Hippocampal synaptic and membrane function in the DBA/2J-mdx mouse model of Duchenne muscular dystrophy.

Dystrophin deficiency is associated with alterations in cell physiology. The functional consequences of dystrophin deficiency are particularly severe for muscle physiology, as observed in Duchenne muscle dystrophy (DMD). DMD is caused by the absence of a 427 kDa isoform of dystrophin. However, in addition to muscular dystrophy symptoms, DMD is frequently associated with memory and attention deficits and epilepsy. While this may be associated with a role for dystrophin in neuronal physiology, it is not clear what neuronal alterations are linked with DMD. Our work shows that CA1 pyramidal neurons from DBA/2J-mdx mice have increased afterhyperpolarization compared to WT controls. All the other electrotonic and electrogenic membrane properties were unaffected by this genotype. Finally, basal synaptic transmission, short-term and long-term synaptic plasticity at Schaffer collateral to CA1 glutamatergic synapses were unchanged between mdx and WT controls. These data show that the excitatory component of hippocampal activity is largely preserved in DBA/2J-mdx mice. Further studies, extending the investigation to the inhibitory GABAergic function, may provide a more complete picture of the functional, network alterations underlying impaired cognition in DMD. In addition, the investigation of changes in neuronal single conductance biophysical properties associated with this genotype, is required to identify the functional alterations associated with dystrophin deficiency and clarify its role in neuronal function.

To Treat or Not to Treat?

Background and Purpose- The 2015 updated US Food and Drug Administration alteplase package insert altered several contraindications. We thus explored clinical factors influencing alteplase treatment decisions for patients with minor stroke. Methods- An expert panel selected 7 factors to build a series of survey vignettes: National Institutes of Health Stroke Scale (NIHSS), NIHSS area of primary deficit, baseline functional status, previous ischemic stroke, previous intracerebral hemorrhage, recent anticoagulation, and temporal pattern of symptoms in first hour of care. We used a fractional factorial design (150 vignettes) to provide unconfounded estimates of the effect of all 7 main factors, plus first-order interactions for NIHSS. Surveys were emailed to national organizations of neurologists, emergency physicians, and colleagues. Physicians were randomized to 1 of 10 sets of 15 vignettes, presented randomly. Physicians reported the subjective likelihood of giving alteplase on a 0 to 5 scale; scale categories were anchored to 6 probabilities from 0% to 100%. A conjoint statistical analysis was applied. Results- Responses from 194 US physicians yielded 156 with complete vignette data: 74% male, mean age 46, 80% neurologists. Treatment mean probabilities for individual vignettes ranged from 6% to 95%. Treatment probability increased from 24% for NIHSS score =1 to 41% for NIHSS score =5. The conjoint model accounted for 25% of total observed response variance. In contrast, a model accounting for all possible interactions accounted for 30% variance. Four of the 7 factors accounted jointly for 58% of total relative importance within the conjoint model: previous intracerebral hemorrhage (18%), recent anticoagulation (17%), NIHSS (13%), and previous ischemic stroke (10%). Conclusions- Four main variables jointly account for only a small fraction (<15%) of the total variance related to deciding to treat with intravenous alteplase, reflecting high variability and complexity. Future studies should consider other variables, including physician characteristics.

Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus.

Stimulation of group I mGluRs elicits several forms of translation-dependent neuronal plasticity including epileptogenesis. The translation process underlying plasticity induction is controlled by repressors including the fragile X mental retardation protein (FMRP). In the absence of FMRP-mediated repression, a condition that occurs in a mouse model (Fmr1(-/-)) of fragile X syndrome, group I mGluR-activated translation is exaggerated causing enhanced seizure propensity. We now show that glutamate exposure (10 µm for 30 min) reduced FMRP levels in wild-type mouse hippocampal slices. Downregulation of FMRP was dependent on group I mGluR activation and was blocked by a proteasome inhibitor (MG-132). Following glutamate exposure, synaptic stimulation induced prolonged epileptiform discharges with properties similar to those observed in Fmr1(-/-) preparations. In both cases, prolonged epileptiform discharges were blocked by group I mGluR antagonists (LY367385 + MPEP) and their induction was prevented by protein synthesis inhibitor (anisomycin). The results suggest that stimulation of group I mGluRs during glutamate exposure caused proteolysis of FMRP. Reduction of FMRP led to enhanced synaptic group I mGluR-mediated translation. Elevated translation facilitated the recruitment of group I mGluR-mediated prolonged epileptiform discharges.

To treat or not to treat? Pilot survey for minor and rapidly improving stroke.

BACKGROUND AND PURPOSE: Minor strokes and rapidly improving stroke symptoms are frequent exclusions for intravenous tissue-type plasminogen activator. We explored factors influencing tissue-type plasminogen activator treatment decision for minor strokes/rapidly improving stroke symptoms. METHODS: A pilot survey, including 110 case scenarios, was completed by 17 clinicians from 2 academic medical centers. Respondents were asked whether they would treat each case with tissue-type plasminogen activator at 60 minutes after emergency department admission. Cases varied by (1) National Institutes of Health Stroke Scale score at treatment decision time, (2) symptom pattern over time (improvement or worsening and then improving), (3) type of neurological deficit (3 main domains: motor, visual/sensory/ataxia, and language/neglect), and (4) age/occupation (4 profiles). Logistic regression was used to predict probability of omission (pO). A binomial regression model was used to predict probability of treatment decision. RESULTS: Predicted probability of treatment decision was affected by National Institutes of Health Stroke Scale score (P<0.001) and age/occupation profiles (P<0.001) but not by symptom patterns (P=0.334). There were significant, albeit modest, main effects on probability of treatment decision for neurological domains. Responses were most likely omitted (P=0.027) for cases improvement pattern and language/neglect domain (pO=0.74; 95% confidence interval, 0.52-0.89) and with visual/sensory/ataxia domain (pO=0.74; confidence interval, 0.37-0.93) when compared with improvement pattern and motor domain (pO=0.17; confidence interval, 0.06-0.42) and to any worsening and then improving patterns (0.37

Rapidly improving stroke symptoms: a pilot, prospective study.

BACKGROUND: Rapidly improving stroke symptoms (RISSs) are a controversial exclusion for intravenous recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke (AIS). We estimated the frequency of 4 prespecified RISS definitions and explored their relationship to clinical outcome. METHODS: Pilot, prospective study of AIS patients admitted within 4.5 hours of symptom onset. Serial assessments using National Institute of Health Stroke Scale (NIHSS) were performed every 20 ± 5 minutes until a rt-PA treatment decision was made, independent of the study. Improvement was calculated as the difference between baseline NIHSS and treatment decision NIHSS. RISS was defined as a 4-point or greater improvement, 25% or greater, 50% or greater, and according to the previously reported TREAT (The Re-examining Acute Eligibility for Thrombolysis) criteria. Unfavorable outcome was defined as modified Rankin Scale score more than 1 at 90 days after stroke. Logistic regression determined if RISS definition(s) related to the outcome. RESULTS: Fifty patients with AIS were enrolled: mean age 65 years; median baseline NIHSS score 5 (interquartile range, 2-11). RISS frequencies were 10%-22% based on definition. Median treatment decision NIHSS score is 5 (interquartile range, 2-9). Twenty-three (46%) patients received rt-PA. None of the 3 non-TREAT RISS definitions was independently associated with the outcome. Five of fifty (10%) were RISS according to the TREAT criteria, all 5 had good outcome without rt-PA. CONCLUSIONS: A Serial NIHSS assessment before treatment decision is feasible and may help determine the frequency and magnitude of RISS. This is the first prospective estimate of RISS frequency and outcome according to various prespecified definitions. The TREAT RISS frequency as a more restrictive definition may better predict good outcome of RISS in future, larger studies.

Persistent receptor activity underlies group I mGluR-mediated cellular plasticity in CA3 neuron.

Plastic changes in cortical activities induced by group I metabotropic glutamate receptor (mGluR) stimulation include epileptogenesis, expressed in vitro as the conversion of normal neuronal activity to persistent, prolonged synchronized (ictal) discharges. At present, the mechanism that maintains group I mGluR-induced plasticity is not known. We examined this issue using hippocampal slices from guinea pigs and mice. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG), 30-50 µm)] stimulation of group I mGluRs induces persistent prolonged synchronized (ictal-like) discharges in CA3 that are associated with three identified excitatory cellular responses-suppression of spike afterhyperpolarizations, activation of a voltage-dependent cationic current, and increase in neuronal input resistance. Persistent prolonged synchronized discharges and the underlying excitatory cellular responses maintained following induction were reversibly blocked by mGluR1 antagonists [(S)-+-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385), 50, 100 µm; CPCCOEt (hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, 100 µm], and to a lesser extent by the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride, 50 µm]. Activation of persistent cellular responses to DHPG were unaffected by tetrodotoxin (0.5-1 µm) or perfusion with low Ca(2+)(0.2 mm)-Mn(2+)(0.5 mm) media-conditions that suppress endogenous glutamate release. The pharmacological profile of the blocking action of the group I mGluR antagonist MCPG [(RS)-α-methyl-4-carboxyphenylglycine, 50-500 µm] on persistent cellular responses was different from that on cellular responses directly activated by DHPG. These data indicate that transient stimulation of group I mGluRs alters receptor properties, rendering them persistently active in the absence of applied agonist or endogenous glutamate activation. Persistent receptor activities, primarily involving mGluR1, maintain excitatory cellular responses and emergent prolonged synchronized discharges.

Development of a Transition to Residency Course Using a Design Thinking Framework.

PROBLEM: Transition to residency (TTR) courses help alleviate medical students' concerns about preparing for residency; however, existing TTR courses are often limited to teaching clinical or procedural skills without addressing the nonclinical skills necessary for transitioning to practice. This report describes the use of design thinking (DT) to develop a learner-centered TTR course at the State University of New York Downstate Health Sciences University. APPROACH: DT consists of 5 steps: discovery, interpretation, ideation, experimentation, and evolution. The first 3 steps were used for needs assessments and course design. During the discovery step, empathetic, semistructured interviews of interns, program directors, and graduating medical students were conducted to identify concerns about starting residency. During the interpretation step, thematic analysis of interviews was performed to identify areas of concerning attitudes and deficient skills and to inform content. In the ideation step, a 2-week curriculum was designed, including didactic lectures, small group discussions and workshops, simulation, and procedure labs, to address the defined content areas. OUTCOMES: During the fourth step, implementation, a 2-week pilot elective course of the designed curriculum was conducted in spring 2021 with 6 students. Participant feedback from 2 students collected 6 months into internship found the procedures and simulated clinical skills cases high yield, appropriate, relevant to intern practice, and valuable. The course size in spring 2022 increased to 19 students, and the curriculum was refined based on the feedback of the previous pilot course (from 2 students and 4 faculty members) and from a precourse student survey (5 students). NEXT STEPS: The last step of DT, evolution, included determining larger-scale feasibility while maintaining learner-centeredness and conducting a programmatic evaluation. The iterative, adaptable approach of DT is suitable for TTR design and is generalizable. Other institutions can adapt the DT approach to develop their own institutional TTR programs.

Sex-Related Differences in Utilization and Outcomes of Extracorporeal Cardio-Pulmonary Resuscitation for Refractory Cardiac Arrest.

Sparse data exist on sex-related differences in extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest (rCA). We explored the role of sex on the utilization and outcomes of ECPR for rCA by retrospective analysis of the Extracorporeal Life Support Organization (ELSO) International Registry. The primary outcome was in-hospital mortality. Exploratory outcomes were discharge disposition and occurrence of any specific extracorporeal membrane oxygenation (ECMO) complications. From 1992 to 2020, a total of 7,460 adults with ECPR were identified: 30.5% women; 69.5% men; 55.9% Whites, 23.7% Asians, 8.9% Blacks, and 3.8% Hispanics. Women's age was 50.4 ± 16.9 years (mean ± standard deviation) and men's 54.7 ± 14.1 ( p < 0.001). Ischemic heart disease occurred in 14.6% women vs. 18.5% men ( p < 0.001). Overall, 28.5% survived at discharge, 30% women vs. 27.8% men ( p = 0.138). In the adjusted analysis, sex was not associated with in-hospital mortality (odds ratio [OR] = 0.93 [confidence interval {CI} = 0.80-1.08]; p = 0.374). Female sex was associated with decreased odds of neurologic, cardiovascular, and renal complications. Despite being younger and having fewer complications during ECMO, women had in-hospital mortality similar to men. Whether these findings are driven by biologic factors or disparities in health care warrants further investigation.

Dual regulation of fragile X mental retardation protein by group I metabotropic glutamate receptors controls translation-dependent epileptogenesis in the hippocampus.

Group I metabotropic glutamate receptors (mGluRs) stimulation activates translation-dependent epileptogenesis in the hippocampus. This translation is regulated by repressors, including BC1 RNA and fragile X mental retardation protein (FMRP). Recent data indicate that group I mGluR stimulation exerts bidirectional control over FMRP level by activating translation and ubiquitin-proteasome system (UPS)-dependent proteolysis for the up- and downregulation of the protein, respectively. At present, the temporal relationship of translation and proteolysis on FMRP and their interplay for group I mGluR-mediated translation and epileptogenesis are unknown. We addressed these issues by using mouse hippocampal slices. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG)] stimulation of group I mGluRs caused a biphasic change in FMRP level. An initial decrease (within 10 min) was followed by an increase at 30 min. When slices were pretreated with translation inhibitor (anisomycin or cycloheximide), group I mGluRs elicited a sustained decrease in FMRP. This decrease was prevented by a proteasome inhibitor [Z-Leu-Leu-Leu-CHO (MG-132)]. When slices were pretreated with MG-132 alone, DHPG no longer elicited any change in FMRP. MG-132 also suppressed increase in other proteins, including postsynaptic density-95 and α-calcium/calmodulin-dependent protein kinase II, normally elicited by group I mGluR stimulation. Physiological experiments showed that proteasome inhibitor suppressed group I mGluR-induced prolonged synchronized discharges. However, proteasome inhibitor did not affect group I mGluR-induced prolonged synchronized discharges in Fmr1(-/-) preparations, where functional FMRP is absent. The results suggest that constitutive FMRP in hippocampal cells acts as a brake on group I mGluR-mediated translation and epileptogenesis. FMRP downregulation via UPS removes this brake enabling group I mGluR-mediated translation and epileptogenesis.

Teaching Quality Improvement: The Use of Education Theories Across the Medical Education Spectrum.

It is well recognized that the principles and practices of patient safety and quality improvement (QI) need to be included in medical education. The implementation of patient safety and QI learning experiences at the undergraduate medical education (UME) and graduate medical education (GME) levels has been variable. Consistent teaching of QI across the UME-GME-continuing medical education (CME) spectrum may result in a systemic change of improved patient care and patient safety in clinical practice. We propose using education theories to frame the development of QI curricula for a longitudinal integration in medical education and clinical practice. The basic principles of four education theories, namely, reflective practice, deliberate practice, social constructivism, and organizational learning, are briefly described, and examples of their applications to QI teaching are discussed. The incorporation of education theory into the design and implementation of a longitudinal QI curriculum threaded across the UME-GME-CME spectrum may empower learners with a comprehensive and lasting understanding of QI principles and training in patient safety practice, which are essential prerequisites for the formation of a physician workforce capable of creating sustainable change in patient care.

A noteworthy record of Ornithodoros (Alectorobius) coniceps (Ixodida: Argasidae) from Central Italy.

The first record of Ornithodoros (Alectorobius) coniceps (Canestrini) was reported for Italy in 1877, inside the interstices of the ancient mosaics at S. Marco Basilica in Venice. Afterwards only few discoveries of the species are reported for Italy; the last record is dated back to 1984, in L'Aquila town (Abruzzo Region). The present study shows the data of a survey carried out as a result of a massive infestation by O. coniceps in an ancient villa in Anzio town (Latium region) recently restored. In the past decades the villa has been fallen into disrepair, becoming an occasional shelter for wild animals mainly pigeons, that colonized the whole building for generations. This case appears worthy of note because it is the first record of this species after more than 25 years in Italy. A total of 136 specimens were collected by three methods: manual, mechanical aspirators and Wilson traps. Wilson trapping indicates positive O. coniceps tropism for CO(2).

Respiratory Auscultation Lab Using a Cardiopulmonary Auscultation Simulation Manikin.

Introduction: Mastery of respiratory auscultation skills is fundamental for clinicians to develop. We created a case-based educational session utilizing a high-fidelity simulator to teach lung sound auscultation to medical students at our institution. We employed a hypothesis-driven approach and deliberate practice to enhance students' learning experience and retention of acquired skills. Methods: We developed the session to teach second-year medical students how to discriminate between normal and pathological respiratory sounds within the context of clinical vignettes. Faculty facilitators, in conjunction with near-peer educators, made use of a high-fidelity auscultation manikin to guide students through case-based problem sets. Students were given the opportunity to auscultate the manikin while being observed and receiving feedback from the faculty. Results: We introduced the manikin in 2016, with a total of 759 second-year medical students from four class years having participated in the session since then. Students evaluated the session through an end-of-the-week and end-of-unit survey. The survey showed an overall improvement in learner satisfaction over previous years. Survey results and feedback were used to make adjustments to the session. Discussion: Our respiratory auscultation session was well received overall. Proper faculty development is crucial for implementing the session. Because of the focus on deliberate practice, adequate time must be allotted to hold the session. This program is reproducible with similar high-fidelity simulators.

Curated collection for clinician educators: Six key papers on residency recruitment.

INTRODUCTION: All emergency medicine (EM) residency programs must recruit new medical school graduates each year. The process is often overwhelming, with each program receiving far more applicants than available positions. We searched for evidence-based best practices to guide residency programs in screening, interviewing, and ranking applicants to ensure a high-performing and diverse residency class. METHODS: A literature search was conducted on the topic of residency recruitment, utilizing a call on social media as well as multiple databases. After identifying relevant articles, we performed a modified Delphi process in three rounds, utilizing junior educators as well as more senior faculty. RESULTS: We identified 51 relevant articles on the topic of residency recruitment. The Delphi process yielded six articles that were deemed most highly relevant over the three rounds. Transparency with selection criteria, holistic application review, standardized letters of evaluation, and blinding applicant files for interviewers were among noted best practices. CONCLUSIONS: Well-supported evidence-based practices exist for residency recruitment, and programs may benefit from understanding which common recruitment practices offer the most value. The articles discussed here provide a foundation for faculty looking to improve their program's recruiting practices.

Examining the Relationship of Clinical and Laboratory Parameters With Infectiousness to Phlebotomus perniciosus and Its Potential Infectivity in Dogs With Overt Clinical Leishmaniasis.

Infected dogs are considered the main domestic animal reservoirs for Leishmania infantum parasite. Infectiousness to competent phlebotomine vectors has been associated with many factors, the main being the severity of the disease exhibited by infected dogs. This study examines the relationship between different clinical parameters and the infectiousness to colonized Phlebotomus perniciosus sand flies having a blood meal on dogs. Data obtained in the present study come from an untreated group of Leishmania sick dogs submitted to xenodiagnosis for the evaluation of a spot on insecticide solution. Seventeen dogs were diagnosed as affected by leishmaniasis through clinical examination, immunofluorescence antibody test (IFAT) serology, and loop-mediated isothermal amplification (LAMP). The disease severity (clinical score) was staged by using a numeric value derived from eight clinical and parasitological parameters. Xenodiagnosis was performed on caged dogs exposed for 1.5 h to sand-fly bites. The following parameters related to sand flies were examined: blood feeding (% of blood engorged females), promastigote detection (% of promastigote-positive sand flies), promastigote burden, and the promastigote stage maturation (potential transmissibility rate). Statistical relationship between the clinical score and entomological parameters was investigated, as well as the possible correlation between each clinical and laboratory parameters and sand fly infection/infectivity. The severity of clinical score may influence the blood feeding by, and the probability of promastigote detection in, sand flies; skin lesions seem to be the main factor that influences the rate of blood feeding. Promastigote burden is related to IFAT titer, skin lesions, and clinical score. All entomological parameters are strongly related among them. This study confirms that both P. perniciosus infection and infectivity are influenced by a dog's clinical condition.

Neuronal Network Excitability in Alzheimer's Disease: The Puzzle of Similar versus Divergent Roles of Amyloid ß and Tau.

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicates that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression, may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aß and tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aß production suffer from seizures and epilepsy before the development of plaques. Similarly, pathologic accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aß on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments.

Software Training in HEP.

The long-term sustainability of the high-energy physics (HEP) research software ecosystem is essential to the field. With new facilities and upgrades coming online throughout the 2020s, this will only become increasingly important. Meeting the sustainability challenge requires a workforce with a combination of HEP domain knowledge and advanced software skills. The required software skills fall into three broad groups. The first is fundamental and generic software engineering (e.g., Unix, version control, C++, and continuous integration). The second is knowledge of domain-specific HEP packages and practices (e.g., the ROOT data format and analysis framework). The third is more advanced knowledge involving specialized techniques, including parallel programming, machine learning and data science tools, and techniques to maintain software projects at all scales. This paper discusses the collective software training program in HEP led by the HEP Software Foundation (HSF) and the Institute for Research and Innovation in Software in HEP (IRIS-HEP). The program equips participants with an array of software skills that serve as ingredients for the solution of HEP computing challenges. Beyond serving the community by ensuring that members are able to pursue research goals, the program serves individuals by providing intellectual capital and transferable skills important to careers in the realm of software and computing, inside or outside HEP.

Cellular plasticity for group I mGluR-mediated epileptogenesis.

Stimulation of group I metabotropic glutamate receptors (mGluRs) by the agonist (S)-dihydroxyphenylglycine in the hippocampus transforms normal neuronal activity into prolonged epileptiform discharges. The conversion is long lasting in that epileptiform discharges persist after washout of the inducing agonist and serves as a model of epileptogenesis. The group I mGluR model of epileptogenesis took on special significance because epilepsy associated with fragile X syndrome (FXS) may be caused by excessive group I mGluR signaling. At present, the plasticity mechanism underlying the group I mGluR-mediated epileptogenesis is unknown. I(mGluR(V)), a voltage-gated cationic current activated by group I mGluR agonists in CA3 pyramidal cells in the hippocampus, is a possible candidate. I(mGluR(V)) activation is associated with group I mGluR agonist-elicited epileptiform discharges. For I(mGluR(V)) to play a role in epileptogenesis, long-term activation of the current must occur after group I mGluR agonist exposure or synaptic stimulation. We observed that I(mGluR(V)), once induced by group I mGluR agonist stimulation in CA3 pyramidal cells, remained undiminished for hours after agonist washout. In slices prepared from FXS model mice, repeated stimulation of recurrent CA3 pyramidal cell synapses, effective in eliciting mGluR-mediated epileptiform discharges, also induced long-lasting I(mGluR(V)) in CA3 pyramidal cells. Similar to group I mGluR-mediated prolonged epileptiform discharges, persistent I(mGluR(V)) was no longer observed in preparations pretreated with inhibitors of tyrosine kinase, of extracellular signal-regulated kinase 1/2, or of mRNA protein synthesis. The results indicate that I(mGluR(V)) is an intrinsic plasticity mechanism associated with group I mGluR-mediated epileptogenesis.

BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability.

Regulatory RNAs have been suggested to contribute to the control of gene expression in eukaryotes. Brain cytoplasmic (BC) RNAs are regulatory RNAs that control translation initiation. We now report that neuronal BC1 RNA plays an instrumental role in the protein-synthesis-dependent implementation of neuronal excitation-repression equilibria. BC1 repression counter-regulates translational stimulation resulting from synaptic activation of group I metabotropic glutamate receptors (mGluRs). Absence of BC1 RNA precipitates plasticity dysregulation in the form of neuronal hyperexcitability, elicited by group I mGluR-stimulated translation and signaled through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. Dysregulation of group I mGluR function in the absence of BC1 RNA gives rise to abnormal brain function. Cortical EEG recordings from freely moving BC1(-/-) animals show that group I mGluR-mediated oscillations in the gamma frequency range are significantly elevated. When subjected to sensory stimulation, these animals display an acute group I mGluR-dependent propensity for convulsive seizures. Inadequate RNA control in neurons is thus causally linked to heightened group I mGluR-stimulated translation, neuronal hyperexcitability, heightened gamma band oscillations, and epileptogenesis. These data highlight the significance of small RNA control in neuronal plasticity.

Detection of weak intramolecular interactions in Ru(3)(CO)(12) by topological analysis of charge density distributions.

The presence of weak intramolecular interactions among the axial carbon atoms in Ru(3)(CO)(12), previously detected by topological analysis of the 120 K X-ray derived charge density, has been here confirmed by theoretical calculations on the isolated, "gas-phase" molecule, using the all-electron B97D/3-21G approach, as well as by further experimental determinations of higher accuracy on data collected at 100 K. The importance of using density functional theory (DFT) approaches where dispersion terms are explicitly added to the usual Kohn-Sham energy to reproduce such weak intramolecular interactions has been evidenced. This result confirms the multipole approach as an efficient and sensitive tool to extract fine details of electron density distributions.

Laboratory transmission of an Asian strain of Leishmania tropica by the bite of the southern European sand fly Phlebotomus perniciosus.

Imported cases of anthroponotic cutaneous leishmaniasis due to Leishmania tropica are increasingly documented in Europe. We investigated the ability of Phlebotomus perniciosus, a competent vector of Leishmania infantum widespread in southwestern Europe, to support the growth and transmissibility of an Asian strain of L. tropica recently isolated from a refugee. Parasite growth behavior was investigated in laboratory-reared sand flies fed artificially with promastigotes as well as in sand flies infected after biting on footpad lesions induced in hamsters by promastigote inoculation. The evolution of infection was checked by gut microscopy and quantitative real-time PCR, and it was found to be similar between promastigote- and amastigote-initiated infections. In 80% of infected sand flies, despite survival and flourishing growth of promastigotes after blood digestion and defecation, either the parasites died, or failed to migrate to the foregut and/or to mature into infective forms. However, in the remaining 20% L. tropica developed into abundant metacyclic promastigotes. The quantitative real-time PCR assay detected variable loads of gut promastigotes irrespective of morphological evidence of viability or progressive/final death. Parasite transmissibility was investigated by exposing naive hamsters to P. perniciosus previously infected on chronic lesions induced in hamsters which survived to take a second blood meal. Two months post exposure, lesions developed in skin sites bitten by sand flies confirmed to harbor metacyclic promastigotes; in the following months, the presence of viable and transmissible L. tropica parasites in lesions was demonstrated by xenodiagnosis assays. Our findings support the hypothesis that, in particular epidemiological situations, P. perniciosus may play the role of an occasional L. tropica vector.