Miracle-dz/UniFAR-FTUs huggingface dataset:
The emergence of a functionally flexible brain during early infancy

Significance While adult brains are known to be functionally flexible, the emergence of a functionally flexible brain during early infancy is largely uncharted due the lack of approaches to assess neural flexibility in infants. Using recent advances of multilayer network approaches and a cohort of typically developing children who underwent longitudinal MRI during the first 2 y of life, we investigated the developmental characteristics of brain neural flexibility. The temporal and spatial emergence of a functionally flexible brain was revealed. Brain regions with high neural flexibility appear consistent with the core regions supporting cognitive flexibility processing in adults, whereas brain regions governing basic brain functions exhibit lower neural flexibility, demonstrating the emergence of functionally flexible brain during early infancy. Adult brains are functionally flexible, a unique characteristic that is thought to contribute to cognitive flexibility. While tools to assess cognitive flexibility during early infancy are lacking, we aimed to assess the spatiotemporal developmental features of “neural flexibility” during the first 2 y of life. Fifty-two typically developing children 0 to 2 y old were longitudinally imaged up to seven times during natural sleep using resting-state functional MRI. Using a sliding window approach, MR-derived neural flexibility, a quantitative measure of the frequency at which brain regions change their allegiance from one functional module to another during a given time period, was used to evaluate the temporal emergence of neural flexibility during early infancy. Results showed that neural flexibility of whole brain, motor, and high-order brain functional networks/regions increased significantly with age, while visual regions exhibited a temporally stable pattern, suggesting spatially and temporally nonuniform developmental features of neural flexibility. Additionally, the neural flexibility of the primary visual network at 3 mo of age was significantly and negatively associated with cognitive ability evaluated at 5/6 y of age. The “flexible club,” comprising brain regions with neural flexibility significantly higher than whole-brain neural flexibility, were consistent with brain regions known to govern cognitive flexibility in adults and exhibited unique characteristics when compared to the functional hub and diverse club regions. Thus, MR-derived neural flexibility has the potential to reveal the underlying neural substrates for developing a cognitively flexible brain during early infancy.
Are Complex Skull Fractures Indicative of Either Child Abuse or Major Trauma in the Era of 3-Dimensional Computed Tomography Imaging?

Objective The aim of the study was to determine whether complex skull fractures are more indicative of child abuse or major trauma than simple skull fractures. Design This is a retrospective chart and imaging review of children diagnosed with a skull fracture. Subjects were from 2 pediatric tertiary care centers. Children younger than 4 years who underwent a head computed tomography with 3-dimensional rendering were included. We reviewed the medical records and imaging for type of skull fracture, abuse findings, and reported mechanism of injury. A complex skull fracture was defined as multiple fractures of a single skull bone, fractures of more than 1 skull bone, a nonlinear fracture, or diastasis of greater than 3 mm. Abuse versus accident was determined at the time of the initial evaluation with child abuse physician team confirmation. Results From 2011 to 2012, 287 subjects were identified by International Classification of Diseases, Ninth Revision, code. The 147 subjects with a cranial vault fracture and available 3-dimensional computed tomography composed this study's subjects. The average age was 12.3 months. Seventy four (50.3%) had complex and 73 (49.7%) had simple fractures. Abuse was determined in 6 subjects (4.1%), and a determination could not be made for 5 subjects. Adding abused children from 2013 to 2014 yielded 15 abused subjects. Twelve of the abused children (80%) had complex fractures; more than the 66 (48.5%) of 136 accidentally injured children (P = 0.001; relative risk = 1.65 [1.21–2.24]). However, among children with a complex fracture, the positive predictive value for abuse was only 7%. Conclusions Complex skull fractures frequently occur from accidental injuries. This study suggests that the presence of complex skull fractures should not be used alone when making a determination of abuse.
Streptococcus suis Research: Progress and Challenges

Streptococcus suis is considered among the top bacterial pathogens leading to important economic losses to the swine industry, with the incidence of disease increasing as the prophylactic use of antimicrobial is being vanished worldwide. S. suis is also a zoonotic agent afflicting people in close contact with infected pigs or pork meat. Besides, in some Asian countries, it is considered a major public health concern for the general population as well. Antimicrobial resistance is one of the most important global health challenges, and in the absence of preventive measures (such as effective vaccines), S. suis remains a risk for increased antimicrobial resistance and transmission of resistance genes to other bacteria beyond the host animal species. The studies in this Special Issue have evidenced the importance of swine population demographics and management on disease control, progress in molecular tools to better understand the epidemiology of S. suis infections in swine and humans, and the mechanisms involved in different aspects of the immuno-pathogenesis of the disease. The importance of reducing the prophylactic use of antimicrobials in livestock productions and the development of alternative control measures, including vaccination, are herein discussed.
Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains

Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking. We exposed three murine strains, C57BL/6J, 129X1/SvJ, and BALB/cJ, to cigarette smoke for 3 months before the induction of a midshaft transverse femoral osteotomy. We evaluated fracture healing 4 weeks after the osteotomy using radiography, micro‐computed tomography (μCT), and biomechanical testing. Radiographic analysis demonstrated a significant decrease in the fracture healing capacity of smoking 129X1/SvJ mice. μCT results showed delayed remodeling of fracture calluses in all three strains after cigarette smoke exposure. Biomechanical testing indicated the most significant impairment in the functional properties of 129X1/SvJ in comparison with C57BL/6J and BALB/cJ mice after cigarette smoke exposure. Thus, the 129X1/SvJ strain is most suitable in simulating smoking‐induced impaired fracture healing. Furthermore, in smoking 129X1/SvJ murine models, we investigated the molecular and cellular alterations in fracture healing caused by cigarette smoking using histology, flow cytometry, and multiplex cytokine/chemokine analysis. Histological analysis showed impaired chondrogenesis in cigarette smoking. In addition, the important reparative cell populations, including skeletal stem cells and their downstream progenitors, demonstrated decreased expansion after injury as a result of cigarette smoking. Moreover, significantly increased pro‐inflammatory mediators and the recruitment of immune cells in fracture hematomas were demonstrated in smoking mice. Collectively, our findings demonstrate the significant cellular and molecular alterations during fracture healing impaired by smoking, including disrupted chondrogenesis, aberrant skeletal stem and progenitor cell activity, and a pronounced initial inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).
Amyloid-β regulates gap junction protein connexin 43 trafficking in cultured primary astrocytes

Altered expression and function of astroglial gap junction protein connexin 43 (Cx43) has increasingly been associated to neurotoxicity in Alzheimer disease (AD). Although earlier studies have examined the effect of increased β-amyloid (Aβ) on Cx43 expression and function leading to neuronal damage, underlying mechanisms by which Aβ modulates Cx43 in astrocytes remain elusive. Here, using mouse primary astrocyte cultures, we have examined the cellular processes by which Aβ can alter Cx43 gap junctions. We show that Aβ25-35 impairs functional gap junction coupling yet increases hemichannel activity. Interestingly, Aβ25-35 increased the intracellular pool of Cx43 with a parallel decrease in gap junction assembly at the surface. Intracellular Cx43 was found to be partly retained in the endoplasmic reticulum-associated cell compartments. However, forward trafficking of the newly synthesized Cx43 that already reached the Golgi was not affected in Aβ25-35-exposed astrocytes. Supporting this, treatment with 4-phenylbutyrate, a well-known chemical chaperone that improves trafficking of several transmembrane proteins, restored Aβ-induced impaired gap junction coupling between astrocytes. We further show that interruption of Cx43 endocytosis in Aβ25-35-exposed astrocytes resulted in their retention at the cell surface in the form of functional gap junctions indicating that Aβ25-35 causes rapid internalization of Cx43 gap junctions. Additionally, in silico molecular docking suggests that Aβ can bind favorably to Cx43. Our study thus provides novel insights into the cellular mechanisms by which Aβ modulates Cx43 function in astrocytes, the basic understanding of which is vital for the development of alternative therapeutic strategy targeting connexin channels in AD.
Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women with Hypothalamic Amenorrhea.

CONTEXT Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN We compared patients with HA to control women. SETTING The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS Women with HA (n=106) and control women (ClinSeq study; n=468). INTERVENTIONS We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS RSVs were overrepresented in women with HA compared with controls (P = 0.007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS Women with HA are enriched for RSVs in genes that cause IHH suggesting that variation in genes associated with GnRH neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise and/or stress.
Receptor-independent modulation of cAMP-dependent protein kinase and protein phosphatase signaling in cardiac myocytes by oxidizing agents

The contraction and relaxation of the heart is controlled by stimulation of the β1-adrenoreceptor (AR) signaling cascade, which leads to activation of cAMP-dependent protein kinase (PKA) and subsequent cardiac protein phosphorylation. Phosphorylation is counteracted by the main cardiac protein phosphatases, PP2A and PP1. Both kinase and phosphatases are sensitive to intramolecular disulfide formation in their catalytic subunits that inhibits their activity. Additionally, intermolecular disulfide formation between PKA type I regulatory subunits (PKA-RI) has been described to enhance PKA's affinity for protein kinase A anchoring proteins, which alters its subcellular distribution. Nitroxyl donors have been shown to affect contractility and relaxation, but the mechanistic basis for this effect is unclear. The present study investigates the impact of several nitroxyl donors and the thiol-oxidizing agent diamide on cardiac myocyte protein phosphorylation and oxidation. Although all tested compounds equally induced intermolecular disulfide formation in PKA-RI, only 1-nitrosocyclohexalycetate (NCA) and diamide induced reproducible protein phosphorylation. Phosphorylation occurred independently of β1-AR activation, but was abolished after pharmacological PKA inhibition and thus potentially attributable to increased PKA activity. NCA treatment of cardiac myocytes induced translocation of PKA and phosphatases to the myofilament compartment as shown by fractionation, immunofluorescence, and proximity ligation assays. Assessment of kinase and phosphatase activity within the myofilament fraction of cardiac myocytes after exposure to NCA revealed activation of PKA and inhibition of phosphatase activity thus explaining the increase in phosphorylation. The data suggest that the NCA-mediated effect on cardiac myocyte protein phosphorylation orchestrates alterations in the kinase/phosphatase balance.
Combining therapeutic vaccines with chemo- and immunotherapies in the treatment of cancer

ABSTRACT Introduction Breakthroughs in cancer immunotherapy have spurred interest in the development of vaccines to mediate prophylactic protection and therapeutic efficacy against primary tumors or to prevent relapse. However, immunosuppressive mechanisms employed by cancer cells to generate effective resistance have hampered clinical translation of therapeutic cancer vaccines. To enhance vaccine efficacy, the immunomodulatory properties of cytoreductive therapies could amplify a cancer-specific immune response. Areas covered Herein, the authors discuss therapeutic cancer vaccines that harness whole cells and antigen-targeted vaccines. First, recent advancements in both autologous and allogeneic whole-cell vaccines and combinations with checkpoint blockade and chemotherapy are reviewed. Next, tumor antigen-targeted vaccines using peptide-based vaccines and DNA-vaccines are discussed. Finally, combination therapies using antigen-targeted vaccines are reviewed. Expert opinion A deeper understanding of the immunostimulatory properties of cytoreductive therapies has supported their utility in combination therapies involving cancer vaccines as a potential strategy to induce a durable anti-tumor immune response for multiple types of cancers. Based on current evidence, combination therapies may have synergies that depend on the identity of the cytotoxic agent, vaccine target, dosing schedule, and cancer type. Together, these observations suggest that combining cancer vaccines with immunomodulatory cytoreductive therapy is a promising strategy for cancer therapy.
Stress Impairs Intentional Memory Control through Altered Theta Oscillations in Lateral Parietal Cortex

Accumulating evidence suggests that forgetting is not necessarily a passive process but that we can, to some extent, actively control what we remember and what we forget. Although this intentional control of memory has potentially far-reaching implications, the factors that influence our capacity to intentionally control our memory are largely unknown. Here, we tested whether acute stress may disrupt the intentional control of memory and, if so, through which neural mechanism. We exposed healthy men and women to a stress (n = 27) or control (n = 26) procedure before they aimed repeatedly to retrieve some previously learned cue-target pairs and to actively suppress others. While control participants showed reduced memory for suppressed compared with baseline pairs in a subsequent memory test, this suppression-induced forgetting was completely abolished after stress. Using magnetoencephalography (MEG), we show that the reduced ability to suppress memories after stress is associated with altered theta activity in the inferior temporal cortex when the control process (retrieval or suppression) is triggered and in the lateral parietal cortex when control is exerted, with the latter being directly correlated with the stress hormone cortisol. Moreover, the suppression-induced forgetting was linked to altered connectivity between the hippocampus and right dorsolateral prefrontal cortex (PFC), which in turn was negatively correlated to stress-induced cortisol increases. These findings provide novel insights into conditions under which our capacity to actively control our memory breaks down and may have considerable implications for stress-related psychopathologies, such as posttraumatic stress disorder (PTSD), that are characterized by unwanted memories of distressing events. SIGNIFICANCE STATEMENT It is typically assumed that forgetting is a passive process that can hardly be controlled. There is, however, evidence that we may actively control, to some extent, what we remember and what we forget. This intentional memory control has considerable implications for mental disorders in which patients suffer from unwanted (e.g., traumatic) memories. Here, we demonstrate that the capacity to intentionally control our memory breaks down after stress. Using magnetoencephalography (MEG), we show that this stress-induced memory control deficit is linked to altered activity in the lateral parietal cortex and the connectivity between the hippocampus and right prefrontal cortex (PFC). These findings provide novel insights into conditions under which memory control fails and are highly relevant in the context of stress-related psychopathologies.
Directed and target focused multi‐sectoral adolescent HIV prevention: Insights from implementation of the ‘DREAMS Partnership’ in rural South Africa

The “DREAMS Partnership” promotes a multi‐sectoral approach to reduce adolescent girls and young women's (AGYW) vulnerability to HIV in sub‐Saharan Africa. Despite widespread calls to combine structural, behavioural and biomedical HIV prevention interventions, this has not been delivered at scale. In this commentary, we reflect on the two‐year rollout of DREAMS in a high HIV incidence, rural and poor community in northern KwaZulu‐Natal, South Africa to critically appraise the capacity for a centrally co‐ordinated and AGYW‐focused approach to combination HIV prevention to support sustainable development for adolescents.
Prevalence of Antibodies to SARS-CoV-2 in Italian Adults and Associated Risk Factors

We aimed to assess the prevalence of and factors associated with anti- severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positivity in a large population of adult volunteers from five administrative departments of the Liguria and Lombardia regions. A total of 3609 individuals were included in this analysis. Participants were tested for anti-SARS-CoV-2 antibodies [Immunoglobulin G (IgG) and M (IgM) class antibodies] at three private laboratories (Istituto Diganostico Varelli, Medical Center, and Casa della Salute di Genova). Demographic data, occupational or private exposure to SARS-CoV-2-infected patients, and prior medical history consistent with SARS-CoV-2 infection were collected according to a preplanned analysis. The overall seroprevalence of anti-SARS-CoV-2 antibodies (IgG and/or IgM) was 11.0% [398/3609; confidence interval (CI) 10.0%–12.1%]. Seroprevalence was higher in female inmates than in male inmates (12.5% vs. 9.2%, respectively, p = 0.002), with the highest rate observed among adults aged >55 years (13.2%). A generalized estimating equations model showed that the main risk factors associated with SARS-CoV-2 seroprevalence were the following: an occupational exposure to the virus [Odd ratio (OR) = 2.36; 95% CI 1.59–3.50, p = 0.001], being a long-term care facility resident (OR = 4.53; 95% CI 3.19–6.45, p = 0.001), and reporting previous symptoms of influenza-like illness (OR = 4.86; 95% CI 3.75–6.30, p = 0.001) or loss of sense of smell or taste (OR = 41.00; 95% CI 18.94–88.71, p = 0.001). In conclusion, we found a high prevalence (11.0%) of SARS-CoV-2 infection that is significantly associated with residing in long-term care facilities or occupational exposure to the virus. These findings warrant further investigation into SARS-CoV-2 antibody prevalence among the Italian population.
Mortality and hospitalisation in the Danish Helicopter Emergency Medical Service (HEMS) population from 2014 to 2018: a national population-based study of HEMS triage

Objective To describe characteristics and outcomes for patients where the Danish Helicopter Emergency Medical Service (HEMS) either transported the patient to hospital, treated the patient on scene but did not transport the patient or was dispatched but cancelled en route to the patient (aborted mission), and to assess the field triage by comparing these outcomes. Design National population-based study. Setting and participants HEMS dispatches are undertaken from the five Danish emergency dispatch medical centres according to national guidelines. The study analysed all primary missions with helicopter take off where the patient was admitted to hospital between 1st October 2014 and 30th April 2018. Main outcome measures Mortality rates, admittance to an intensive care unit (ICU), need of mechanical ventilation and length of hospital stay (LOS). Results 6931 patients were admitted to hospital; 3311 patients were air lifted, 164 patients were ground escorted by a HEMS physician, 1421 were assisted on scene by HEMS, but escorted by the ground units and 2035 missions were aborted. The mortality was highest among the airlifted and ground escorted patients, and lowest among the patients in the aborted mission group. Mortality for the airlifted patients increased from 8.2% (95% CI; 7.3 to 9.2) at day 1 to 19.5% (95% CI; 18.2 to 20.9) after 1 year. The airlifted and ground escorted patients were frequently admitted to ICU and subsequently mechanically ventilated and they also had an increased LOS compared with the patients only assisted on scene by HEMS and the patients in the aborted mission group. Conclusion Patients to whom HEMS are dispatched are often critically ill or injured and have a relatively high mortality. The patients airlifted or ground escorted to hospital by HEMS appear more critically ill or injured compared with the assisted patients and the patients in the aborted mission group. The on-scene triage seems appropriate.