Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynamic Shaping of the Defensive Peripersonal Space through Predictive Motor Mechanisms: When the “Near” Becomes “Far”

The hand blink reflex is a subcortical defensive response, known to dramatically increase when the stimulated hand is statically positioned inside the defensive peripersonal space (DPPS) of the face. Here, we tested in a group of healthy human subjects the hand blink reflex in dynamic conditions, investigating whether the direction of the hand movements (up-to/down-from the face) could modulate it. We found that, on equal hand position, the response enhancement was present only when the hand approached to (and not receded from) the DPPS of the face. This means that, when the hand is close to the face but the subject is planning to move the hand down, the predictive motor system can anticipate the consequence of the movement: the “near” becomes “far. ” We found similar results both in passive movement condition, when only afferent (visual and proprioceptive) information can be used to estimate the final state of the system, and in motor imagery task, when only efferent (intentional) information is available to predict the consequences of the movement. All these findings provide evidence that the DPPS is dynamically shaped by predictive mechanisms run by the motor system and based on the integration of feedforward and sensory feedback signals. SIGNIFICANCE STATEMENT The defensive peripersonal space (DPPS) has a crucial role for survival, and its modulation is fundamental when we interact with the environment, as when we move our arms. Here, we focused on a defensive response, the hand blink reflex, known to increase when a static hand is stimulated inside the DPPS of the face. We tested the hand blink reflex in dynamic conditions (voluntary, passive, and imagined movements) and we found that, on equal hand position, the response enhancement was present only when the hand approached to (and not receded from) the DPPS of the face. This suggests that, through the integration of efferent and afferent signals, the safety boundary around the body is continuously shaped by the predictive motor system.
Potential new gene therapy option with sitimagene ceradenovec for newly diagnosed patients with glioblastoma multiforme

Glioblastoma multiforme (GBM) is associated with a poor prognosis with a 5-year survival rate of less than 5%, making GBM one of the most aggressive neoplastic malignancies. However significant strides have been made over the past few years with respect to understanding the pathophysiology as well as treatment modalities. The use of local therapies, particularly gene therapy, has been evaluated, but have yet to make a major clinical impact on treatment of GBM. In a study published by Westphal and colleagues in The Lancet Oncology, the use of sitimagene ceradenovec, a first generation replication-deficient adenovirus containing a prodrug converting enzyme, herpes-simplex virus thymidine kinase, followed by intravenous ganciclovir administration and standard therapy was evaluated compared with standard therapy alone. Patients who received sitimagene ceradenovec had improved time to death or re-intervention, but did not show improvement in overall survival. Patients receiving sitimagene ceradenovec experienced more adverse effects related to treatment, including seizures and hyponatremia. While further studies need to be conducted to determine clinical significance, gene therapy appears to be a viable approach for patients who may be resistant to chemotherapy.
Optimizing the Allocation of Resources among HIV Prevention Interventions in Honduras

Faced with a growing HIV/AIDS epidemic and limited resources for prevention policymakers need to decide how to distribute funds between different HIV prevention interventions to achieve the maximum impact on the epidemic. This paper presents a model that policymakers can use to determine the resource allocation that will prevent the maximum number of new HIV infections at any given budget level. A large group of stakeholders in Honduras generated the data needed to run the model through consultations and consensus. The optimal allocation exercise was conducted in Honduras the country most affected by the HIV/AIDS epidemic in Central America with an adult prevalence rate of 1.4%. In Honduras the epidemic is still concentrated in high-risk groups but has begun spreading into the general population. The majority of transmissions occur through heterosexual sex followed by sex between men and mother-to-child transmission. (excerpt)
Melanoma immunotherapy

Immunotherapy is a cornerstone in the treatment of melanoma, and is intended to modulate the host immunity against the tumor. Immunotherapy can be used in an adjuvant setting, after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages. Development of novel therapeutic approaches and the optimization of existing therapies hold a great promise in the field of melanoma therapy research. Different clinical trials are ongoing, and immunotherapy is showing the ability to confirm durable clinical benefits in selected groups of melanoma patients. The aim of this review is to summarize different types of immunotherapy agents, as well as to discuss different strategies, complementary regimens, and possible biomarkers of response to the treatment.
Successful treatment of a patient with Li–Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib

We report the case of a young, never-smoker woman with Li–Fraumeni syndrome and advanced lung adenocarcinoma refractory to multiple lines of conventional chemotherapy and negative for actionable alterations by routine testing. Comprehensive genomic profiling by clinical-grade next generation sequencing was performed on 3320 exons of 184 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer. The tumor was found to harbor both EGFR L858R and ERBB2 S310F alterations and also tested positive for a known TP53 germline mutation. The presence of the EGFR mutation was further validated by direct sequencing. Based on these results, a dual EGFR/ERBB2 inhibitor, afatinib, was chosen for treatment. The patient achieved a rapid, complete, and durable response to afatinib monotherapy, both clinically and radiographically. The treatment was very well tolerated. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of p53 mutations with concurrent EGFR and ERBB2 aberrations. As this case powerfully illustrates, the combination of broad genomic profiling and targeted therapy guided by mutational analysis offers the possibility of precision management of refractory advanced adenocarcinoma in the background of neoplastic syndromes.
Anoxic Encephalopathy: Outcome After Inpatient Rehabilitation

To determine the functional outcome following acute rehabilitation for anoxic en cephalopathy using the Functional Independence Measure (FIM). Background: Patients with anoxic encephalopathy are reported in the literature to have poor functional outcome. However, there are few existing studies that use stan dardized functional measures to assess functional gains in anoxic patients during in patient rehabilitation. Methods: We retrospectively reviewed charts of 34 consecutive patients with the primary diagnosis of cerebral anoxia admitted to an inpatient rehabilitation unit. The criteria for admission to the rehabilitation unit were wakefulness and ability to follow one step commands. Outcome measures included discharge residence and the FIM score. Results: Of 34 patients, 26 had sufficient data for inclusion. Discharge FIM scores were significantly improved over admission FIM (p = < 0.0001) for all categories. FIM efficiency score was 0.45 (mean [FIMdis FIMadm]/mean LOS). Seventy-six per cent (20 patients) were discharged home, four patients were transferred ,to nursing home care, one patient was transferred to an acute, hospital for unrelated medical ill ness, and one patient was sent to long-term rehabilitation. Conclusion: Patients with anoxic encephalopathy experience significant functional improvement during inpatient rehabilitation. These results are compared to other brain injury populations, and clinical implications are discussed.
Ischemia/Reperfusion Induces Interferon-Stimulated Gene Expression in Microglia

Innate immune signaling is important in the pathophysiology of ischemia/reperfusion (stroke)-induced injury and recovery. Several lines of evidence support a central role for microglia in these processes. Recent work has identified Toll-like receptors (TLRs) and type I interferon (IFN) signaling in both ischemia/reperfusion-induced brain injury and ischemic preconditioning-mediated neuroprotection. To determine the effects of “ischemia/reperfusion-like” conditions on microglia, we performed genomic analyses on wild-type (WT) and TLR4−/− cultured microglia after sequential exposure to hypoxia/hypoglycemia and normoxia/normoglycemia (H/H–N/N). We observed increased expression of type 1 IFN-stimulated genes (ISGs) as the predominant transcriptomal feature of H/H–N/N-exposed WT, but not TLR4−/−, microglia. Microarray analysis on ex vivo sorted microglia from ipsilateral male mouse cortex after a transient in vivo ischemic pulse also demonstrated robust expression of ISGs. Type 1 IFNs, including the IFN-αs and IFN-β, activate the interferon-α/β receptor (IFNAR) complex. We confirmed both in vitro H/H–N/N- and in vivo ischemia/reperfusion-induced microglial ISG responses by quantitative real-time PCR and demonstrated that both were dependent on IFNAR1. We characterized the effects of hypoxia/hypoglycemia on phosphorylation of signal transducer and activator of transcription 1 (STAT1), release of type 1 IFNs, and surface expression of IFNAR1 in microglia. We demonstrated that IFN-β induces dose-dependent secretion of ISG chemokines in cultured microglia and robust ISG expression in microglia both in vitro and in vivo. Finally, we demonstrated that the microglial ISG chemokine responses to TLR4 agonists were dependent on TLR4 and IFNAR1. Together, these data suggest novel ischemia/reperfusion-induced pathways for both TLR4-dependent and -independent, IFNAR1-dependent, type 1 IFN signaling in microglia. SIGNIFICANCE STATEMENT Stroke is the fifth leading cause of death in the United States and is a leading cause of serious long-term disability worldwide. Innate immune responses are critical in stroke pathophysiology, and microglia are key cellular effectors in the CNS response to ischemia/reperfusion. Using a transcriptional analysis approach, we identified a robust interferon (IFN)-stimulated gene response within microglia exposed to ischemia/reperfusion in both in vitro and in vivo experimental paradigms. Using a number of complementary techniques, we have demonstrated that these responses are dependent on innate immune signaling components including Toll-like receptor-4 and type I IFNs. We have also elucidated several novel ischemia/reperfusion-induced microglial signaling mechanisms.
Psychotic Symptoms, Anger, and Anxiety as Determinants of Agrresive Behavior

textabstractAs an introduction on the topic of this dissertation, it might be interesting to look at some other cases of psychiatric patients that displayed clear-cut aggressive behavior towards other persons: Case 1. Twenty-nine-year-old man, who stabbed his mother’s fiance in the chest with the intention to kill. He was on leave from a mental hospital where he had been admitted for the past eight years. Case 2. Forty-four-year-old man, who has regularly been treated in mental hospitals over the past 15 years under the diagnosis schizophrenia. He had now been moved out to an apartment in the community. In connection with alcohol abuse, he murdered his male drinking partner by repeatedly stabbing him in the back as well as in the chest and the head. He states that he had not been feeling well for the last couple of weeks prior to the attack, but he had not taken his medication. Case 3. Twenty-year-old man, with no known previous psychiatric symptoms. He tried to kill his younger brother by pounding his head repeatedly (more than 40 times) against a stone floor. Case 4. Thirty-year-old woman, who has regularly been treated in mental hospitals for many years, mostly under the diagnosis paranoia. She has made several suicide attempts. Here she tried to kill her mother by first strangling her with an electric cable and then by setting her bed on fire. She stated that her mother both read her mind and took it away from her. Case 5. Twenty-nine-year-old man, regularly treated with neuroleptics as well as electro-convulsive shock treatment in mental hospitals over a period of several years. He has repeatedly been the subject of involuntary psychiatric treatment after having threatened to kill his grandmother. Finally, he stabbed her to death with a knife to the heart. He stated that he felt persecuted by his grandmother. Case 6. Twenty-nine-year-old man, regularly treated in mental hospitals for the past decade, mostly for depression. He tried to kill his father by stabbing him with a knife in the chest. He has not given any explanation for his action. Just a month prior to the crime, he was discharged from a mental hospital where he was the subject of involuntary psychiatric treatment. Case 7. Forty-six-year-old man, regularly treated in mental hospitals for many years, usually with a diagnosis of paranoia. He often complained that his food was poisoned and that he was being persecuted. He tried to kill a female neighbor by hitting her repeatedly with a crowbar. During the month prior to the crime, he had not bothered to take his neuroleptics. Case 8. Sixteen-year-old man, with no previous contact with psychiatry. He had, though, a troublesome adolescence including alcohol and drug abuse, and criminality. He entered a police station and tried to fire a loaded gun at a police officer (the gun misfired). Case 9. Forty-six-year-old man, living in a hostel for alcohol abusers. He had no known history of mental illness, although he did have a severe drinking problem. He stabbed his roommate to death, after they had become disunite.
Dietary silicon and bone health

†‡ Summary Silicon (Si) is the third most abundant trace element of the human body and is especially associated with connective tissues such as in bone, skin and blood vessels. Dietary Si is predominately derived from plant-foods and, generally, is readily broken down and absorbed in the gastrointestinal tract in the form of orthosilicic acid. Cereals and cereal products (especially beer), green beans and some mineral water are examples of major dietary sources of Si. The majority of absorbed Si is then excreted in urine although some is taken up into tissues. Average Si intakes are around 25 mg/day in the Western World. In this review, dietary sources of Si, its metabolism and evidence for its biological role in bone health are presented.
Signal Propagation in Drosophila Central Neurons

Drosophila is an important model organism for investigating neural development, neural morphology, neurophysiology, and neural correlates of behaviors. However, almost nothing is known about how electrical signals propagate in Drosophila neurons. Here, we address these issues in antennal lobe projection neurons, one of the most well studied classes of Drosophila neurons. We use morphological and electrophysiological data to deduce the passive membrane properties of these neurons and to build a compartmental model of their electrotonic structure. We find that these neurons are electrotonically extensive and that a somatic recording electrode can only imperfectly control the voltage in the rest of the cell. Simulations predict that action potentials initiate at a location distant from the soma, in the proximal portion of the axon. Simulated synaptic input to a single dendritic branch propagates poorly to the rest of the cell and cannot match the size of real unitary synaptic events, but we can obtain a good fit to data when we model unitary input synapses as dozens of release sites distributed across many dendritic branches. We also show that the true resting potential of these neurons is more hyperpolarized than previously thought, attributable to the experimental error introduced by the electrode seal conductance. A leak sodium conductance also contributes to the resting potential. Together, these findings have fundamental implications for how these neurons integrate their synaptic inputs. Our results also have important consequences for the design and interpretation of experiments aimed at understanding Drosophila neurons and neural circuits.
The Role of CREB, SRF, and MEF2 in Activity-Dependent Neuronal Plasticity in the Visual Cortex

The transcription factors CREB (cAMP response element binding factor), SRF (serum response factor), and MEF2 (myocyte enhancer factor 2) play critical roles in the mechanisms underlying neuronal plasticity. However, the role of the activation of these transcription factors in the different components of plasticity in vivo is not well known. In this study, we tested the role of CREB, SRF, and MEF2 in ocular dominance plasticity (ODP), a paradigm of activity-dependent neuronal plasticity in the visual cortex. These three proteins bind to the synaptic activity response element (SARE), an enhancer sequence found upstream of many plasticity-related genes (Kawashima et al., 2009; Rodríguez-Tornos et al., 2013), and can act cooperatively to express Arc, a gene required for ODP (McCurry et al., 2010). We used viral-mediated gene transfer to block the transcription function of CREB, SRF, and MEF2 in the visual cortex, and measured visually evoked potentials in awake male and female mice before and after a 7 d monocular deprivation, which allowed us to examine both the depression component (Dc-ODP) and potentiation component (Pc-ODP) of plasticity independently. We found that CREB, SRF, and MEF2 are all required for ODP, but have differential effects on Dc-ODP and Pc-ODP. CREB is necessary for both Dc-ODP and Pc-ODP, whereas SRF and MEF2 are only needed for Dc-ODP. This finding supports previous reports implicating SRF and MEF2 in long-term depression (required for Dc-ODP), and CREB in long-term potentiation (required for Pc-ODP). SIGNIFICANCE STATEMENT Activity-dependent neuronal plasticity is the cellular basis for learning and memory, and it is crucial for the refinement of neuronal circuits during development. Identifying the mechanisms of activity-dependent neuronal plasticity is crucial to finding therapeutic interventions in the myriad of disorders where it is disrupted, such as Fragile X syndrome, Rett syndrome, epilepsy, major depressive disorder, and autism spectrum disorder. Transcription factors are essential nuclear proteins that trigger the expression of gene programs required for long-term functional and structural plasticity changes. Our results elucidate the specific role of the transcription factors CREB, SRF, and MEF2 in the depression and potentiation components of ODP in vivo, therefore better informing future attempts to find therapeutic targets for diseases where activity-dependent plasticity is disrupted.
Abstract 20450: Impact of Addressing Social and Behavioral Factors in Reducing Heart Failure Readmission

Background: United States 30-day hospital readmission rate (RR) for heart failure (HF) is averaging 22.6% and represents a financial burden for CMS and now to hospitals via potential penalties leveraged by Medicare. Efforts to improve RR must identify and treat underlying causes, and these may include social and behavioral factors not heretofore discerned. Methods: We evaluated multiple social and behavioral factors using validated questionnaires in 74 consecutive patients admitted for HF to determine their prevalence and their possible influence over HF admissions including 30-day readmission. Measures included depression, medication adherence, quantified sodium consumption, heart failure quality of life, sleep-related concerns, and other socio-economic factors including medication affordability and family support. Specific problems were systematically addressed during hospitalization and follow-up. In addition, patients were closely monitored during the 30-days post-discharge with oral diuretics adjusted as needed based in change in daily weight. Results: The average age was 71±13 years, 61% were male, and the mean ejection fraction was 36 ±19%. Frequently admitted patients (≥ 2 HF admissions in the last 12 months) differed from standard patients: *p The combination of addressing and treating these factors reduced subsequent 30-day readmission from 25% to 12% (p Conclusions: Social and behavioral issues are commonly found in HF patients and are more prevalent in patients with a high frequency of HF hospitalizations. Identifying and systematically addressing these factors can lead to a reduction in hospital utilization.
Centrin depletion causes cyst formation and other ciliopathy-related phenotypes in zebrafish

Most bona fide centrosome proteins including centrins, small calcium-binding proteins, participate in spindle function during mitosis and play a role in cilia assembly in non-cycling cells. Although the basic cellular functions of centrins have been studied in lower eukaryotes and vertebrate cells in culture, phenotypes associated with centrin depletion in vertebrates in vivo has not been directly addressed. To test this, we depleted centrin2 in zebrafish and found that it leads to ciliopathy phenotypes including enlarged pronephric tubules and pronephric cysts. Consistent with the ciliopathy phenotypes, cilia defects were observed in differentiated epithelial cells of ciliated organs such as the olfactory bulb and pronephric duct. The organ phenotypes were also accompanied by cell cycle deregulation namely mitotic delay resulting from mitotic defects. Overall, this work demonstrates that centrin2 depletion causes cilia-related disorders in zebrafish. Moreover, given the presence of both cilia and mitotic defects in the affected organs, it suggests that cilia disorders may arise from a combination of these defects.
Biphasic Action of Inducible Nitric Oxide Synthase in a Hindlimb Ischemia Model

We investigated the influence of inducible nitric oxide synthase (iNOS) on acute ischemic injury and chronic angiogenesis. In a hindlimb ischemia model, NO produced by endothelial NO synthase (eNOS) reduces ischemic injury and promotes angiogenesis. However, the effect of the large amounts of NO generated by induced iNOS is unclear. Experimental groups of mice were as follows: (1) wild-type group (Wild), (2) iNOS-knockout group (iNOS-KO), and (3) aminoguanidine-treated wild-type group (Wild + AG), which received aminoguanidine from day 0 to day 3 after ischemia. Acute ischemic injury was evaluated by measuring the plasma CK value and ischemic score. Chronic angiogenesis was evaluated by microangiography and with a non-contact type Doppler blood flowmeter on day 3. Compared with the Wild group (251 ± 34.7 IU/l), the CK value was significantly elevated in the iNOS-KO (497 ± 126.7 IU/l) and Wild + AG (587.2 ± 128.7 IU/l) groups. The ischemic score was significantly increased in the iNOS-KO (92%) and Wild ± AG (66.6%) groups compared with the Wild group (23%). Blood flow was significantly increased in the iNOS-KO group (58.7 ± 15.3%) compared with the Wild (38.1 ± 15.9%) and Wild ± AG (43.5 ± 9.8%) groups in the chronic stage. Microangiography revealed a significantly increased number of blood vessels in the iNOS-KO (0.29 ± 0.02) group compared with the Wild (0.12 ± 0.01) and Wild + AG (0.15 ± 0.02) groups. Our findings indicate that NO generated by iNOS has a biphasic action, reducing acute ischemic injury and inhibiting angiogenesis in the chronic stage.