A Study of the Use, Knowledge, and Beliefs About Cigarettes and Alternative Tobacco Products Among Students at One U.S. Medical School.
In the United States, the prevalence of the use of alternative tobacco products (ATPs) (e.g., hookahs, e-cigarettes, cigars/cigarillos) has increased sharply. As future health care providers, medical students will play a critical role in health promotion and disease prevention. This study investigated medical students' use, knowledge, and beliefs about cigarettes and ATPs. In 2014, the authors surveyed all students enrolled at one medical school in New York City. The survey included questions about personal use of tobacco products, perceptions about the harms of ATPs and their role in disease causation, education about ATPs, and cessation training and practices related to ATPs and cigarettes. The authors compared results across medical school classes. Of 720 students, 431 (59.9%) completed the survey. Of those, 64 (14.7%) were current users of tobacco or smoking products, including cigarettes (17; 3.9%), ATPs (21; 4.8%), or marijuana (39; 8.9%). Many believed that ATPs contributed less than cigarettes to various diseases. Respondents received less cessation training regarding ATPs than cigarettes (P < .0001). They felt less confident providing ATP cessation counseling than cigarette cessation counseling (P < .0001) and were less likely to report counseling patients on ATP cessation than cigarette cessation (46 [10.7%] versus 280 [64.8%], P < .0001). A concerning percentage of surveyed medical students use tobacco products, including ATPs, and lack the knowledge, education, and cessation counseling skills to provide accurate information about them to patients. ATP education should be added to medical school curricula to address this gap.


Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses.
Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, encoding ankyrin-G, have been associated with bipolar disorder, schizophrenia, and autism. Here we demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain structures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investigation of psychiatric risk molecules.


Preparation, Crystal Chemistry, and Hidden Magnetic Order in the Family of Trigonal Layered Tellurates A2Mn(4+)TeO6 (A = Li, Na, Ag, or Tl).
We report the first four magnetic representatives of the trigonal layered A2M(4+)TeO6 (here, M = Mn) family. Na2MnTeO6 was synthesized from NaMnO2, NaNO3, and TeO2 at 650-720 °C, but analogues for which A = Li and K could not be obtained by direct synthesis. However, those for which A = Li, Ag, and Tl (but not K) were prepared by exchange reactions between Na2MnTeO6 and the corresponding molten nitrates. The oxygen content was verified by redox titration. According to the X-ray diffraction Rietveld analysis, the four new compounds are isostructural with Na2GeTeO6, trigonal ( P3̅1 c), based on ilmenite-like layers of edge-shared oxygen octahedra occupied by Mn(4+) and Te(6+) in an ordered manner. These layers are separated by cations A, also in a distorted octahedral coordination. However, off-center displacement of Tl+ is so strong, due to the lone-pair effect, that its coordination is better described as trigonal pyramid. Each MnO6 octahedron shares two opposite faces with AO6 octahedra, whereas TeO6 octahedra avoid sharing faces. Besides this double-layered structure, Na2MnTeO6 was often accompanied by a transient triple-layered rhombohedral polytype. However, it could not be prepared as a single phase and disappeared on annealing at 700-720 °C. All A2MnTeO6 samples (A = Ag, Li, Na, or Tl) revealed the unusual phenomenon of hidden magnetic order. Low-field magnetic susceptibility data exhibit a Curie-Weiss type behavior for all samples under study and do not show any sign of the establishment of long-range magnetic order down to 2 K. In contrast, both the magnetic susceptibility in sufficiently high external magnetic fields and the zero-field specific heat unambiguously revealed an onset of antiferromagnetic order at low temperatures. The frustration index f = Θ/ TN takes values larger than the classical values for three-dimensional antiferromagnets and implies moderate frustration on the triangular lattice.


Pediococcus cerevisiae mutant with altered transport of folates.
A Pediococcus cerevisiae mutant that actively accumulated folate (PteGlu), in contrast to the wild-type, was also found to exhibit changes in the pattern of uptake of 5-methyl-tetrahydrofolate (5-CH3-H4PteGlu) and amethopterin. Most of the 5-CH3-H4PteGlue accumulated through a glucose- and temperature-dependent process, and a concentrative uptake was also found in gluocse-starved cells and in cells incubated at OC. About 75% of the accumulated 5-CH3-H4PteGlu exchanged with amethopterin. In contrast to the wild type, the mutant accumulated both diastereoisomers of 5-CH3-H4PteGlue by glucose-dependent and glucose-independent processes. Amethopterin and PteGlue competitively inhibited the uptake in both processes, with an apparent lower affinity of the carrier for PteGlu than for the analogue. p-Chloromercuribenzoate strongly inhibited the uptake (75%). The p-chloromercuribenzoate-nonsusceptible and temperature-independent uptake was also competed by amethopterin. Metabolic poisons like sodium azide, potassium fluoride, iodoacetate, and 2,4-dimitrophenol inhibited the glucose-dependent process. Uptake, in the absence of glucose, was enhanced by sodium azide and potassium fluoride.


Topological structure prediction in binary nanoparticle superlattices.
Systems of spherical nanoparticles with capping ligands have been shown to self-assemble into beautiful superlattices of fascinating structure and complexity. In this paper, I show that the spherical geometry of the nanoparticle imposes constraints on the nature of the topological defects associated with the capping ligand and that such topological defects control the structure and stability of the superlattices that can be assembled. All these considerations form the basis for the orbifold topological model (OTM) described in this paper. The model quantitatively predicts the structure of super-lattices where capping ligands are hydrocarbon chains in excellent agreement with experimental results, explains the appearance of low packing fraction lattices as equilibrium, why certain similar structures are more stable (bccAB6vs. CaB6, AuCu vs. CsCl, etc.) and many other experimental observations.


D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO).
D-serine is an endogenous N-methyl-D-aspartate (NMDA) receptor coagonist. It is synthesized from L-serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D-amino acid oxidase (DAO), the major D-serine degradative enzyme. Candidate mechanisms include SRR operating in alpha,beta-eliminase mode (converting D-serine to pyruvate) and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which "simulate" the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D-serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [(3)H]D-serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D-serine and pyruvate and decreased [(3)H]D-serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent. The factors regulating D-serine are important for understanding normal NMDA receptor function and because D-serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia.


Financing translation: analysis of the NCATS rare-diseases portfolio.
The portfolio of the National Center for Advancing Translational Sciences (NCATS) rare-diseases therapeutic development program comprises 28 research projects initiated at the preclinical stage. Historical data reveal substantially lower costs and higher success rates but longer preclinical timelines for the NCATS projects relative to the industry averages for early-stage translational medical research and development (R&D) typically cited in literature. Here, we evaluate the potential risks and rewards of investing in a portfolio of rare-disease therapeutics. Using a "megafund" financing structure, NCATS data, and valuation estimates from a panel of industry experts, we simulate a hypothetical megafund in which senior and junior debt yielded 5 and 8%, respectively. The simulated expected return to equity was 14.7%, corresponding to a modified internal rate of return of 21.6%. These returns and the likelihood of private-sector funding can be enhanced through third-party funding guarantees from philanthropies, patient advocacy groups, and government agencies.


Acute coronary syndrome vs. myopericarditis - not always a straightforward diagnosis.
Patient: Male, 58 Final Diagnosis: Myopericarditis Symptoms: Retrosternal thoracic pain Medication: - Clinical Procedure: MRI Specialty: Cardiology. Challenging differential diagnosis. Patients with acute cardiac symptoms, elevated cardiac troponin, and culprit-free angiograms are a consistent proportion of patients admitted with presumed acute coronary syndromes (ACS). Current literature on this population of patients justifies the diagnostic importance of cardiovascular magnetic resonance (CMR) imaging. This report describes the case of a 58-year-old cyclist in which CMR allowed us to perform a diagnosis of myopericarditis mimicking acute STEMI against other evidence. There are several such reports in literature because the clinical presentation of myocarditis is quite variable. This case report emphasizes the importance of cardiovascular magnetic resonance imaging in the differential diagnosis of the etiology of acute coronary syndromes. This is especially important because the signs and symptoms presented are ambiguous and equivalent to those of other diseases, such as myopericarditis, which affects mainly young athletes but also middle-aged athletes.


Identification of neonatal hearing impairment: summary and recommendations.
This article summarizes the results of a multi-center study, "Identification of Neonatal Hearing Impairment," sponsored by the National Institutes of Health. The purpose of this study was to determine the performance characteristics of three measures of peripheral auditory system status, transient evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAEs), and auditory brain stem responses (ABR), applied in the neonatal period in predicting hearing status at 8 to 12 mo corrected age. The design and implementation of this study are described in the first two articles in this series. Seven institutions participated in this study; 7179 infants were evaluated. Graduates of the neonatal intensive care unit and well babies with one or more risk factors for hearing loss were targeted for follow-up testing using visual reinforcement audiometry (VRA) at 8 to 12 mo corrected age. Neonatal test performance was evaluated using the VRA data as the "gold standard." The major results of the study are described in the nine articles preceding this summary article. TEOAEs in response to an 80 dB pSPL click, DPOAEs in response to L1 = 65 and L2 = 50 dB SPL and ABR in response to a 30 dB nHL click performed well as predictors of permanent hearing loss of 30 dB or greater at 8 to 12 mo corrected age. All measures were robust with respect to infant state, test environment and infant medical status. No test performed perfectly. Based on the data from this study, the 1993 National Institutes of Health Consensus Conference-recommended protocol-an OAE test followed by an ABR test for those infants failing the OAE test-would result in low referral rate (96 to 98%). TEOAEs for 80 dB pSPL, ABR for 30 dB nHL and DPOAEs for L1 = 65 dB SPL and L2 = 50 dB SPL perform well in predicting hearing status based on the area under the relative operating characteristic curve. Accuracy for the OAE measurements are best when the speech awareness threshold or the pure-tone average for 2.0 kHz and 4 kHz are used as the gold standard. ABR accuracy varies little as a function of the frequencies included in the gold standard. In addition, 96% of those infants returning for VRA at 8 to 12 mo corrected age were able to provide reliable ear-specific behavioral thresholds using insert earphones and a rigorous psychophysical VRA protocol.


Size determines whether specialized expert processes are engaged for recognition of faces.
Many influential models of face recognition postulate specialized expert processes that are engaged when viewing upright, own-race faces, as opposed to a general-purpose recognition route used for nonface objects and inverted or other-race faces. In contrast, others have argued that empirical differences do not stem from qualitatively distinct processing. We offer a potential resolution to this ongoing controversy. We hypothesize that faces engage specialized processes at large sizes only. To test this, we measured recognition efficiencies for a wide range of sizes. Upright face recognition efficiency increased with size. This was not due to better visibility of basic image features at large sizes. We ensured this by calculating efficiency relative to a specialized ideal observer unique to each individual that incorporated size-related changes in visibility and by measuring inverted efficiencies across the same range of face sizes. Inverted face recognition efficiencies did not change with size. A qualitative face inversion effect, defined as the ratio of relative upright and inverted efficiencies, showed a complete lack of inversion effects for small sizes up to 6°. In contrast, significant face inversion effects were found for all larger sizes. Size effects may stem from predominance of larger faces in the overall exposure to faces, which occur at closer viewing distances typical of social interaction. Our results offer a potential explanation for the contradictory findings in the literature regarding the special status of faces.


Genotyping by sequencing for genomic prediction in a soybean breeding population.
Advances in genotyping technology, such as genotyping by sequencing (GBS), are making genomic prediction more attractive to reduce breeding cycle times and costs associated with phenotyping. Genomic prediction and selection has been studied in several crop species, but no reports exist in soybean. The objectives of this study were (i) evaluate prospects for genomic selection using GBS in a typical soybean breeding program and (ii) evaluate the effect of GBS marker selection and imputation on genomic prediction accuracy. To achieve these objectives, a set of soybean lines sampled from the University of Nebraska Soybean Breeding Program were genotyped using GBS and evaluated for yield and other agronomic traits at multiple Nebraska locations. Genotyping by sequencing scored 16,502 single nucleotide polymorphisms (SNPs) with minor-allele frequency (MAF) > 0.05 and percentage of missing values ≤ 5% on 301 elite soybean breeding lines. When SNPs with up to 80% missing values were included, 52,349 SNPs were scored. Prediction accuracy for grain yield, assessed using cross validation, was estimated to be 0.64, indicating good potential for using genomic selection for grain yield in soybean. Filtering SNPs based on missing data percentage had little to no effect on prediction accuracy, especially when random forest imputation was used to impute missing values. The highest accuracies were observed when random forest imputation was used on all SNPs, but differences were not significant. A standard additive G-BLUP model was robust; modeling additive-by-additive epistasis did not provide any improvement in prediction accuracy. The effect of training population size on accuracy began to plateau around 100, but accuracy steadily climbed until the largest possible size was used in this analysis. Including only SNPs with MAF > 0.30 provided higher accuracies when training populations were smaller. Using GBS for genomic prediction in soybean holds good potential to expedite genetic gain. Our results suggest that standard additive G-BLUP models can be used on unfiltered, imputed GBS data without loss in accuracy.


Successful closure of large blunt macular chorioretinal rupture: a case report.
The authors present a rare case of large chorioretinal rupture caused by blunt traumatic injury of the globe. A 22-year-old woman sustained a blunt injury to her left eye. The best-corrected Snellen visual acuity was 2/20 in her left eye, and hyphema and vitreous hemorrhage were noted. The day after the injury occurred the vitreous hemorrhage had disappeared. Fundus examination revealed a crescent-shaped retinal rupture three disc diameters in size near the macula, and a choroidal rupture six disc diameters in size that was over the vascular arcade. Three days after the injury, vitrectomy with internal limiting membrane peeling was performed. Postoperative prone positioning was maintained for 4 days. Five days postoperatively, closure of the ruptured retina was confirmed. The visual acuity improved to 16/20 4 months after surgery and this was maintained over a 48-month period. In conclusion, early vitrectomy with internal limiting membrane peeling after injury was effective for a case involving severe blunt chorioretinal rupture with closed globe injury.


Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells.
Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53-miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols.


Intracellular trafficking and gene expression of pH-sensitive, artificially enveloped adenoviruses in vitro and in vivo.
Recombinant adenovirus (Ad) has shown great promise in gene therapy. Artificial envelopment of adenovirus within lipid bilayers has previously been shown to decrease the immunogenicity and hepatic affinity of naked Ad in vivo. Unfortunately, this also resulted in a significant reduction of gene expression, which we attributed to poor endosomal release of the Ad from its artificial lipid envelope. In this work, we explored the artificial envelopment of Ad within pH-sensitive DOPE:CHEMS bilayers and characterized this vector by TEM, AFM, dot blot, dynamic light scattering and zeta potential measurements. The artificially enveloped viral vectors exhibited good stability at physiological pH but immediately collapsed and released naked Ad virions at pH 5.5. Intracellular trafficking using confocal laser scanning microscopy (CLSM) revealed that Cy3-labelled Ad enveloped in DOPE:CHEMS bilayers exhibited the characteristic Ad distribution within the cytoplasm that led to virion accumulation around the nuclear membrane, indicating endosomal release of Ad. We obtained equivalent levels of gene expression as those of naked Ad in a series of CAR-positive (CAR+) and CAR-negative (CAR-) cell lines. This suggested that the mechanism of infection for the artificially enveloped Ad remained dependent on the presence of CAR receptors. Finally, the pH-sensitive enveloped Ad were injected intratumorally in human cervical carcinoma xenograft-bearing nude mice, also illustrating their capacity for efficient in vivo marker gene expression. This study is a step forward toward the engineering of functional, artificially enveloped adenovirus vectors for gene transfer applications.


Triglyceride-rich lipoprotein metabolism in women: roles of apoC-II and apoC-III.
Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ). Plasma apoC-II and apoC-III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1 - and VLDL2 -apoB-100 and triglyceride (all P < 0·05). ApoC-II production rate (PR) was positively associated with VLDL1 -apoB-100 concentration, VLDL1 triglyceride concentration and VLDL1 triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1 triglyceride FCR (all P < 0·05). No significant associations were observed between apoC-II and VLDL2 apoB-100 or triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2 -apoB-100 and triglyceride concentrations (all P < 0·05). No significant associations were observed between apoC-III and VLDL-apoB-100 and triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 -apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1 - and VLDL2 -apoB-100 and triglyceride concentrations and FCR. In women, plasma apoC-II and apoC-III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.


The beetroot component betanin modulates ROS production, DNA damage and apoptosis in human polymorphonuclear neutrophils.
The aim of this study was to evaluate the effect of betanin, one of the beetroot major components, on ROS production, DNA damage and apoptosis in human resting and stimulated with phorbol 12-myristate13-acetate polymorphonuclear neutrophils, one of the key elements of the inflammatory response. Incubation of neutrophils with betanin in the concentration range 2-500 µM resulted in significant inhibition of ROS production (by 15-46%, depending on the ROS detection assay). The antioxidant capacity of betanin was most prominently expressed in the chemiluminescence measurements. This compound decreased also the percentage of DNA in comet tails in stimulated neutrophils, but only at the 24 h time point. In resting neutrophils an increased level of DNA in comet tails was observed. Betanin did not affect the activity of caspase-3, in resting neutrophils, but significantly enhanced the enzyme activity in stimulated neutrophils. The western blot analysis showed, however, an increased level of caspase-3 cleavage products as a result of betanin treatment both in resting and stimulated neutrophils. The results indicate that betanin may be responsible for the effect of beetroot products on neutrophil oxidative metabolism and its consequences, DNA damage and apoptosis. The dose and time dependent effects on these processes require further studies.


Ligand-mediated activation of an engineered gs g protein-coupled receptor in osteoblasts increases trabecular bone formation.
Age-dependent changes in skeletal growth play important roles in regulating skeletal expansion and in the course of many diseases affecting bone. How G protein-coupled receptor (GPCR) signaling affects these changes is poorly understood. Previously, we described a mouse model expressing Rs1, an engineered receptor with constitutive G(s) activity. Rs1 expression in osteoblasts from gestation induced a dramatic age-dependent increase in trabecular bone with features resembling fibrous dysplasia; however, these changes were greatly minimized if Rs1 expression was delayed until after puberty. To further investigate whether ligand-induced activation of the G(s)-GPCR pathway affects bone formation in adult mice, we activated Rs1 in adult mice with the synthetic ligand RS67333 delivered continuously via an osmotic pump or intermittently by daily injections. We found that osteoblasts from adult animals can be stimulated to form large amounts of bone, indicating that adult mice are sensitive to the dramatic bone- forming actions of G(s) signaling in osteoblasts. In addition, our results show that intermittent and continuous activation of Rs1 led to structurally similar but quantitatively different degrees of trabecular bone formation. These results indicate that activation of a G(s)-coupled receptor in osteoblasts of adult animals by either intermittent or continuous ligand administration can increase trabecular bone formation. In addition, osteoblasts located at the bone epiphyses may be more responsive to G(s) signaling than osteoblasts at the bone diaphysis. This model provides a powerful tool for investigating the effects of ligand-activated G(s)-GPCR signaling on dynamic bone growth and remodeling.


[Recent topics of chronic inflammatory demyelinating polyneuropathy].
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated polyradiculoneuropathy. The American Academy of Neurology criteria has been used widely in diagnoses, and has generated clinical and pathological information. Recently, the EFNS/PNS criteria revised the concept of conventional "typical CIDP" and "atypical CIDP", with atypical CIDP including five phenotypes: DADS (distal acquired demyelinating symmetric), MADSAM (multifocal acquired demyelinating sensory and motor), focal, pure motor, and pure sensory neuropathy. However, the concepts of pure sensory, pure motor, and "idiopathic" DADS neuropathy do not have sufficient pathogenic support. MADSAM neuropathy shows significant hypertrophic nerve roots and/or plexuses. Since the characteristic multifocal distribution should correspond to the hypertrophic distribution, MADSAM or "hypertrophic CIDP" may be the promising phenotype of atypical CIDP. Clinical trials indicate that IVIg is more effective in a short time than corticosteroids for the treatment of CIDP, although corticosteroids maintain a longer immune suppression than IVIg. These results suggest that "hybrid therapies", IVIg induction and corticosteroid maintenance, may be effective. A recent study showed that IVIg stabilizes axonal potentials and axonal membranes, and our group showed that juxtaparanodal TAG-1 may be associated with IVIg responsiveness. Although CIDP is a demyelinating disease, the involvement of axon or axon-myelin interactions should be considered.


Age and sex-specific associations of carotid pulsatility with small vessel disease burden in transient ischemic attack and ischemic stroke.
Background Although large artery stiffness has been implicated in the pathogenesis of cerebral small vessel disease, whether carotid pulsatility, a convenient surrogate marker of arterial stiffness, is similarly associated with global burden of small vessel disease is unknown. Aims To determine the age and sex-specific associations of carotid pulsatility with global burden of small vessel disease. Methods We studied consecutive patients with transient ischemic attack or non-disabling ischemic stroke from the Oxford Vascular Study who had a brain MRI and carotid duplex ultrasound during 2002-2014. We determined clinical correlates of common carotid artery (CCA) and internal carotid artery (ICA) pulsatility index (PI) and their associations with the total small vessel disease score on MRI, stratified by age (median = 72). Results In 587 patients, correlates of CCA and ICA-PI were both independently associated with age, diabetes, and premorbid mean pulse pressure after adjustment for age, sex, and cardiovascular risk factors (all p < 0.05). ICA-PI was strongly associated with small vessel disease markers and burden, particularly lacunes, in patients aged<70 (age and sex-adjusted odds ratio of top vs. bottom pulsatility index quartile: 5.35, 1.95-14.70, p = 0.001; increasing small vessel disease score: 2.30, 1.01-5.25, p = 0.048), but not in patients aged ≥ 70 ( p > 0.05). No associations between CCA-PI with small vessel disease score were noted at any age. In 94 consecutive patients who also received transcranial Doppler ultrasound, strong associations between middle cerebral artery (MCA)-PI and an increasing small vessel disease score were noted (unadjusted OR-MCA: 4.26, 1.45-12.55, p = 0.009; ICA: 2.37, 0.81-6.87, p = 0.11; CCA: 1.33, 0.45-3.96, p=0.61). Conclusions ICA and MCA-PI are associated with global small vessel disease burden, especially in individuals aged<70 and may be causally related.


SU-D-217A-02: Effects of Enegy-Window Width and Spectral Effective Energy on Estimation of Gamma Camera Deadtime Using the Decay Method.
Assessment of count-rate performance (CRP) is part of routine quality assurance (QA) for gamma cameras. Manufacturers often specify deadtime (t) based on the NEMA decay method (NEMA 1-2007). The spectral conditions prescribed by NEMA are often difficult to duplicate during routine clinical QA testing and the appropriate energy window is poorly defined. The objective of this investigation is to evaluate the effects of energy-window selection and spectral conditions on estimates of t using the NEMA decay method. CRP was evaluated intrinsically over a period of 48 hours with Tc-99m for two Siemens Symbia gamma camera detectors using the NEMA decay method. CRP measurement was repeated with varying amounts of scattering material (0-8 cm of acrylic) placed between the source and detectors to transform the incident spectrum. CRP measurements were also repeated using different photopeak-window widths (2-75%) as well as an open energy-window. The CRP data were fit to the paralyzable detector model via non-linear least-squares minimization to estimate t. Estimates of t increased linearly with decreasing spectral effective energy. The effective energy was varied from 142-to-99 keV, which consequently altered the estimates of t by ∼0.095μs or 21% (p<0.01). Additionally, estimates of t increased as a power-law when the fraction of measured counts in the photopeak window decreased relative to open-window (total) counts. The ratio photopeak-window counts to open- window counts were varied from 1-to-0.12 which consequently altered the estimates of t by ∼8μs or 180%. The estimated change in t between 15% and 20% photopeak window is -0.13μs or 12.5%. Repeat measurements demonstrated that estimates of t using the decay method are precise to <2%. Deadtime (t) determined using the decay method varied significantly with the spectral effective energy and photopeak-window width. Careful attention to measurement conditions are imperative when measuring t using the decay method for comparison against manufacturer's specifications or trending as part of routine QA program.


Integrative annotation of chromatin elements from ENCODE data.
The ENCODE Project has generated a wealth of experimental information mapping diverse chromatin properties in several human cell lines. Although each such data track is independently informative toward the annotation of regulatory elements, their interrelations contain much richer information for the systematic annotation of regulatory elements. To uncover these interrelations and to generate an interpretable summary of the massive datasets of the ENCODE Project, we apply unsupervised learning methodologies, converting dozens of chromatin datasets into discrete annotation maps of regulatory regions and other chromatin elements across the human genome. These methods rediscover and summarize diverse aspects of chromatin architecture, elucidate the interplay between chromatin activity and RNA transcription, and reveal that a large proportion of the genome lies in a quiescent state, even across multiple cell types. The resulting annotation of non-coding regulatory elements correlate strongly with mammalian evolutionary constraint, and provide an unbiased approach for evaluating metrics of evolutionary constraint in human. Lastly, we use the regulatory annotations to revisit previously uncharacterized disease-associated loci, resulting in focused, testable hypotheses through the lens of the chromatin landscape.


Behavioral and Neural Evidence of the Rewarding Value of Exercise Behaviors: A Systematic Review.
In a time of physical inactivity pandemic, attempts to better understand the factors underlying the regulation of exercise behavior are important. The dominant neurobiological approach to exercise behavior considers physical activity to be a reward; however, negative affective responses during exercise challenge this idea. Our objective was to systematically review studies testing the automatic reactions triggered by stimuli associated with different types of exercise behavior (e.g. physical activity, sedentary behaviors) and energetic cost variations (e.g. decreased energetic cost, irrespective of the level of physical activity). We also examined evidence supporting the hypothesis that behaviors minimizing energetic cost (BMEC) are rewarding. Two authors systematically searched, screened, extracted, and analyzed data from articles in the MEDLINE database. We included 26 studies. Three outcomes of automatic processes were tested: affective reactions, attentional capture, and approach tendencies. Behavioral results show that physical activity can become attention-grabbing, automatically trigger positive affect, and elicit approach behaviors. These automatic reactions explain and predict exercise behaviors; however, the use of a wide variety of measures prevents drawing solid conclusions about the specific effects of automatic processes. Brain imaging results are scarce but show that stimuli associated with physical activity and, to a lesser extent, sedentary behaviors activate regions involved in reward processes. Studies investigating the rewarding value of behaviors driving energetic cost variations such as BMEC are lacking. Reward is an important factor in exercise behavior. The literature based on the investigation of automatic behaviors seems in line with the suggestion that physical activity is rewarding, at least for physically active individuals. Results suggest that sedentary behaviors could also be rewarding, although this evidence remains weak due to a lack of investigations. Finally, from an evolutionary perspective, BMEC are likely to be rewarding; however, no study has investigated this hypothesis. In sum, additional studies are required to establish a strong and complete framework of the reward processes underlying automatic exercise behavior.


Age-related alterations in functional connectivity patterns during working memory encoding of emotional items.
Previous findings indicate age-related differences in frontal-amygdala connectivity during emotional processing. However, direct evidence for age differences in brain functional activation and connectivity during emotional processing and concomitant behavioral implications is lacking. In the present study, we examined the impact of aging on the neural signature of selective attention to emotional information during working memory (WM) encoding. Participants completed an emotional WM task in which they were asked to attend to emotional targets and ignore irrelevant distractors. Despite an overall reduction in accuracy for older relative to younger adults, no behavioral age effect was observed as a function of emotional valence. The functional connectivity patterns of left ventrolateral prefrontal cortex showed that younger adults recruited one network for encoding of both positive and negative emotional targets and this network contributed to higher memory accuracy in this cohort. Older adults, on the other hand, engaged two distinct networks for encoding of positive and negative targets. The functional connectivity analysis using left amygdala further demonstrated that older adults recruited one single network during encoding of positive as well as negative targets whereas younger adults recruited this network only for encoding of negative items. The engagement of amygdala functional network also contributed to higher memory performance and faster response times in older adults. Our findings provide novel insights into the differential roles of functional brain networks connected to the medial PFC and amygdala during encoding of emotionally-valenced items with advancing age.


Arginine-enveloped virus inactivation and potential mechanisms.
Arginine synergistically inactivates enveloped viruses at a pH or temperature that does little harm to proteins, making it a desired process for therapeutic protein manufacturing. However, the mechanisms and optimal conditions for inactivation are not fully understood, and therefore, arginine viral inactivation is not used industrially. Optimal solution conditions for arginine viral inactivation found in the literature are high arginine concentrations (0.7-1 M), a time of 60 min, and a synergistic factor of high temperature (≥40°C), low pH (≤pH 4), or Tris buffer (5 mM). However, at optimal conditions full inactivation does not occur over all enveloped viruses. Enveloped viruses that are resistant to arginine often have increased protein stability or membrane stabilizing matrix proteins. Since arginine can interact with both proteins and lipids, interaction with either entity may be key to understanding the inactivation mechanism. Here, we propose three hypotheses for the mechanisms of arginine induced inactivation. Hypothesis 1 describes arginine-induced viral inactivation through inhibition of vital protein function. Hypothesis 2 describes how arginine destabilizes the viral membrane. Hypothesis 3 describes arginine forming pores in the virus membrane, accompanied by further viral damage from the synergistic factor. Once the mechanisms of arginine viral inactivation are understood, further enhancement by the addition of functional groups, charges, or additives may allow the inactivation of all enveloped viruses in mild conditions.


High rates of gene flow by pollen and seed in oak populations across Europe.
Gene flow is a key factor in the evolution of species, influencing effective population size, hybridisation and local adaptation. We analysed local gene flow in eight stands of white oak (mostly Quercus petraea and Q. robur, but also Q. pubescens and Q. faginea) distributed across Europe. Adult trees within a given area in each stand were exhaustively sampled (range [239, 754], mean 423), mapped, and acorns were collected ([17,147], 51) from several mother trees ([3], [47], 23). Seedlings ([65,387], 178) were harvested and geo-referenced in six of the eight stands. Genetic information was obtained from screening distinct molecular markers spread across the genome, genotyping each tree, acorn or seedling. All samples were thus genotyped at 5-8 nuclear microsatellite loci. Fathers/parents were assigned to acorns and seedlings using likelihood methods. Mating success of male and female parents, pollen and seed dispersal curves, and also hybridisation rates were estimated in each stand and compared on a continental scale. On average, the percentage of the wind-borne pollen from outside the stand was 60%, with large variation among stands (21-88%). Mean seed immigration into the stand was 40%, a high value for oaks that are generally considered to have limited seed dispersal. However, this estimate varied greatly among stands (20-66%). Gene flow was mostly intraspecific, with large variation, as some trees and stands showed particularly high rates of hybridisation. Our results show that mating success was unevenly distributed among trees. The high levels of gene flow suggest that geographically remote oak stands are unlikely to be genetically isolated, questioning the static definition of gene reserves and seed stands.


Treatment of psoriasis with piritrexim, a lipid-soluble folate antagonist.
Methotrexate is an effective and convenient treatment for severe psoriasis whose use is limited by the development of hepatic fibrosis and cirrhosis in a small number of patients. The mechanism of hepatotoxicity is unknown, but it is believed to be the result of intracellular polyglutamation and prolonged retention of methotrexate within the cell. Piritrexim isethionate is a lipid-soluble antifolate that has a mechanism of action similar to that of methotrexate. Since it is not polyglutamated, piritrexim could be effective in the treatment of psoriasis without the associated long-term hepatotoxicity. A 12-week phase I/II clinical trial of severe chronic plaque psoriasis assessed the safety and efficacy of oral piritrexim therapy. Based on experience gained from oncologic trials, each patient received a twice-daily dosage for 5 consecutive days every 2 weeks. Dosages ranged from 25 to 100 mg twice a day. Improvement in both lesion scores and percentage of body involvement was significant at a dose of 50 mg or more twice daily. Fifteen of 19 patients who completed 12 weeks of therapy demonstrated greater than 50% improvement in lesion scores. Improvement was limited by recrudescence of lesions over the 9-day rest period. Adverse experiences were minimal and dose related. Piritrexim is efficacious in the treatment of psoriasis.


Electron-Injection-Engineering Induced Phase Transition toward Stabilized 1T-MoS2 with Extraordinary Sodium Storage Performance.
Phase transition engineering, with the ability to alter the electronic structure and physicochemical properties of materials, has been widely used to achieve the thermodynamically unstable metallic phase MoS2 (1T-MoS2), although the complex operating conditions and low yield of previous strategies make the large-scale fabrication of 1T-MoS2 a big challenge. Herein, we report a facile electron injection strategy for phase transition engineering and fabricate a composite of conductive TiO chemically bonded to 1T-MoS2 nanoflowers (TiO-1T-MoS2 NFs) on a large scale. The underlying mechanism analysis reveals that electron-injection-engineering triggers a reorganization of the Mo 4d orbitals and results in a 100% phase transition of MoS2 from 2H to 1T. In the TiO-1T-MoS2 NFs composite, the 1T-MoS2 demonstrates a higher electronic conductivity, a lower Na+ diffusion barrier, and a more restricted S release than 2H-MoS2. In addition, conductive TiO bonding successfully resolves the stability challenge of the 1T phase. These merits endow TiO-1T-MoS2 NFs electrodes with an excellent rate capability (650/288 mAh g-1 at 50/20 000 mA g-1, respectively) and an outstanding cyclability (501 mAh g-1 at 1000 mA g-1 after 700 cycles) in sodium ion batteries. Such an improvement signifies that this facile and scalable phase-transition engineering combined with a deep mechanism analysis offers an important reference for designing advanced materials for various applications.


Prophylactic drug management for febrile seizures in children.
Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; but also to evaluate any other drug intervention where there was a sound biological rationale for its use. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2016, Issue 7); MEDLINE (1966 to July 2016); Embase (1966 to July 2016); Database of Abstracts of Reviews of Effectiveness (DARE) (July 2016). We imposed no language restrictions. We also contacted researchers in the field to identify continuing or unpublished studies. Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptic, antipyretic or other plausible agents with each other, placebo or no treatment. Two review authors (RN and MO) independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding and exclusions. For the 2016 update a third author (MC) checked all original inclusions, data analyses, and updated the search. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36, and 48 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. We assessed the presence of publication bias using funnel plots. We included 40 articles describing 30 randomised trials with 4256 randomised participants. We analysed 13 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbitone, phenytoin, valproate, pyridoxine, ibuprofen or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, acetaminophen or placebo; nor for continuous phenobarbitone versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam.There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment, with a risk ratio (RR) of 0.64 (95% confidence interval (CI) 0.48 to 0.85 at six months), RR of 0.69 (95% CI 0.56 to 0.84) at 12 months, RR 0.37 (95% CI 0.23 to 0.60) at 18 months, RR 0.73 (95% CI 0.56 to 0.95) at 24 months, RR 0.58 (95% CI 0.40 to 0.85) at 36 months, RR 0.36 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 60 to 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow-up (RR 0.59 (95% CI 0.42 to 0.83) at 6 months; RR 0.54 (95% CI 0.42 to 0.70) at 12 months; and RR 0.69 (95% CI 0.53 to 0.89) at 24 months). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64), an effect found against an extremely high (83.3%) recurrence rate in the controls, which is a result that needs replication.The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone-treated children were found in two studies. In general, adverse effects were recorded in up to 30% of children in the phenobarbitone-treated group and in up to 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbitone versus placebo (eight studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months, with too few studies to identify publication bias for the other comparisons.Most of the reviewed antiepileptic drug trials are of a methodological quality graded as low or very low. Methods of randomisation and allocation concealment often do not meet current standards; and treatment versus no treatment is more commonly seen than treatment versus placebo, leading to obvious risks of bias. Trials of antipyretics and zinc were of higher quality. We found reduced recurrence rates for children with febrile seizures for intermittent diazepam and continuous phenobarbitone, with adverse effects in up to 30%. Apparent benefit for clobazam treatment in one trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.


Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein.
Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along with endosomal sorting complex required for transport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs punctain late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor , prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-κB and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.


Control of root meristem establishment in conifers.
The evolution of terrestrial plant life was made possible by the establishment of a root system, which enabled plants to migrate from aquatic to terrestrial habitats. During evolution, root organization has gradually progressed from a very simple to a highly hierarchical architecture. Roots are initiated during embryogenesis and branch afterward through lateral root formation. Additionally, adventitious roots can be formed post-embryonically from aerial organs. Induction of adventitious roots (ARs) forms the basis of the vegetative propagation via cuttings in horticulture, agriculture and forestry. This method, together with somatic embryogenesis, is routinely used to clonally multiply conifers. In addition to being utilized as propagation techniques, adventitious rooting and somatic embryogenesis have emerged as versatile models to study cellular and molecular mechanisms of embryo formation and organogenesis of coniferous species. Both formation of the embryonic root and the AR primordia require the establishment of auxin gradients within cells that coordinate the developmental response. These processes also share key elements of the genetic regulatory networks that, e.g. are triggering cell fate. This minireview gives an overview of the molecular control mechanisms associated with root development in conifers, from initiation in the embryo to post-embryonic formation in cuttings.


Standardization of global hip fracture audit could facilitate learning, improve quality, and guide evidence-based practice.
National hip fracture registries audit similar aspects of care but there is variation in the actual data collected; these differences restrict international comparison, benchmarking, and research. The Fragility Fracture Network (FFN) published a revised minimum common dataset (MCD) in 2022 to improve consistency and interoperability. Our aim was to assess compatibility of existing registries with the MCD. We compared 17 hip fracture registries covering 20 countries (Argentina; Australia and New Zealand; China; Denmark; England, Wales, and Northern Ireland; Germany; Holland; Ireland; Japan; Mexico; Norway; Pakistan; the Philippines; Scotland; South Korea; Spain; and Sweden), setting each of these against the 20 core and 12 optional fields of the MCD. The highest MCD adherence was demonstrated by the most recently established registries. The first-generation registries in Scandinavia collect data for 60% of MCD fields, second-generation registries (UK, other European, and Australia and New Zealand) collect for 75%, and third-generation registries collect data for 85% of MCD fields. Five of the 20 core fields were collected by all 17 registries (age; sex; surgery date/time of operation; surgery type; and death during acute admission). Two fields were collected by most (16/17; 94%) registries (date/time of presentation and American Society of Anesthesiologists grade), and five more by the majority (15/17; 88%) registries (type, side, and pathological nature of fracture; anaesthetic modality; and discharge destination). Three core fields were each collected by only 11/17 (65%) registries: prefracture mobility/activities of daily living; cognition on admission; and bone protection medication prescription. There is moderate but improving compatibility between existing registries and the FFN MCD, and its introduction in 2022 was associated with an improved level of adherence among the most recently established programmes. Greater interoperability could be facilitated by improving consistency of data collection relating to prefracture function, cognition, bone protection, and follow-up duration, and this could improve international collaborative benchmarking, research, and quality improvement.


Alterations in cardiac sarcoplasmic reticulum calcium transport in the postischemic "stunned" myocardium.
This study examined the possibility that the postischemic mechanical depression observed in the "stunned" myocardium is a result of an alteration in the control of intracellular calcium. Regional myocardial stunning was produced in five open-chest dogs by eight to twelve 5-minute occlusions of the left anterior descending coronary artery, alternated with 10-minute reflow periods and followed by a final 60-minute period of reperfusion. Systolic segment shortening in the postischemic zone, measured by sonomicrometry, fell from 14.9% at baseline to -1.1% at the end of reperfusion. Sarcoplasmic reticulum isolated from stunned myocardium demonstrated a 17% reduction in oxalate-supported 45Ca2+ transport compared with sarcoplasmic reticulum from normal myocardium (0.93 vs. 1.12 mumol Ca2+/mg protein/min, p less than 0.005). There was also a 20% decrease in the maximal activation by Ca2+ of the sarcoplasmic reticulum Ca2+, Mg2+-ATPase (2.46 vs. 1.96 mumol Pi/mg protein/min, p less than 0.005), and a downward shift in the Ca2+-activation curve of the Ca2+, Mg2+-ATPase. These results indicate that myocardial stunning is associated with damage to the calcium-transport system of the sarcoplasmic reticulum. Altered intracellular control may contribute to the inability of the stunned heart to maintain normal mechanical function.


Raman-induced temporal condensed matter physics in gas-filled photonic crystal fibers.
Raman effect in gases can generate an extremely long-living wave of coherence that can lead to the establishment of an almost perfect temporal periodic variation of the medium refractive index. We show theoretically and numerically that the equations, regulate the pulse propagation in hollow-core photonic crystal fibers filled by Raman-active gas, are exactly identical to a classical problem in quantum condensed matter physics - but with the role of space and time reversed - namely an electron in a periodic potential subject to a constant electric field. We are therefore able to infer the existence of Wannier-Stark ladders, Bloch oscillations, and Zener tunneling, phenomena that are normally associated with condensed matter physics, using purely optical means.


Beyond Books: Public Libraries As Partners For Population Health.
Public libraries are not usually included in discussions about improving population health. They are, however, well positioned to be partners in building a culture of health through programming that addresses the social determinants of health. The Healthy Library Initiative, a partnership between the University of Pennsylvania and the Free Library of Philadelphia (the public library system that serves the city), has undertaken such efforts in Philadelphia. In this article we report findings from an assessment of how ten highly subscribed programs address the social determinants of health, as well as results of interviews with community residents and library staff. Of the 5.8 million in-person Free Library visits in 2015, 500,000 included attendance at specialized programs that addressed multiple health determinants, such as housing and literacy. Library staff provided intensive support to vulnerable populations including homeless people, people with mental illness and substance use, recent immigrants, and children and families suffering from trauma. We found that public libraries are trusted institutions that have broad population reach and untapped potential to improve population health.


"Iron-saturated" bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice.
Tamoxifen is used in hormone therapy for estrogen-receptor (ER)-positive breast cancer, but also has chemopreventative effects against ER-negative breast cancers. This study sought to investigate whether oral iron-saturated bovine lactoferrin (Fe-Lf), a natural product which enhances chemotherapy, could improve the chemotherapeutic effects of tamoxifen in the treatment of ER-negative breast cancers. In a model of breast cancer prevention, female Balb/c mice treated with tamoxifen (5 mg/Kg) were fed an Fe-Lf supplemented diet (5 g/Kg diet) or the base diet. At week 2, 4T1 mammary carcinoma cells were injected into an inguinal mammary fat pad. In a model of breast cancer treatment, tamoxifen treatment was not started until two weeks following tumor cell injection. Tumor growth, metastasis, body weight, and levels of interleukin 18 (IL-18) and interferon γ (IFN-γ) were analyzed. Tamoxifen weakly (IC(50) ~ 8 μM) inhibited the proliferation of 4T1 cells at pharmacological concentrations in vitro. In the tumor prevention study, a Fe-Lf diet in combination with tamoxifen caused a 4 day delay in tumor formation, and significantly inhibited tumor growth and metastasis to the liver and lung by 48, 58, and 66% (all P < 0.001), respectively, compared to untreated controls. The combination therapy was significantly (all P < 0.05) more effective than the respective monotherapies. Oral Fe-Lf attenuated the loss of body weight caused by tamoxifen and cancer cachexia. It prevented tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing IL-18 and IFN-γ. It increased the levels of Lf in leukocytes residing in gut-associated lymphoid tissues. B, T and Natural killer (NK) cells containing high levels of Lf were identified in 4T1 tumors, suggesting they had migrated from the intestine. Similar effects of Fe-Lf and tamoxifen on tumor cell viability were seen in the treatment of established tumors. The results indicate that Fe-Lf is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors.


Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.
Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.


Dental implants in the diabetic patient: a retrospective study.
It has become increasingly common for controlled diabetic patients to be considered as candidates for dental implants. This study reports on the results of placing implants in 34 patients with diabetes who were treated with 227 Brånemark implants. At the time of second-stage surgery, 214 of the implants had osseointegrated, a survival rate of 94.3%. Only one failure was identified among the 177 implants followed through final restoration, a clinical survival rate of 99.9%. Screening for diabetes and trying to ensure that implant candidates are in metabolic control are recommended to increase the chances of successful osseointegration. Antibiotic protection and avoidance of smoking should also be considered.


Choosing Healthy Eating for Infant Health (CHErIsH) study: protocol for a feasibility study.
Childhood obesity is a public health challenge. There is evidence for associations between parents' feeding behaviours and childhood obesity risk. Primary care provides a unique opportunity for delivery of infant feeding interventions for childhood obesity prevention. Implementation strategies are needed to support infant feeding intervention delivery. The Choosing Healthy Eating for Infant Health (CHErIsH) intervention is a complex infant feeding intervention delivered at infant vaccination visits, alongside a healthcare professional (HCP)-level implementation strategy to support delivery. This protocol provides a description of a non-randomised feasibility study of an infant feeding intervention and implementation strategy, with an embedded process evaluation and economic evaluation. Intervention participants will be parents of infants aged ≤6 weeks at recruitment, attending a participating HCP in a primary care practice. The intervention will be delivered at the infant's 2, 4, 6, 12 and 13 month vaccination visits and involves brief verbal infant feeding messages and additional resources, including a leaflet, magnet, infant bib and sign-posting to an information website. The implementation strategy encompasses a local opinion leader, HCP training delivered prior to intervention delivery, electronic delivery prompts and additional resources, including a training manual, poster and support from the research team. An embedded mixed-methods process evaluation will examine the acceptability and feasibility of the intervention, the implementation strategy and study processes including data collection. Qualitative interviews will explore parent and HCP experiences and perspectives of delivery and receipt of the intervention and implementation strategy. Self-report surveys will examine fidelity of delivery and receipt, and acceptability, suitability and comprehensiveness of the intervention, implementation strategy and study processes. Data from electronic delivery prompts will also be collected to examine implementation of the intervention. A cost-outcome description will be conducted to measure costs of the intervention and the implementation strategy. This study received approval from the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Study findings will be disseminated via peer-reviewed publications and conference presentations.


A new mechanism for chloramphenicol, florfenicol and clindamycin resistance: methylation of 23S ribosomal RNA at A2503.
The gene product of cfr from Staphylococcus sciuri confers resistance to chloramphenicol, florfenicol and clindamycin in Staphylococcus spp. and Escherichia coli. Cfr is not similar to any other known chloramphenicol resistance determinant. Comparative investigation of E. coli with and without a plasmid-encoded Cfr showed a decreased drug binding to ribosomes in the presence of Cfr. As chloramphenicol/florfenicol and clindamycin have partly overlapping drug binding sites on the ribosome, the most likely explanation is that Cfr modifies the RNA in the drug binding site. This hypothesis was supported by drug footprinting data that showed both a decreased drug binding and an enhanced reverse transcriptase stop at position 2504, which corresponds to a modification at position A2503 at the drug binding site. A 45 n long RNA fragment containing the appropriate region was isolated and MALDI-TOF mass spectrometry in combination with tandem mass spectrometry showed an additional methylation at position A2503. Moreover, reduced methylation was detected at nucleotide C2498. The results show that Cfr is an RNA methyltransferase that targets nucleotide A2503 and inhibits ribose methylation at nucleotide C2498, thereby causing resistance to chloramphenicol, florfenicol and clindamycin.


Comparing the status of women and men in academic medicine.
To explore the status and academic productivity of women compared with men in academic internal medicine. Mail survey done in 1986. A total of 107 major teaching hospitals in the United States. Full-time (1693 of 2510) faculty in cardiology, rheumatology, and general internal medicine; 67% of eligible men and 70% of eligible women. Academic productivity defined as research grants awarded, abstracts accepted, and papers published in refereed journals; academic advancement as determined by academic rank and tenure status; and monetary compensation. Women entered academic medicine with shorter periods of fellowship training and were less likely to be members in the Alpha Omega Alpha honor society, but they had job descriptions similar to those of men, with similar allocation of work between research, clinical, and teaching activities. After adjustment, women and men were similar in the numbers of research grants funded as principal investigator (1.9 compared with 2.0), abstracts accepted (6.8 compared with 6.1), and papers published in refereed journals (28.8 compared with 29.2; all with P > 0.20). Women were as likely as men to have tenure, but they had lower academic rank (full or associate professor; 33% compared with 47%, P < 0.001) and received less compensation ($72,000 compared with $79,600 annually; P < 0.001). Although women do similar professional tasks and achieve similar levels of academic productivity, they receive fewer rewards for their work, both in academic rank and monetary compensation.


Nurse Adaptability and Post-traumatic Stress Disorder Symptoms During the COVID-19 Pandemic: The Effects of Family and Perceived Organizational Support.
To examine the effect of family and perceived organizational support on the relationship between nurse adaptability and their experience with COVID-related PTSD (post-traumatic stress disorder) symptoms in frontline nurses working on COVID-19 units. Proximity to and survival of life-threatening events contribute to a diagnosis of PTSD, which is characterized by avoidance of reminders of trauma, intrusive thoughts, flashbacks of events, sleep disturbances, and hypervigilance. Using the job-demands and resource model, we examined the effect of adaptability, family support, and perceived organizational support on PTSD symptoms for nurses during the COVID-19 pandemic. Specifically, we tested whether perceptions of environmental supports-i.e., family and organizational support-moderated the relationship between nurse adaptability and COVID-related PTSD symptoms. A sample of frontline nurses working on COVID-19 units during the COVID-19 pandemic in Texas (N = 277) participated in this cross-sectional, observational study. Frontline Nurses reported demographic information and completed surveys designed to measure adaptability, perceived organizational support, family support, and COVID-related PTSD symptoms. Adaptability was significantly positively correlated (medium effects) to perceived organizational and family support (r = 0.51 and 0.56, respectively, p < 0.01). Adaptability and perceived organizational support were also negatively correlated with COVID-related PTSD symptoms (medium effects). Adaptability was negatively correlated with COVID-related PTSD symptoms, supporting Hypothesis 1 (r = -0.43, p < 0.01). Perceived organizational support was also significantly negatively correlated with COVID-19-related PTSD symptoms (r = -0.30, p < 0.01). Family support was not significantly correlated with COVID-related PTSD but was positively related to experiencing COVID-related PTSD after other variables were accounted for. Findings suggest that individual adaptability and organizational support may reduce PTSD severity in frontline nurses working during a crisis; however, family support may increase PTSD symptoms. We provide suggestions for strengthening individual adaptability and healthcare leadership including remaining highly engaged to show support by providing rapid communication, remaining calm during difficult circumstances, and maintaining a consistent, physical presence during difficult times. Moreover, our results suggest additional support for nurses with families to adapt to crisis.


Gene expression patterns of two dominant tallgrass prairie species differ in response to warming and altered precipitation.
To better understand the mechanisms underlying plant species responses to climate change, we compared transcriptional profiles of the co-dominant C4 grasses, Andropogon gerardii Vitman and Sorghastrum nutans (L.) Nash, in response to increased temperatures and more variable precipitation regimes in a long-term field experiment in native tallgrass prairie. We used microarray probing of a closely related model species (Zea mays) to assess correlations in leaf temperature (Tleaf) and leaf water potential (LWP) and abundance changes of ~10,000 transcripts in leaf tissue collected from individuals of both species. A greater number of transcripts were found to significantly change in abundance levels with Tleaf and LWP in S. nutans than in A. gerardii. S. nutans also was more responsive to short-term drought recovery than A. gerardii. Water flow regulating transcripts associated with stress avoidance (e.g., aquaporins), as well as those involved in the prevention and repair of damage (e.g., antioxidant enzymes, HSPs), were uniquely more abundant in response to increasing Tleaf in S. nutans. The differential transcriptomic responses of the co-dominant C4 grasses suggest that these species may cope with and respond to temperature and water stress at the molecular level in distinct ways, with implications for tallgrass prairie ecosystem function.


A Pilot Randomized Controlled Trial of the ACCESS Program: A Group Intervention to Improve Social, Adaptive Functioning, Stress Coping, and Self-Determination Outcomes in Young Adults with Autism Spectrum Disorder.
The purpose of this pilot randomized controlled trial was to investigate the acceptability and efficacy of the Acquiring Career, Coping, Executive control, Social Skills (ACCESS) Program, a group intervention tailored for young adults with autism spectrum disorder (ASD) to enhance critical skills and beliefs that promote adult functioning, including social and adaptive skills, self-determination skills, and coping self-efficacy. Forty-four adults with ASD (ages 18-38; 13 females) and their caregivers were randomly assigned to treatment or waitlist control. Compared to controls, adults in treatment significantly improved in adaptive and self-determination skills, per caregiver report, and self-reported greater belief in their ability to access social support to cope with stressors. Results provide evidence for the acceptability and efficacy of the ACCESS Program.


European Chemicals Agency dossier submissions as an experimental data source: refinement of a fish toxicity model for predicting acute LC50 values.
As a result of the stringent data requirements of the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) regulation, a vast amount of ecotoxicological data has become available through the dissemination portal of the European Chemicals Agency (ECHA). As of April 2014, the database contained 12,439 unique substances from 47,909 dossiers. This vast database could be used to refine existing, or to create new, non-testing methods, such as quantitative structure-activity relationships (QSARs). Acute fish toxicity data were mined from the ECHA database using the eChemPortal; after filtering for single organic substances, 1159 experimental data points remained, representing 564 compounds. To evaluate the quality and accessibility of this data, the authors used the data to refine and improve an existing QSAR. The reliability of the data submitted to the ECHA database, as well as the effectiveness of the Klimisch scoring system, were assessed by comparing the refined QSAR with established QSAR benchmarks. The model developed meets all Organisation for Economic Co-operation and Development principles, has strong internal (leave-one-out internally cross-validated correlation coefficient [Q(2)(LOO)] = 0.91) and external (external coefficient of determination (predicted vs experimental [test set])) validation statistics, and can provide reliable fish median lethal concentration (LC50) predictions for non-polar narcotics. Although some issues with dossier misinformation were discovered, it was found that the ECHA dissemination portal is a valuable and reliable data source. When queried using the eChemPortal, chemical dossiers containing reliable data could be found quickly. The ECHA dissemination portal holds great potential for future QSAR development and improvement, such as updating QSARs within the Ecological Structure-Activity Relationships (ECOSAR) program.


Broad-range PCR-TTGE for the first-line detection of bacterial pathogen DNA in ticks.
Ticks are known or suspected vectors for a wide range of bacterial pathogens. One of the first steps for tick-borne risk assessment is the detection of these pathogens in their vectors. In the present study, a broad-range PCR amplification of the eubacterial gene encoding the 16S rRNA gene combined with Temporal Temperature Gradient gel Electrophoresis (TTGE) was evaluated as a method allowing the one-step detection of bacterial pathogen DNA in ticks. Firstly, DNA extracts from bacteria known to be tick-borne pathogens, i.e., Borrelia burgdorferi lato sensu, Anaplasma phagocytophilum, Spotted Fever Group (SFG) Rickettsia spp., were used to establish a TTGE pathogen DNA reference marker. Secondly, we used broad-range PCR-TTGE to detect the presence of DNA from these three pathogens in 55 DNA extracts from pools of 10 nymphal Ixodes ricinus ticks, which have been previously shown to carry DNA from at least one of those bacteria by specific PCR. Among the 20 B. burgdorferi specific-PCR samples, 15 (75%) were also found to be positive using PCR-TTGE. Sixteen of the seventeen (94%) Rickettsia spp. PCR-specific samples were positive using PCR-TTGE detection and all PCR-specific positive extracts (11/11, 100%) for A. phagocytophilum were also positive using PCR-TTGE. Moreover, we identified unexpected bacterial sequences that were not related to any of the three pathogens such as a sequence related to Spiroplasma sp. Thus, broad-range PCR-TTGE allowed the single step detection of DNA from up to 3 pathogens in the same co-infected samples as well as detection of DNA from unexpected bacteria.


Predictors of mortality among HIV infected patients taking antiretroviral treatment in Ethiopia: a retrospective cohort study.
Studies indicate that there is high early mortality among patients starting antiretroviral treatment in sub-Saharan Africa. However, there is paucity of evidence on long term survival of patients on anti-retroviral treatment in the region. The objective of this study is to examine mortality and its predictors among a cohort of HIV infected patients on anti-retroviral treatment retrospectively followed for five years. A retrospective cohort study was conducted among HIV infected patients on ART in eastern Ethiopia. Cox regression and Kaplan-Meier analyses were performed to investigate factors that influence time to death and survival over time. A total of 1540 study participants were included in the study. From the registered patients in the cohort, the outcome of patients as active, deceased, lost to follow up and transfer out was 1005 (67.2%), 86 (5.9%), 210 (14.0%) and 192 (12.8%) respectively. The overall mortality rate provides an incidence density of 2.03 deaths per 100 person years (95% CI 1.64 - 2.50). Out of a total of 86 deaths over 60 month period; 63 (73.3%) died during the first 12 months, 10 (11.6%) during the second year, and 10 (11.6%) in the third year of follow up. In multivariate analysis, the independent predictors for mortality were loss of more 10% weight loss, bedridden functional status at baseline, ≤ 200 CD4 cell count/ml, and advanced WHO stage patients. A lower level of mortality was detected among the cohort of patients on antiretroviral treatment in eastern Ethiopia. Previous history of weight loss, bedridden functional status at baseline, low CD4 cell count and advanced WHO status patients had a higher risk of death. Early initiation of ART, provision of nutritional support and strengthening of the food by prescription initiative, and counseling of patients for early presentation to treatment is recommended.


Contrasting roles for TLR ligands in HIV-1 pathogenesis.
The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention.


Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction.
Patients with coronary artery disease (CAD) and severe left ventricular (LV) dysfunction have a high but variable annual mortality and some may benefit from myocardial revascularization. This study aimed to evaluate the prognostic value of positron emission tomography (PET), and its interrelation with the choice of medical therapy or revascularization for predicting survival and improvement in symptoms of heart failure in patients with CAD and LV dysfunction. Ninety-three consecutive patients with angiographic CAD and a mean LV ejection fraction of 0.25 who underwent cardiac PET studies for assessment of hypoperfused yet viable myocardium ("mismatch pattern") using N-13 ammonia and 18-F deoxyglucose were followed up for an average of 13.6 months. Fifty patients underwent medical treatment and 43 underwent revascularization. The Cox model analysis showed that the extent of mismatch had a negative effect (p = 0.02), whereas revascularization had a positive effect on survival (p = 0.04). The annual survival probability of patients with mismatch receiving medical therapy was lower than of those without mismatch (50 vs 92%, p = 0.007). Patients with mismatch who underwent revascularization had a higher survival rate than those treated medically (88 vs 50%, P = 0.03). The presence of mismatch also predicted improvement in heart failure symptoms after revascularization (p < 0.001). These results suggest that the presence of mismatch in patients with CAD and severe LV dysfunction is associated with poor annual survival with medical therapy. Revascularization in patients with PET mismatch appears to be associated with improved survival and heart failure symptoms.


[Epidemiological distribution characteristics of peripheral blood mosaic chromosomal alteration in adults from 10 regions of China].
Objective: To describe the epidemiological distribution characteristics of peripheral blood mosaic chromosomal alteration (mCA) in community adults aged 30-79 years in 10 regions of China. Methods: A total of 100 297 participants with complete baseline information (demographic characteristics, lifestyle, physical examination, etc.) and genotyping data of blood-derived DNA in ten regions of the China Kadoorie Biobank study were included. The mCAs were detected with the Mosaic Chromosomal Alterations pipeline, and logistic regression models were used to compare the differences in the detection rate of mCAs in different regions and populations. Results: A total of 5 810 mCA carriers were detected, with the detection rate of 5.8%. The standardized detection rate was 5.1%. The baseline detection rate of mCA increased with age, which were 3.4%, 5.0%, and 9.4% in those aged 30-, 51-, and >60 years, respectively (trend test P<0.001). A more significant proportion of mCAs were found in men (8.0%) than women (4.0%), as well as in urban areas (6.4%) than in rural areas (5.3%), the difference was significant (P<0.001). After adjusting for age and gender, the detection rate of mCA was higher in current smokers or people quitting smoking due to illness and people with low physical activity level, and the mCA detection rate was lower in obesy people (5.3%) than that in people with normal body weight (5.9%) (P=0.006). Conclusions: The detection rate of mCAs varied with region and population in community adults aged 30-79 years in 10 regions of China. The study results might contribute to the molecular identification of aging populations and guide precision prevention of age-related diseases such as cancers.


The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination.
Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.


Impacts of Cross-Linkers on Biological Effects of Mesoporous Silica Nanoparticles.
Chemically synthesized cross-linkers play decisive roles in variable cargos attached to nanoparticles (NPs). Previous studies reported that surface properties, such as the size, charge, and surface chemistry, are particularly important determinants influencing the biological fate and actions of NPs and cells. Recent studies also focused on the relationship of serum proteins with the surface properties of NPs (also called the protein corona), which is recognized as a key factor in determining the cytotoxicity and biodistribution. However, there is concern that cross-linkers conjugated onto NPs might induce undesirable biological effects. Cell responses induced by cross-linkers have not yet been precisely elucidated. Herein, using mesoporous silica nanoparticles (MSNs) the surfaces of which were separately conjugated with four popular heterobifunctional cross-linkers, i.e., N-[α-maleimidoacetoxy]succinimide ester (AMAS), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and maleimide poly(ethylene glycol) succinimidyl carboxymethyl ester (MAL-PEG-SCM), we investigated cross-linker-conjugated MSNs to determine whether they can cause cytotoxicity, or enhance reactive oxygen species (ROS) generation, nuclear factor (NF)-κB activation, and p-p38 or p21 protein expressions in RAW264.7 macrophage cells. Furthermore, we also separately conjugated two biomolecules containing TAT peptides and bovine serum albumin (BSA) as model systems to study their cell responses in detail. Finally, in vivo mice studies evaluated the biodistribution and blood assays (biochemistry and complete blood count) of PEG-derivative NPs, and results suggested that TAT peptides caused significant white blood cell (WBC)-related cell and platelet abnormalities, as well as liver and kidney dysfunction compared to BSA when conjugated onto MSNs. The results showed that attention to cross-linkers should be considered an issue in the surface modification of NPs. We anticipate that our results could be helpful in developing biosafety nanomaterials.


Designing Optimal Perovskite Structure for High Ionic Conduction.
Solid-oxide fuel/electrolyzer cells are limited by a dearth of electrolyte materials with low ohmic loss and an incomplete understanding of the structure-property relationships that would enable the rational design of better materials. Here, using epitaxial thin-film growth, synchrotron radiation, impedance spectroscopy, and density-functional theory, the impact of structural parameters (i.e., unit-cell volume and octahedral rotations) on ionic conductivity is delineated in La0.9 Sr0.1 Ga0.95 Mg0.05 O3- δ . As compared to the zero-strain state, compressive strain reduces the unit-cell volume while maintaining large octahedral rotations, resulting in a strong reduction of ionic conductivity, while tensile strain increases the unit-cell volume while quenching octahedral rotations, resulting in a negligible effect on the ionic conductivity. Calculations reveal that larger unit-cell volumes and octahedral rotations decrease migration barriers and create low-energy migration pathways, respectively. The desired combination of large unit-cell volume and octahedral rotations is normally contraindicated, but through the creation of superlattice structures both expanded unit-cell volume and large octahedral rotations are experimentally realized, which result in an enhancement of the ionic conductivity. All told, the potential to tune ionic conductivity with structure alone by a factor of ≈2.5 at around 600 °C is observed, which sheds new light on the rational design of ion-conducting perovskite electrolytes.


Caesium fluoride-mediated hydrocarboxylation of alkenes and allenes: scope and mechanistic insights.
A caesium fluoride-mediated hydrocarboxylation of olefins is disclosed that does not rely on precious transition metal catalysts and ligands. The reaction occurs at atmospheric pressures of CO2 in the presence of 9-BBN as a stoichiometric reductant. Stilbenes, β-substituted styrenes and allenes could be carboxylated in good yields. The developed methodology can be used for preparation of commercial drugs as well as for gram scale hydrocarboxylation. Computational studies indicate that the reaction occurs via formation of an organocaesium intermediate.


Exploring the Potential of MicroRNA Let-7c as a Therapeutic for Prostate Cancer.
Prostate cancer (PCa) is one of the leading causes of mortality worldwide and often presents with aberrant microRNA (miRNA) expression. Identifying and understanding the unique expression profiles could aid in the detection and treatment of this disease. This review aims to identify miRNAs as potential therapeutic targets for PCa. Three bio-informatic searches were conducted to identify miRNAs that are reportedly implicated in the pathogenesis of PCa. Only hsa-Lethal-7 (let-7c), recognized for its role in PCa pathogenesis, was common to all three databases. Three further database searches were conducted to identify known targets of hsa-let-7c. Four targets were identified, HMGA2, c-Myc (MYC), TRAIL, and CASP3. An extensive review of the literature was undertaken to assess the role of hsa-let-7c in the progression of other malignancies and to evaluate its potential as a therapeutic target for PCa. The heterogeneous nature of cancer makes it logical to develop mechanisms by which the treatment of malignancies is tailored to an individual, harnessing specific knowledge of the underlying biology of the disease. Resetting cellular miRNA levels is an exciting prospect that will allow this ambition to be realized.


Hyperglycosylation of glycopeptidolipid of Mycobacterium smegmatis under nutrient starvation: structural studies.
The presence of a polar species of glycopeptidolipid (GPL) in carbon-starved Mycobacterium smegmatis has been reported previously. In this study, the complete structure of this GPL is established with the help of MALDI-TOF (matrix assisted laser desorption/ionization time of flight) and ESI (electrospray ionization) -MS, (13)C-SEFT (spin echo Fourier transform) -NMR spectroscopy, and HPLC analysis. In the molecule, two units of a 3,4-di-O-methyl derivative of rhamnose are attached to l-alaninol via a 1-->2 linkage. Various methyl derivatives of rhamnose and 6-deoxytalose were synthesized as standards to establish this structure. The accumulation of this polar GPL in M. smegmatis is sigB dependent, as a SigB-overproducing strain of M. smegmatis shows the presence of this spot in the exponential phase, and a sigB-knockout strain of M. smegmatis does not show the presence of any polar GPLs.


Arabidopsis pathology breathes new life into the necrotrophs-vs.-biotrophs classification of fungal pathogens.
SUMMARY Fungal plant pathologists have for many decades attempted to classify pathogens into groups called necrotrophs, biotrophs and, more recently, hemibiotrophs. Although these terms are well known and frequently used, disagreements about which pathogens fall into which classes, as well as the precise definition of these terms, has conspired to limit their usefulness. Dogmas concerning the properties of the classes have been progressively eroded. However, the genetic analysis of disease resistance, particularly in the model plant Arabidopsis thaliana, has provided a biologically meaningful division based on whether defence against fungal pathogens is controlled via the salicylate or jasmonate/ethylene pathways. This mode-of-defence division distinguishes necrotrophs and biotrophs but it limits the biotroph class to pathogens that possess haustoria. The small number and limited range of pathogens that infect Arabidopsis means that several interesting questions are still unanswered. Do hemibiotrophs represents a distinct class or a subclass of the necrotrophs? Does the division apply to other plant families and particularly to cereals? and does this classification help us understand the intricacies of either fungal pathogenicity or plant defence?


SeaView version 4: A multiplatform graphical user interface for sequence alignment and phylogenetic tree building.
We present SeaView version 4, a multiplatform program designed to facilitate multiple alignment and phylogenetic tree building from molecular sequence data through the use of a graphical user interface. SeaView version 4 combines all the functions of the widely used programs SeaView (in its previous versions) and Phylo_win, and expands them by adding network access to sequence databases, alignment with arbitrary algorithm, maximum-likelihood tree building with PhyML, and display, printing, and copy-to-clipboard of rooted or unrooted, binary or multifurcating phylogenetic trees. In relation to the wide present offer of tools and algorithms for phylogenetic analyses, SeaView is especially useful for teaching and for occasional users of such software. SeaView is freely available at http://pbil.univ-lyon1.fr/software/seaview.