulated ferritin light chain (FLC), a component of the ferritin iron storage complex, suggesting that morphine altered neuronal iron metabolism. Indeed, prior to FHC upregulation, morphine increased cytoplasmic labile iron levels as a function of decreased endolysosomal iron. In line with this, chelation of endolysosomal iron (but not extracellular iron) blocked morphine-induced FHC upregulation and dendritic spine reduction, whereas iron overloading mimicked the effect of morphine on FHC and dendritic spines. Overall, these data demonstrate that iron mediates morphine-induced FHC upregulation and consequent dendritic spine deficits and implicate endolysosomal iron efflux to the cytoplasm in these effects., (Copyright © 2019 Nash et al.)

Festa, L, Tarperi, C, Skroce, K, Boccia, G, Lippi, G, La Torre, A, and Schena, F. Effects of flywheel strength training on the running economy of recreational endurance runners. J Strength Cond Res 33(3): 684-690, 2019-Running economy (RE) has been defined as the most important determining factor in endurance performance in both elite and recreational runners. The purpose of this study was to evaluate the effect of flywheel strength training (FST) and high-intensity training (HIT) protocols on RE and strength parameters in a group of recreational runners. Twenty-nine recreational runners were recruited to take part in the study and were randomly assigned to FST (n = 9; 44.5 ± 6.0 years; V[Combining Dot Above]O2max 48.8 ± 5.2 ml·min·kg), HIT (n = 9; 42.2 ± 8.6 years; V[Combining Dot Above]O2max 50.3 ± 3.7 ml·min·kg), or low-intensity training (LIT) (n = 11; 45.4 ± 8.0 years; V[Combining Dot Above]O2max 50.2 ± 6.8 ml min kg) groups. Before and after 8 weeks of an experimental period, maximal oxygen uptake (V[Combining Dot Above]O2max), ventilatory thresholds (VTs), maximal dynamic force (1 repetition maximum [1RM]), and anthropometric data were evaluated. The FST group showed significant increases (p < 0.05) in 1RM and RE. No differences were found in the other groups. Significative changes are found for all groups on average speed on 2 and 10 km (p < 0.05). Anthropometric data were unchanged after the training period. The results of this study indicate that in recreational runners, FST seems able to obtain improvements in RE and neuromuscular adaptation.

Since the impact of possible prothrombotic factors on blood coagulation resulting from exercise remains elusive, this study investigated the acute effects of middle-distance endurance running on blood coagulation parameters in middle-aged athletes. The study population consisted of 33 male endurance runners who were engaged in a 21.1 km run under competitive conditions. Blood samples were collected before the run, immediately after the run, and 3 hours after run completion. Samples were assessed for activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, D-dimer, factor VIII (FVIII), von Willebrand factor antigen (VWF:Ag), endogenous thrombin potential (area under the curve of thrombin generation [TGA-AUC]), and peak thrombin generation (TGA-PK). Post-run variations were expressed as delta (Δ). At baseline, APTT was found to be significantly associated with ABO blood group, VWF:Ag, and FVIII; fibrinogen with age; VWF:Ag with BMI, training regimen, and ABO blood group; APTT with FVIII; FVIII with VWF:Ag and ABO blood group; APTT with VWF:Ag; and TGA-PK with ABO blood group, PT, and TGA-AUC. Immediately after the run, statistically significant increases were observed for PT, D-dimer, VWF:Ag, and FVIII, while statistically significant reductions could be observed for APTT, TGA-AUC, and TGA-PK. Fibrinogen values remained unchanged. Significant correlations were observed between Δ VWF:Ag and Δ FVIII, Δ APTT and Δ VWF:Ag, Δ APTT and Δ FVIII, Δ TGA-AUC and Δ TGA-PK, and between Δ D-dimer and Δ TGA-AUC and Δ TGA-PK. No Δ variation was associated with running time. The results of this study seemingly suggest that middle-distance competitive running may evoke several prothrombotic changes in blood coagulation., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The effect of muscle fatigue on rate of force development (RFD) is usually assessed during tasks that require participants to reach as quickly as possible maximal or near-maximal force. However, endurance sports require athletes to quickly produce force of submaximal, rather than maximal, amplitudes. Thus, this study investigated the effect of muscle fatigue induced by long-distance running on the capacity to quickly produce submaximal levels of force. Twenty-one male amateur runners were evaluated before and shortly after a half-marathon race. Knee extensors force was recorded under maximal voluntary and electrically evoked contractions. Moreover, a series of ballistic contractions at different submaximal amplitudes (from 20 to 100% of maximal voluntary force) was obtained, by asking the participants to reach submaximal forces as fast as possible. The RFD was calculated for each contraction. After the race, maximal voluntary activation, resting doublet twitch, maximal force, and RFD during maximal contraction decreased (-12, -12, -21, and -19%, respectively, all P -values < 0.0001). Nevertheless, the RFD values measured during ballistic contractions up to 60% of maximal force were unaffected (all P -values > 0.4). Long-distance running impaired the capacity to quickly produce force in ballistic contractions of maximal, but not of submaximal, amplitudes. Overall, these findings suggest that central and peripheral fatigue do not affect the quickness to which muscle contracts across a wide range of submaximal forces. This is a relevant finding for running and other daily life activities that rely on the production of rapid submaximal contractions rather than maximal force levels.

Women are known to be less fatigable than men in single-joint exercises, but fatigue induced by running has not been well understood. Here we investigated sex differences in central and peripheral fatigue and in rate of force development (RFD) in the knee extensors after a half-marathon run. Ten male and eight female amateur runners (aged 25-50 years) were evaluated before and immediately after a half-marathon race. Knee extensors forces were obtained under voluntary and electrically evoked isometric contractions. Maximal voluntary isometric contraction (MVC) force and peak RFD were recorded. Electrically doublet stimuli were delivered during the MVC and at rest to calculate the level of voluntary activation and the resting doublet twitch. After the race, decreases in MVC force (males: -11%, effect size [ES] 0.52; females: -11% ES 0.33), voluntary activation (males: -6%, ES 0.87; females: -4%, ES 0.72), and resting doublet twitch (males: -6%, ES 0.34; females: -8%, ES 0.30) were found to be similar between males and females. The decrease in peak RFD was found to be similar between males and females (males: -14%, ES 0.43; females: -15%, ES 0.14). Half-marathon run induced both central and peripheral fatigue, without any difference between men and women. The maximal and explosive strength loss was found similar between sexes. Together, these findings do not support the need of sex-specific training interventions to increase the tolerance to neuromuscular fatigue in half-marathoners.

Background: The sympatho-adrenergic activation during exercise is implicated in many cardiovascular respiratory and metabolic adaptations which have been thought to partially explain the different levels of performance observed between trained and untrained subjects. To date, no evidence exists about the association between competition performance and markers of "acute stress response". We designed this study to investigate; (i) the acute sympatho-adrenergic activation during endurance exercise in recreational runners by measuring plasma levels of free metanephrine (MN) and normethanephrine (NMN) before and after a half-marathon run; (ii) the association between the metanephrines levels and the running time., Methods: 26 amateur runners (15 males, 11 females) aged 30 to 63 years were enrolled. The quantification of MN and NMN was performed by LC-MS/MS. Anthropometric ergonomic and routine laboratory data were recorded. Statistical analyses included paired T -test, univariate and multivariate regressions., Results: The post-run values of MN and NMN displayed a nearly 3.5 and 7 fold increase respectively compared to the baseline values ( p < 0.0001 for both). NMN pre-run values and pre/post run delta values showed a significant direct and inverse association ( p = 0.021 and p = 0.033, respectively) with running performance. No correlations were found for MN values., Conclusion: NMN is a reliable marker of sympatho-adrenergic activation by exercise and can predict endurance performance in the individual athlete. Adaptation phenomenon occurring not only in the adrenal medulla might represent the biological mechanism underlying this association. Further studies on sympatho-adrenergic activation, competition performance and training status should contemplate the measurement of these metabolites instead of their unstable precursors., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

We examined whether the presence of fatigue induced by prolonged running influenced the time courses of force generating capacities throughout a series of intermittent rapid contractions. Thirteen male amateur runners performed a set of 15 intermittent isometric rapid contractions of the knee extensor muscles, (3s/5s on/off) the day before (PRE) and immediately after (POST) a half marathon. The maximal voluntary contraction force, rate of force development (RFD peak ), and their ratio (relative RFD peak ) were calculated. At POST, considering the first (out of 15) repetition, the maximal force and RFD peak decreased (p<0.0001) at the same extent (by 22±6% and 24±22%, respectively), resulting in unchanged relative RFD peak (p=0.6). Conversely, the decline of RFD peak throughout the repetitions was more pronounced at POST (p=0.02), thus the decline of relative RFD peak was more pronounced (p=0.007) at POST (-25±13%) than at PRE (-3±13%). The main finding of this study was that the fatigue induced by a half-marathon caused a more pronounced impairment of rapid compared to maximal force in the subsequent intermittent protocol. Thus, the fatigue-induced impairment in rapid muscle contractions may have a greater effect on repeated, rather than on single, attempts of maximal force production., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The ability to modulate angiogenesis by chemical tools has several important applications in different scientific fields. With the perspective of finding novel proangiogenic molecules, we searched peptide sequences with a chemical profile similar to that of the QK peptide, a well described VEGF mimetic peptide. We found that residues 1617-1627 of the IQGAP1 protein show molecular features similar to those of the QK peptide sequence. The IQGAP1-derived synthetic peptide was analyzed by NMR spectroscopy and its biological activity was characterized in endothelial cells. These studies showed that this IQGAP1-derived peptide has a biological activity similar to that of VEGF and could be considered as a novel tool for reparative angiogenesis.

Background: Despite being a recessive trait, the O blood group is the most frequent worldwide among the ABO blood types. Since running performance has been recognized as a major driver of evolutionary advantage in humans, we planned a study to investigate whether the ABO blood group may have an influence on endurance running performance in middle-aged recreational athletes., Methods: The study population consisted of 52 recreational, middle-aged, Caucasian athletes (mean age: 49±13 years, body mass index, 23.4±2.3 kg/m 2 ), regularly engaged in endurance activity. The athletes participated to a scientific event called "Run for Science" (R4S), entailing the completion of a 21.1 km (half-marathon) run under competing conditions. The ABO blood type status of the participants was provided by the local Service of Transfusion Medicine., Results: In univariate analysis, running performance was significantly associated with age and weekly training, but not with body mass index. In multiple linear regression analysis, age and weekly training remained significantly associated with running performance. The ABO blood group status was also found to be independently associated with running time, with O blood type athletes performing better than those with non-O blood groups. Overall, age, weekly training and O blood group type explained 62.2% of the total variance of running performance (age, 41.6%; training regimen, 10.5%; ABO blood group, 10.1%)., Conclusions: The results of our study show that recreational athletes with O blood group have better endurance performance compared to those with non-O blood group types. This finding may provide additional support to the putative evolutionary advantages of carrying the O blood group., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: This study was aimed to investigate the acute effect of medium-distance running on bile acids concentration and composition, in order to verify whether the positive impact of physical exercise on cancer risk may also be mediated by variation of bile acids concentration and composition in serum., Methods: The concentration and composition of serum bile acids was analyzed in 30 middle-aged and healthy recreational athletes with a reference liquid chromatography-mass spectrometry technique, immediately before and shortly after the end of the running trial. The concentration of bile acids after the run was adjusted for plasma volume change., Results: All athletes successfully completed the trial. After correction of values for the individual plasma volume change calculated after the run, the serum concentration of total bile acids was found to be significantly reduced by approximately 46%. A statistically significant decrease was observed for cholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, glycoursodeoxycholic and hyodeoxycholic acids, whereas the concentration of the remaining compounds remained unvaried after the run. A considerable variation of bile acids profile was also observed. No significant association was found between running performance and variation of bile acids concentrations., Conclusion: These results show that middle distance running acutely decreases the concentration of total bile acids in serum, especially that of the more mutagenic and carcinogenic compounds, so providing an intriguing support to the favorable effects of physical exercise for lowering the risk of many gastrointestinal cancers., Competing Interests: CONFLICTS OF INTEREST No potential conflict of interest was reported by the authors.

Monitoring surface electromyographic (EMG) signals can provide useful insights for characterizing muscle fatigue, which is defined as an exercise-induced strength loss. This experiment investigated the muscle fiber conduction velocity (CV) changes induced by an endurance run. The day before and immediately after a half-marathon run (21.097 km) 11 amateur runners performed maximum voluntary contractions (MVCs) of knee extensor muscles. During the MVC, multichannel EMG was recorded from the vastus lateralis and EMG amplitude and CV were calculated. After the run, knee extensors showed a decreased strength (-13  ±  9%, p  =  0.001) together with a reduction in EMG amplitude (-13  ±  10%, p  =  0.003) and in CV (-6  ±  8%, p  =  0.032). Knee extensor strength loss positively correlated with vastus lateralis CV differences (r  =  0.76, p  =  0.006). Thus, the exercises-induced muscle fatigue was associated not only with a decrease in EMG amplitude, but also with a reduction in CV. This finding suggests that muscle fibers with higher CV (i.e. those with greater fiber size) were the most impaired during strength production after an endurance run.

The aim of this study was to evaluate DNA damage in response to increasing bulks of aerobic physical exercise. Fifteen adult and trained athletes performed four sequential trials with increasing running distance (5-, 10-, 21- and 42-km) in different periods of the year. The γ-H2AX foci parameters were analyzed before and 3h after the end of each trial. The values of all γ-H2AX foci parameters were enhanced after the end of each trial, with values gradually increasing from the 5- to the 42-km trial. Interestingly, a minor increase of γ-H2AX foci was still evident after 5- to 10-km running, but a much higher increase occurred when the running distance exceeded 21km. The generation of DNA injury was then magnified by running up to 42-km. The increase of each γ-H2AX foci parameter was then found to be associated with both running distance and average intensity. In multivariate linear regression analysis, the running distance was significantly associated with average intensity and post-run variation in the percentage of cells with γ-H2AX foci. We can hence conclude that aerobic exercise may generate an acute DNA damage in trained athletes, which is highly dependent upon running distance and average intensity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Synaptodendritic pruning and alterations in neurotransmission are the main underlying causes of HIV-associated neurocognitive disorders (HAND). Our studies in humans and nonhuman primates indicated that the protein ferritin heavy chain (FHC) is a critical player in neuronal changes and ensuing cognitive deficit observed in these patients. Here we focus on the effect of HIV proteins and inflammatory cytokines implicated in HAND on neuronal FHC levels, dendritic changes, and neurocognitive behavior. In two well characterized models of HAND (HIV transgenic and gp120-treated rats), we report reductions in spine density and dendritic branches in prefrontal cortex pyramidal neurons compared with age-matched controls. FHC brain levels are elevated in these animals, which also show deficits in reversal learning. Moreover, IL-1β, TNF-α, and HIV gp120 upregulate FHC in rat cortical neurons. However, although the inflammatory cytokines directly altered neuronal FHC, gp120 only caused significant FHC upregulation in neuronal/glial cocultures, suggesting that glia are necessary for sustained elevation of neuronal FHC by the viral protein. Although the envelope protein induced secretion of IL-1β and TNF-α in cocultures, TNF-α blockade did not affect gp120-mediated induction of FHC. Conversely, studies with an IL-1β neutralizing antibody or specific IL-1 receptor antagonist revealed the primary involvement of IL-1β in gp120-induced FHC changes. Furthermore, silencing of neuronal FHC abrogates the effect of gp120 on spines, and spine density correlates negatively with FHC levels or cognitive deficit. These results demonstrate that viral and host components of HIV infection increase brain expression of FHC, leading to cellular and functional changes, and point to IL-1β-targeted strategies for prevention of these alterations. Significance statement: This work demonstrates the key role of the cytokine IL-1β in the regulation of a novel intracellular mediator [i.e., the protein ferritin heavy chain (FHC)] of HIV-induced dendritic damage and the resulting neurocognitive impairment. This is also the first study that systematically investigates dendritic damage in layer II/III prefrontal cortex neurons of two different non-infectious models of HIV-associated neurocognitive disorders (HAND) and reveals a precise correlation of these structural changes with specific biochemical and functional alterations also reported in HIV patients. Overall, these data suggest that targeting the IL-1β-dependent FHC increase may represent a valid strategy for neuroprotective adjuvant therapies in HAND., (Copyright © 2015 the authors 0270-6474/15/3510550-12$15.00/0.)

We here show a new relationship between the human p14ARF oncosuppressor and the MDM2 oncoprotein. MDM2 overexpression in various cancer cell lines causes p14ARF reduction inducing its degradation through the proteasome. The effect does not require the ubiquitin ligase activity of MDM2 and preferentially occurs in the cytoplasm. Interestingly, treatment with inhibitors of the PKC (Protein Kinase C) pathway and use of p14ARF phosphorylation mutants indicate that ARF phosphorylation could play a role in MDM2 mediated ARF degradation reinforcing our previous observations that ARF phosphorylation influences its stability and biological activity. Our study uncovers a new potentially important mechanism through which ARF and MDM2 can counterbalance each other during the tumorigenic process.