Protein kinases in mammalian sperm capacitation and the acrosome reaction.
Binding to the zona pellucida of an egg stimulates the spermatozoon to undergo the acrosome reaction, a process that enables it to penetrate the egg. Before this binding, the spermatozoon undergoes a series of biochemical transformations in the female reproductive tract, collectively called capacitation. Only capacitated spermatozoa can bind to the zona pellucida and undergo the acrosome reaction. Protein kinases may be involved in the regulation of intracellular Ca2+ during capacitation and the acrosome reaction. The first event in capacitation is the increase in intracellular calcium, bicarbonate and hydrogen peroxide, which collectively activate adenylyl cyclase to produce cyclic AMP, which activates protein kinase A to phosphorylate certain proteins. During capacitation, there is an increase in membrane-bound phospholipase C, and this binding is highly stimulated by the addition of epidermal growth factor to the cells. The capacitated spermatozoon binds to the zona pellucida of the egg via specific receptors and it is suggested that the zona pellucida binds to at least two different receptors in the sperm head plasma membrane. One is a Gi-coupled receptor that can activate phospholipase Cbeta1 and may regulate adenylyl cyclase to further increase cyclic AMP concentrations. The cyclic AMP activates protein kinase A to open a calcium channel in the outer acrosomal membrane, resulting in a relatively small increase in cytosolic calcium. This increase in Ca2+ leads to activation of phospholipase Cgamma, which is coupled to the second tyrosine kinase receptor. The products of phosphatidyl-inositol bisphosphate hydrolysis by phospholipase C, diacylglycerol and inositol-trisphosphate, induce the activation of protein kinase C and a calcium channel in the outer acrosomal membrane, respectively. Protein kinase C opens a calcium channel in the plasma membrane and, together with the inositol-trisphosphate-activated calcium channel, leads to a second and higher increase in cytosolic calcium. In addition, the depletion of calcium in the acrosome activates a capacitative calcium entry mechanism in the plasma membrane, leading to a rapid increase in cytosolic calcium (300-500 nmol l(-1)). This increase in intracellular calcium concentration (and pH) leads to membrane fusion and the acrosome reaction.


Optimal control based seizure abatement using patient derived connectivity.
Epilepsy is a neurological disorder in which patients have recurrent seizures. Seizures occur in conjunction with abnormal electrical brain activity which can be recorded by the electroencephalogram (EEG). Often, this abnormal brain activity consists of high amplitude regular spike-wave oscillations as opposed to low amplitude irregular oscillations in the non-seizure state. Active brain stimulation has been proposed as a method to terminate seizures prematurely, however, a general and widely-applicable approach to optimal stimulation protocols is still lacking. In this study we use a computational model of epileptic spike-wave dynamics to evaluate the effectiveness of a pseudospectral method to simulated seizure abatement. We incorporate brain connectivity derived from magnetic resonance imaging of a subject with idiopathic generalized epilepsy. We find that the pseudospectral method can successfully generate time-varying stimuli that abate simulated seizures, even when including heterogeneous patient specific brain connectivity. The strength of the stimulus required varies in different brain areas. Our results suggest that seizure abatement, modeled as an optimal control problem and solved with the pseudospectral method, offers an attractive approach to treatment for in vivo stimulation techniques. Further, if optimal brain stimulation protocols are to be experimentally successful, then the heterogeneity of cortical connectivity should be accounted for in the development of those protocols and thus more spatially localized solutions may be preferable.


Multimorbidity and vulnerability among those living with psychosis in Indigenous populations in Cape York and the Torres Strait.
Previous research has found an alarmingly high rate of psychosis in Indigenous1 patients from remote communities of Cape York and the Torres Strait with the treated prevalence of psychosis four times higher than that found for the Australian population. This study assesses comorbid illness and risk factors among this same cohort of psychosis patients. Data were collated from a clinical database that contains complete psychiatric records from 1992 to 2015, extracted for all Indigenous patients who received treatment for a psychotic disorder from the Remote Area Mental Health Service. Descriptive analysis and logistic regression models explored differences across subgroups of ethnicity and sex, and relationships between co-morbid disorders and risk factors. All multivariate models included variables of age, year of birth, sex and ethnicity. Sixty per cent of participants (n = 256) experienced a comorbid mental or substance use disorder. Forty-five per cent (n = 192) of participants experienced a physical comorbidity. The most frequent physical health outcomes were injury (29%, n = 93), diabetes (18%, n = 58) and cardiovascular disease (21%, n = 68). Risk factors considered to play a potential biological or neurodevelopmental role in the development of psychosis were approximately three times more likely in Aboriginal (odds ratio = 3.2; 95% confidence interval = [2.0, 4.9]) versus Torres Strait Islander patients, and those born after 1980 (odds ratio = 2.5; 95% confidence interval = [1.6, 3.9]) versus those born prior to 1980. Environmental or contextual factors were associated with significantly greater risk among Aboriginal (odds ratio = 3.8; 95% confidence interval = [2.4, 6.0]) compared with Torres Strait Islander patients. Our data expose the perinatal and early environment of Indigenous children who later developed a psychotic disorder. As risk factors for schizophrenia may be cumulative and interactive, both with each other and with critical periods of neurodevelopmental vulnerability, our results suggest possible causes for the increasing prevalence of psychotic disorders between 1992 and 2015.


New Y-SNPs in QM3 indigenous populations of Colombia.
In evolutionary studies of human populations based on the Y chromosome, the majority of Native Americans belong to the QM3 lineage. Therefore, to study the history of groups inhabiting northern South America, it is necessary to have a higher resolution of the tree. The objective of this work was to identify new SNPs of the QM3 lineage that would allow the evaluation of the phylogenetic relationships between Andean and Amazonian populations of Colombia. Sequences previously obtained from two Y chromosomes of Amazonian populations were used, from which 13 potential SNPs were selected and typed in 171 Amazonian samples from the Vaupés region and in 60 samples from the Pasto, Nasa, Embera, Arhuaco and Kogüi ethnic groups of the Andean region. In addition, the main SNPs/markers (L56, L54, M346, M848, Z780, CTS11780) defining autochthonous Q lineages were typed, along with others defined by different SNPs/markers as reported in the literature (CTS11357, SA05, Z19319, Z5915, and Z19384). It was found that all the new SNPs are present in the Amazonian samples and only 2 of them are shared with the Embera, Nasa and Pasto, but none with the Kogüi and Arhuaco from the northern Andes, in the Colombian Caribbean. Combining the 13 variants of the present study with 14 previously reported and using TMRCA, a new QM3 tree proposal is generated. This method makes it possible to increase the number of sublineages of QM3 with a higher resolution and to detect differences between the different populations of Vaupés in the Amazon, as in the case of the Kubeos and Pisamiras, the latter of which is in grave danger of extinction. These new sublineages are useful for microevolutionary studies of the Amerindian populations of South America.


Invoking Side-Chain Functionality for the Mediation of Regioselectivity during Ring-Opening Polymerization of Glucose Carbonates.
The extent of participation of side-chain functionalities during the 1,5,7-triazabicyclo[5.4.0]dec-5-ene (TBD) organobase-catalyzed ring-opening polymerizations (ROP) of six-membered cyclic d-glucose-based carbonates was found to result in significantly different regiochemical outcomes. High regioselectivity was observed for naturally derived poly(4,6-d-glucose carbonate)s (PGCs) containing carbonate side chain substituents in the 2- and 3-positions, whereas regioirregularity was found for analogous PGCs with ether side-chain substituents. The backbone connectivities and structural details of these PGCs were examined through a combination of comprehensive 1D and 2D NMR studies on unimers and dimers, verifying the ring-opening preferences and indicating the contribution of side-chain functionalities in regioselective ROP processes. A molecular understanding of the curious role of side-chain functionalities was demonstrated via density functional theory calculations, revealing stabilization effects of intermolecular hydrogen bonding between the side-chain functionalities and TBD in the transition states. Overall, this work provides fundamental insights into the organocatalytic ROP of these specific six-membered asymmetric cyclic glucose carbonates. More importantly, these findings serve as a foundation for future design strategies that incorporate adjacent functionalities within monomers to act as directing groups and impart molecular interactions that define regiochemical ring-opening.


Advances in the clinical use of patient-reported outcomes in thoracic surgery.
Patient-reported outcomes (PROs) are increasingly recognized as a clinical tool for measuring and improving patient-centric care. This review provides a summary on recent advances in the use of PROs in the field of thoracic surgery. PROs have been used as primary endpoints in clinical trials and observational studies evaluating clinical care pathways and quantifying the benefits of minimally invasive surgical techniques for patients undergoing lung surgery. Qualitative and quantitative research has yielded fundamental insights into which PRO domains are meaningful and valued by patients after lung surgery. Patient experience and recovery after esophagectomy have been further characterized by using PROs. New disease-specific survey tools for patients have been developed to track long-term symptoms after esophageal reconstruction. Patient satisfaction has emerged as the key metric used to gauge the patient centeredness of hospital systems. Advances have been made in the application of PROs in multiple areas of thoracic surgery, which include lung and esophageal surgery. The growing focus on the use of PROs in clinical pathways has led to a better understanding on how to optimize patient experience.


Chronic administration of the L-type calcium channel blocker nimodipine can facilitate the acquisition of sequence learning in a radial-arm maze.
Nimodipine, a dihydropyridine L-type voltage-gated calcium-channel blocker, was examined for its potential effect on the acquisition of a complex-arm sequence task in an automated radial maze. Young (60-day-old) male Wistar rats were injected with saline or nimodipine (5 mg/kg) 15 min prior to radial maze training, or immediately following the radial maze testing. The results of the learning task (over 7 days of testing) showed that rats injected with nimodipine each training session acquired the task more quickly and more efficiently compared to saline-treated animals. There were no significant differences for rats that were pre-/post-treated with nimodipine during the maze-learning task. The number of incorrect arm entries and number of additional lever presses in the same arm were found to be significantly lower in rats treated with nimodipine compared to saline-injected controls. The beneficial effect of nimodipine treatment occurred only in rats that were acquiring the task, and not in rats that had already learned the arm sequence paradigm. There were no potential non-specific influences on locomotor activity or appetite caused by chronic nimodipine treatments. These results strongly suggest that nimodipine can facilitate the acquisition of a complex learning task.


Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors.
Ibogaine (IBO) is an alkaloid with putative antiaddictive properties, alleviating opiates dependence and withdrawal. The glutamate N-methyl-D-aspartate (NMDA) receptors have been implicated in the physiological basis of drug addiction; accordingly, IBO acts as a noncompetitive NMDA antagonist. The purpose of this study was to evaluate the effects of IBO on naloxone-induced withdrawal syndrome in morphine-dependent mice, focusing on the role of NMDA receptors. Jumping, a major behavioral expression of such withdrawal, was significantly (P<.01) inhibited by IBO (40 and 80 mg/kg, 64.2% and 96.9% inhibition, respectively) and MK-801 (0.15 and 0.30 mg/kg, 67.3% and 97.7%, respectively) given prior to naloxone. Coadministration of the lower doses of IBO (40 mg/kg) and MK-801 (0.15 mg/kg) results in 94.7% inhibition of jumping, comparable to the effects of higher doses of either IBO or MK-801. IBO and MK-801 also significantly inhibited NMDA-induced (99.0% and 71.0%, respectively) jumping when given 30 min (but not 24 h) prior to NMDA in nonaddictive mice. There were no significant differences in [3H]MK-801 binding to cortical membranes from naive animals, morphine-dependent animals, or morphine-dependent animals treated with IBO or MK-801. This study provides further evidence that IBO does have an inhibitory effect on opiate withdrawal symptoms and suggests that the complex process resulting in morphine withdrawal includes an IBO-sensitive functional and transitory alteration of NMDA receptor.


[Frequency of Trichomonas vaginalis infection in couples with fertility problems].
One-hundred and seventy two couples which went for the first time to the Infertility Service of the National Institute of Endocrinology from June 1999 to June 2000, were studied to find out the frequency of Trichomonas vaginalis infection in this group, and determine its interaction with a number of clinical and risk variables. The results yielded that 10.5% were positive to the parasite, the prevailing symptom was leukorrea in women and 96.6% of men showed no symptoms. It was highly significant the fact of having a previous pathological history that might be related to infertility and current T. vaginalis infection. This protozoon was frequently associated with Candida sp. and causative agents of bacterial vaginosis in women and Haemophilus influenzae in men. This parasite seems to play an important role as a likely causative agent to be considered in fertility problems.


Efficacy of a Neurofeedback Training on Attention and Driving Performance: Physiological and Behavioral Measures.
Increased attention and lower stress levels are associated with more functional and safe driving behavior, since they contribute to reduce distractibility and risk-taking at the wheel. Previous neuroscience research highlighted that NeuroFeedback (NF) training mediated by wearable devices could be effective in terms of neurocognitive strengthening and attention regulation with a direct effect on driving attentional performance. Thus, this research aims to test the effectiveness of a NF protocol on a sample of drivers, to observe its impact on attentional skills and psychophysiological levels of stress involved in driving behavior. 50 participants were randomly assigned to the experimental and active control group. The experimental condition consisted of a 21-day mindfulness NF training with incremental duration sessions. A pre- (t0) and post-treatment (t1) assessment included behavioral, psychometric, neuropsychological, and psychophysiological autonomic measures. Specifically, the Driver Behavior Questionnaire (DBQ) and the Active Box (AB) device were used to evaluate the everyday driving behavior. Results underlined an improvement in driving behavior performance and a decrease of violations at the wheel of the experimental group (EXPg) at t1 measured, respectively by AB and DBQ. About the autonomic and neuropsychological measure, an increase in heart rate (HR) and an increased accuracy at the Stroop Task were detected: a specific increase of Stroop-related HR was found for the EXPg at t1. Also, reduced reaction times were found in the Multiple Features Target Cancellation for the EXPg at t1. Overall, the EXPg displayed a physiological, behavioral and neuropsychological increased efficiency related to attention as well as a driving-related behavioral improvement after NF training.


Hardware-Efficient Stochastic Binary CNN Architectures for Near-Sensor Computing.
With recent advances in the field of artificial intelligence (AI) such as binarized neural networks (BNNs), a wide variety of vision applications with energy-optimized implementations have become possible at the edge. Such networks have the first layer implemented with high precision, which poses a challenge in deploying a uniform hardware mapping for the network implementation. Stochastic computing can allow conversion of such high-precision computations to a sequence of binarized operations while maintaining equivalent accuracy. In this work, we propose a fully binarized hardware-friendly computation engine based on stochastic computing as a proof of concept for vision applications involving multi-channel inputs. Stochastic sampling is performed by sampling from a non-uniform (normal) distribution based on analog hardware sources. We first validate the benefits of the proposed pipeline on the CIFAR-10 dataset. To further demonstrate its application for real-world scenarios, we present a case-study of microscopy image diagnostics for pathogen detection. We then evaluate benefits of implementing such a pipeline using OxRAM-based circuits for stochastic sampling as well as in-memory computing-based binarized multiplication. The proposed implementation is about 1,000 times more energy efficient compared to conventional floating-precision-based digital implementations, with memory savings of a factor of 45.


Proteomic Characterization of Epithelial-Like Extracellular Vesicles in Advanced Endometrial Cancer.
Endometrial cancer (EC) is the most frequent gynecological cancer. Tumor dissemination affecting ∼20% of EC patients is characterized at the primary carcinoma by epithelial-to-mesenchymal transition (EMT) associated with myometrial infiltration. At distant sites, the interaction of circulating tumor cells (CTCs) with the microenvironment is crucial for metastatic colonization, with a participation of the extracellular vesicles (EVs). We comprehensively approached these primary and secondary sites to study the impact of tumor EVs on the metastatic efficiency of CTCs in EC. Tumor EVs in circulation reproduce the epithelial phenotype predominant in the primary carcinoma, whereas CTCs are characterized by an EMT phenotype. We modeled this EMT-related clinical scenario in the Hec1A endometrial cell line and characterized the epithelial-like EVs in circulation by SILAC proteome analysis. The identification of proteins involved in cell-cell and cell-matrix interaction and binding, together with in vitro evidence of an improved adhesion of CTC to a functionalized endothelium, suggests a contribution of the epithelial-like EVs in the homing of CTCs at metastatic sites. Accordingly, adhesion protein LGALS3BP was found to be significantly enriched in circulating EVs from a cohort of EC patients with a high risk of recurrence by targeted proteomics (multiple reaction monitoring), highlighting its potential in liquid biopsy in EC.


Barrett's esophagus: combined treatment using argon plasma coagulation and laparoscopic antireflux surgery.
The treatment of Barrett's esophagus is still controversial. Actually, the only method to prevent the development to cancer is endoscopic surveillance, which ensures good results in terms of long-term survival. An ideal treatment capable of destroying columnar metaplasia, followed by squamous epithelium regeneration could potentially result in a decrease of the incidence of adenocarcinoma. Recently most ablative techniques were used, such as photodynamic therapy, ablation therapy with Nd-YAG laser or argon plasma coagulation and endoscopic mucosal resection. We started a prospective study in January 1998, enrolling 94 patients affected by Barrett's esophagus and candidates for antireflux repair in order to assess the effectiveness and the results of endoscopic coagulation with argon plasma combined with surgery in the treatment of uncomplicated Barrett's esophagus. All patients underwent endoscopic treatment with argon plasma; we observed complete response in 68 patients (72.34%), 27 of them (39.7%) underwent antireflux surgery and the other 41 continued medical therapy. Post-operatively 19 patients (70%) underwent regular surveillance endoscopies and in two cases metaplasia recurred. The final objective of these combined treatments should be the complete eradication of metaplastic mucosa. Our experience was that argon plasma coagulation combined with antireflux surgery or proton pump inhibitor therapy gave satisfactory results, even if follow-up is too short to evaluate the potential evolution of metaplasia to cancer. For this reason, we recommend that this technique should be done only in specialized centres and that these patients continue their endoscopic surveillance program.


Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule.
Poly (ADP-ribose) polymerase-1 (PARP1) is a major member of the PARP superfamily that is involved in DNA damage signalling and other important cellular processes. Here we report the development of a small molecule targeting PARP1 based on the PROTAC strategy. In the MDA-MB-231 cell line, the representative compound 3 can induce significant PARP1 cleavage and programmed cell death.


Decision-directed multivariate empirical bayes classification with nonstationary priors.
A decision-directed learning strategy is presented to recursively estimate (i.e., track) the time-varying a priori distribution for a multivariate empirical Bayes adaptive classification rule. The problem is formulated by modeling the prior distribution as a finite-state vector Markov chain and using past decisions to estimate the time evolution of the state of this chain. The solution is obtained by implementing an exact recursive nonlinear estimator for the rate vector of a multivariate discrete-time point process representing the decisions. This estimator obtains the Doob decomposition of the decision process with respect to the a-field generated by all past decisions and corresponds to the nonlinear least squares estimate of the prior distribution. Monte Carlo simulation results are provided to assess the performance of the estimator.


Deriving an optimal threshold of waist circumference for detecting cardiometabolic risk in sub-Saharan Africa.
Waist circumference (WC) thresholds derived from western populations continue to be used in sub-Saharan Africa (SSA) despite increasing evidence of ethnic variation in the association between adiposity and cardiometabolic disease and availability of data from African populations. We aimed to derive a SSA-specific optimal WC cut-point for identifying individuals at increased cardiometabolic risk. We used individual level cross-sectional data on 24 181 participants aged ⩾15 years from 17 studies conducted between 1990 and 2014 in eight countries in SSA. Receiver operating characteristic curves were used to derive optimal WC cut-points for detecting the presence of at least two components of metabolic syndrome (MS), excluding WC. The optimal WC cut-point was 81.2 cm (95% CI 78.5-83.8 cm) and 81.0 cm (95% CI 79.2-82.8 cm) for men and women, respectively, with comparable accuracy in men and women. Sensitivity was higher in women (64%, 95% CI 63-65) than in men (53%, 95% CI 51-55), and increased with the prevalence of obesity. Having WC above the derived cut-point was associated with a twofold probability of having at least two components of MS (age-adjusted odds ratio 2.6, 95% CI 2.4-2.9, for men and 2.2, 95% CI 2.0-2.3, for women). The optimal WC cut-point for identifying men at increased cardiometabolic risk is lower (⩾81.2 cm) than current guidelines (⩾94.0 cm) recommend, and similar to that in women in SSA. Prospective studies are needed to confirm these cut-points based on cardiometabolic outcomes.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.240.


[Experience with the use of sodium oxybutyrate electrophoresis by sinusoidal modulated currents in the combined treatment of patients with stable stenocardia].
Stable angina pectoris (functional class I, II, III) was treated by SHE with sinusoidal modulated current plus sodium chloride baths against placebo plus balneotherapy. Macro- and microcirculatory analysis of cardiovascular function and clinical evidence indicated that the addition of the electrophoresis raises the efficacy of the treatment 2-3-fold. The use of the combination proposed is advocated in prevention and treatment of stable angina pectoris.


Probe-based confocal laser endomicroscopy compared with standard four-quadrant biopsy for evaluation of neoplasia in Barrett's esophagus.
Surveillance of Barrett's esophagus includes endoscopic inspection with biopsy of suspicious lesions followed by four-quadrant biopsy of the remaining mucosa. We assessed the ability of probe-based confocal laser endomicroscopy (pCLE) to replace biopsy in the endoscopic evaluation of patients with Barrett's esophagus in a prospective and controlled setting. A total of 68 patients who were referred for endoscopic assessment of Barrett's esophagus were included across three centers. pCLE recordings were interpreted live during the examination as well as in a blinded manner at least 3 months after endoscopy. pCLE diagnosis of neoplasia based on pre-defined criteria was compared with histopathology from suspicious as well as four-quadrant biopsies. A total of 670 pairs of biopsies and pCLE video sequences were available for analysis, with neoplasia (high-grade dysplasia or cancer) being histologically diagnosed in 8.3 %. Specificity and negative predictive value of pCLE in excluding neoplasia was 0.97 (90 %CI 0.95 - 0.98) and 0.93 (0.91 - 0.95) for the blinded evaluation, and 0.95 (0.90 - 0.98) and 0.92 (0.90 - 0.94) for the on-site assessment. Positive predictive values (PPVs) and sensitivity were rather poor for both settings (46 %/28 % [blinded] and 18 %/12 % [on-site], respectively). pCLE can be regarded as non-inferior to endoscopic biopsy in excluding neoplasia of Barrett's esophagus mucosa. However, due to its low PPV and sensitivity, pCLE may currently not replace standard biopsy techniques for the diagnosis of Barrett's esophagus and associated neoplasia. Further technical development of pCLE and a better understanding of its role in relation to other imaging technologies are necessary.


Techniques for measuring weight bearing during standing and walking.
To classify and assess techniques for measuring the amount of weight bearing during standing and walking. A large variety of weight bearing measuring techniques exists. This review describes their advantages and limitations to assist clinicians and researchers in selecting a technique for their specific application in measuring weight bearing. A literature search was performed in Pubmed-Medline, CINAHL, and EMBASE. Measurement techniques were classified in 'clinical examination', 'scales', 'biofeedback systems', 'ambulatory devices' and 'platforms', and assessed on aspects of methodological quality, application, and feasibility. A total of 68 related articles was evaluated. The clinical examination technique is a crude method to estimate the amount of weight bearing. Scales are useful for static measurements to evaluate symmetry in weight bearing. Biofeedback systems give more reliable, accurate and objective data on weight bearing compared to clinical examination and scales, but the high costs could limit their use in physical therapy departments. The ambulatory devices can measure weight bearing with good accuracy and reliability in the hospital and at home. Platforms have the best methodological quality, but are mostly restricted to a gait laboratory, need trained personnel, and are expensive. The choice of a technique largely depends upon the criteria discussed in this review; however the clinical utilisation, the research question posed, and the available budget also play a role. The new developments seen in the field of 'ambulatory devices' are aimed at extending measuring time, and improved practicality in data collection and data analysis. For these latter devices, however, mainly preliminary studies have been published about devices that are not (yet) commercially available.


Short- and long-term stability of alpha asymmetry in infants: Baseline and affective measures.
Asymmetry in cortical activity was tested for short- and long-term stability during the first year of life. Infants (N = 129) completed a total of four laboratory visits: two visits occurred about 1 week apart when infants were 6 months old, and two visits occurred about 1 week apart when infants were 12 months of age. At each laboratory visit, EEG readings were taken during five 1-min, neutral baselines as well as during a negative and a positive emotion-eliciting task. The stability of hemispheric asymmetry was assessed at midfrontal (F3/4, F7/8) and parietal (P3/4) electrode sites. Asymmetry in baseline and fear-eliciting episodes showed moderate short-term stability. Long-term stability was apparent when assessments were composited at 6 months and 12 months. Frontal asymmetry was greater than parietal asymmetry for baseline recordings. There was minimal evidence for stability in asymmetry during positive emotion tasks. Results are discussed with regard to the collection and interpretation of alpha asymmetry measures during infancy.


Joint principal trend analysis for longitudinal high-dimensional data.
We consider a research scenario motivated by integrating multiple sources of information for better knowledge discovery in diverse dynamic biological processes. Given two longitudinal high-dimensional datasets for a group of subjects, we want to extract shared latent trends and identify relevant features. To solve this problem, we present a new statistical method named as joint principal trend analysis (JPTA). We demonstrate the utility of JPTA through simulations and applications to gene expression data of the mammalian cell cycle and longitudinal transcriptional profiling data in response to influenza viral infections.


A snapshot on prokaryotic diversity of the Solimões River basin (Amazon, Brazil).
The Amazon region has the largest hydrographic basin on the planet and is well known for its huge biodiversity of plants and animals. However, there is a lack of studies on aquatic microbial biodiversity in the Solimões River, one of its main water courses. To investigate the microbial biodiversity of this region, we performed 16S rRNA gene clone libraries from Solimões River and adjacent rivers and lakes. Our question was which microorganisms inhabit the different types of aquatic environments in this part of the basin, and how diversity varies among these environments (rivers and lakes). The microbial diversity generating 13 clone libraries of the bacterial 16S rRNA gene and 5 libraries of the archaeal 16S rRNA gene was assessed. Diversity measured by several alpha diversity indices (ACE, Chao, Shannon and Simpson) revealed significant differences in diversity indices between lake and river samples. The site with higher microbial diversity was in the Solimões River (4S), downstream the confluence with Purus River. The most common bacterial taxon was the cosmopolitan Polynucleobacter genus, widely observed in all samples. The phylum Thaumarchaeota was the prevailing archaeal taxon. Our results provide the first insight into the microbial diversity of the world's largest river basin.


A comparison of gait patterns between the offspring of people with medial tibiofemoral osteoarthritis and normal controls.
The aim of this study was to explore the contribution of biomechanical factors to the development and progression of knee osteoarthritis (OA) by investigating whether the offspring of subjects with medial tibiomfemoral OA demonstrate gait abnormalities in the absence of OA. Three-dimensional gait analyses were performed on 9 offspring of people with medial tibiofemoral OA and 9 age, gender and Body Mass Index (BMI) matched individuals with no parental history of knee OA. External knee adduction, extension and flexion moments, as well as the magnitude of foot rotation during early stance were compared between the groups. The offspring of people with medial tibiofemoral OA walked with less external rotation at the foot than control subjects during early stance (4.5 degrees versus 13.5 degrees, p < 0.01). There were no significant differences between groups for the peak knee adduction moments (dominant leg, p = 0.49; non-dominant leg, p = 0.70) or peak knee extension moments (dominant leg, p = 0.46; non-dominant leg, p = 0.48). Moreover, there was no difference between groups for the knee flexion moment occurring when the force adducting the knee was greatest (dominant leg, p = 0.35; non-dominant leg, p = 0.33). Although the offspring of people with medial tibiofemoral OA walked with less external foot rotation than the control subjects during early stance, whether this increases their risk of developing knee OA is yet to be determined.


Achieving Drug and Alcohol Abstinence Among Recently Incarcerated Homeless Women: A Randomized Controlled Trial Comparing Dialectical Behavioral Therapy-Case Management With a Health Promotion Program.
Homeless female ex-offenders (homeless female offenders) exiting jail and prison are at a critical juncture during reentry and transitioning into the community setting. The purpose of the study was to compare the effect of a dialectical behavioral therapy-case management (DBT-CM) program with a health promotion (HP) program on achieving drug and alcohol abstinence among female parolees/probationers residing in the community. We conducted a multicenter parallel randomized controlled trial with 130 female parolees/probationers (aged 19-64 years) residing in the community randomly assigned to either DBT-CM (n = 65) or HP (n = 65). The trial was conducted in four community-based partner sites in Los Angeles and Pomona, California, from February 2015 to November 2016. Treatment assignment was carried out using a computer-based urn randomization program. The primary outcome was drug and alcohol use abstinence at 6-month follow up. Analysis was based on data from 116 participants with complete outcome data. Multivariable logistic regression revealed that the DBT-CM program remained an independent positive predictor of decrease in drug use among the DBT-CM participants at 6 months (p = .01) as compared with the HP program participants. Being non-White (p < .05) and having higher depressive symptom scores (p < .05) were associated with lower odds of drug use abstinence (i.e., increased the odds of drug use) at 6 months. DBT-CM increased drug and alcohol abstinence at 6-month follow-up, compared to an HP program.


True-3D accentuating of grids and streets in urban topographic maps enhances human object location memory.
Cognitive representations of learned map information are subject to systematic distortion errors. Map elements that divide a map surface into regions, such as content-related linear symbols (e.g. streets, rivers, railway systems) or additional artificial layers (coordinate grids), provide an orientation pattern that can help users to reduce distortions in their mental representations. In recent years, the television industry has started to establish True-3D (autostereoscopic) displays as mass media. These modern displays make it possible to watch dynamic and static images including depth illusions without additional devices, such as 3D glasses. In these images, visual details can be distributed over different positions along the depth axis. Some empirical studies of vision research provided first evidence that 3D stereoscopic content attracts higher attention and is processed faster. So far, the impact of True-3D accentuating has not yet been explored concerning spatial memory tasks and cartography. This paper reports the results of two empirical studies that focus on investigations whether True-3D accentuating of artificial, regular overlaying line features (i.e. grids) and content-related, irregular line features (i.e. highways and main streets) in official urban topographic maps (scale 1/10,000) further improves human object location memory performance. The memory performance is measured as both the percentage of correctly recalled object locations (hit rate) and the mean distances of correctly recalled objects (spatial accuracy). It is shown that the True-3D accentuating of grids (depth offset: 5 cm) significantly enhances the spatial accuracy of recalled map object locations, whereas the True-3D emphasis of streets significantly improves the hit rate of recalled map object locations. These results show the potential of True-3D displays for an improvement of the cognitive representation of learned cartographic information.


The effect of a patient education booklet and BP 'tracker' on knowledge about hypertension. A randomized controlled trial.
Home blood pressure (BP) monitoring is increasingly prevalent. The Canadian Hypertension Education Program (CHEP) developed a Family Practice BP tracking diary for home readings with an educational booklet. We evaluated the effectiveness of these tools compared with the standard approach of a hypertension information leaflet on BP-related knowledge, attitudes and behaviours of hypertensive family practice patients. Single-blind randomized control trial on patients with raised BP. Three practices in Ontario, Quebec and Nova Scotia recruited a total of 109 eligible patients. The average age was 66.1 (SD 9.3) years and 58 (54.7%) were male. There was a statistically significant increase in the mean number of correct responses to 20 hypertension knowledge questions of 1.14 from 15.3 (SD 2.2) at baseline to 16.4 (SD 2.2) at 3 months in both groups (n=72, P<0.001). Patients frequently did not realize that usually more than one drug plus lifestyles changes were necessary to reduce BP to target or that it might take 6 weeks for some drugs to achieve their full effect. The BP tracking diary and the booklet had positive evaluation from the patients. Most patients have a good baseline of knowledge about hypertension but there are still important areas that need to be addressed. The booklet and tracker were well received by patients but the simple leaflet was as effective at improving knowledge.


Peripheral B Cell Deficiency and Predisposition to Viral Infections: The Paradigm of Immune Deficiencies.
In the era of COVID-19, understanding how our immune system responds to viral infections is more pertinent than ever. Immunodeficiencies with very low or absent B cells offer a valuable model to study the role of humoral immunity against these types of infection. This review looks at the available evidence on viral infections in patients with B cell alymphocytosis, in particular those with X-linked agammaglobulinemia (XLA), Good's syndrome, post monoclonal-antibody therapy and certain patients with Common Variable Immune Deficiency (CVID). Viral infections are not as infrequent as previously thought in these conditions and individuals with very low circulating B cells seem to be predisposed to an adverse outcome. Particularly in the case of SARS-CoV2 infection, mounting evidence suggests that peripheral B cell alymphocytosis is linked to a poor prognosis.


The functions of EF-hand proteins from host and zoonotic pathogens.
EF-hand proteins not only regulate biological processes, but also influence immunity and infection. In this review, we summarize EF-hand proteins' functions in host and zoonotic pathogens, with details in structures, Ca2+ affinity, downstream targets and functional mechanisms. Studies entitled as EF-hand-related but with less solid features were also discussed. We believe it could raise cautions and facilitate proper research strategy for researchers.


Consistent within-individual plasticity is sufficient to explain temperature responses in red deer reproductive traits.
Warming global temperatures are affecting a range of aspects of wild populations, but the exact mechanisms driving associations between temperature and phenotypic traits may be difficult to identify. Here, we use a 36-year data set on a wild population of red deer to investigate the causes of associations between temperature and two important components of female reproduction: timing of breeding and offspring size. By separating within- versus between-individual associations with temperature for each trait, we show that within-individual phenotypic plasticity (changes within a female's lifetime) was entirely sufficient to generate the observed population-level association with temperature at key times of year. However, despite apparently adequate statistical power, we found no evidence of any variation between females in their responses (i.e. no "IxE" interactions). Our results suggest that female deer show plasticity in reproductive traits in response to temperatures in the year leading up to calving and that this response is consistent across individuals, implying no potential for either selection or heritability of plasticity. We estimate that the plastic response to rising temperatures explained 24% of the observed advance in mean calving date over the study period. We highlight the need for comparable analyses of other systems to determine the contribution of within-individual plasticity to population-level responses to climate change.


Sex Differences in the Age of Peak Marathon Race Time.
Recent studies showed that women were older than men when achieving their fastest marathon race time. These studies, however, investigated a limited sample of athletes. We investigated the age of peak marathon performance in a large sample of female and male marathon finishers by using data from all finishers. We analyzed the age of peak marathon performance in 1-year and 5-year age intervals of 451,637 runners (i.e. 168,702 women and 282,935 men) who finished the 'New York City Marathon' between 2006 and 2016, using analysis of variance and non-linear regression analysis. During these 11 years, men were faster and older than women, the participation of women increased disproportionately to that of men resulting in a decrease of the male-to-female ratio, and relatively more women participated in the younger age groups. Most women were in the age group 30-34 years and most men in the age group 40-44 years. The fastest race time was shown at 29.7 years in women and 34.8 years in men in the 1-year age intervals, and in age group 30-34 years in women and 35-39 years in men in the 5-year age intervals. In contrast to existing findings reporting a higher age of peak marathon performance in women compared to men, we found that women achieved their best marathon race time ~5 years earlier in life than men in both 1-year and 5-year age intervals. Female athletes and their coaches should plan to achieve their fastest marathon race time at the age of ~30 years.


Criminogenic risk assessment: A meta-review and critical analysis.
A vast body of research underlies the ascendancy of criminogenic risk assessment, which was developed to predict recidivism. It is unclear, however, whether the empirical evidence supports its expansion across the criminal legal system. This meta-review thus attempts to answer the following questions: 1) How well does criminogenic risk assessment differentiate people who are at high risk of recidivism from those at low risk of recidivism? 2) How well do researchers' conclusions about (1) match the empirical evidence? 3) Does the empirical evidence support the theory, policy, and practice recommendations that researchers make based on their conclusions? A systematic literature search identified 39 meta-analyses and systematic reviews that met inclusion criteria. Findings from these meta-analyses and systematic reviews are summarized and synthesized, and their interpretations are critically assessed. We find that criminogenic risk assessment's predictive performance is based on inappropriate statistics, and that conclusions about the evidence are inconsistent and often overstated. Three thematic areas of inferential overreach are identified: contestable inferences from criminalization to criminality, from prediction to explanation, and from prediction to intervention. We conclude by exploring possible reasons for the mismatch between proponents' conclusions and the evidence, and discuss implications for policy and practice.


Neuroprotective and neurotrophic efficacy of phytoestrogens in cultured hippocampal neurons.
Epidemiological data from retrospective and case-control studies have indicated that estrogen replacement therapy (ERT) can decrease the risk of developing Alzheimer's disease. In addition, ERT has been found to promote cellular correlates of memory and to promote neuronal survival both in vivo and in vitro. Phytoestrogens have been proposed as potential alternatives to ERT. To determine whether phytoestrogens exert estrogen agonist effect in neural tissue, investigations of neuroprotective and neurotrophic efficacy of phytoestrogens were conducted. Six phytoestrogens, genistein, genistin, daidzein, daidzin, formononetin, and equol, were tested for their neuroprotective efficacy against two toxic insults, glutamate excitotoxicity and beta-amyloid(25-35). Neuronal membrane damage was quantitatively measured by lactate dehydrogenase (LDH) release, and neuronal mitochondrial viability was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromid (MTT) assay. Results of these studies demonstrated that all phytoestrogens induced a modest but significant reduction in LDH release following exposure to glutamate and beta-amyloid(25-35). In contrast, none of phytoestrogens induced a significant increase in reduced MTT levels, which occurred in the presence of a full estrogen agonist, 17beta-estradiol. Analysis of the neurotrophic potential of genistein and daidzein, two phytoestrogens that exerted a significant reduction in LDH release, demonstrated that neither of these molecules promoted hippocampal neuron process outgrowth. Results of these analyses indicate that although phytoestrogens exert a neuroprotective effect at the plasma membrane, they do not sustain neuron mitochondrial viability nor do they induce cellular correlates of memory as neurite outgrowth and synaptogenesis are putative mechanisms of memory. Data derived from these investigations would predict that phytoestrogens could exert some neuroprotective effects analogous to that of antioxidants, but that these molecules are not functional equivalents to endogenously active 17beta-estradiol or to estrogen replacement formulations and, therefore, would raise the concern that they may not reduce the risk of Alzheimer's disease or sustain memory function in postmenopausal women.


Isolation and characterization of a major tandem repeat family from the human X chromosome.
We report the identification and characterization of a family of repeated restriction fragments whose molecular organization is apparently specific to the human X chromosome. This fragment, identified as an ethidium bromide-staining 2.0 kilobase (kb) band in BamHI-digested DNA from a Chinese hamster-human somatic cell hybrid containing a human X chromosome, has been cloned into pBR325 and characterized. The 2.0 kb repeated family has been assigned to the Xp11 leads to Xq12 region on the X by Southern blot analysis of somatic cell hybrids and is predominantly arranged in tandem clusters of up to seven 2.0 kb monomers. Homologous DNA sequences, not organized as 2.0 kb BamHI fragments, are found elsewhere on the X chromosome and on at least some autosomes, but are not found on the Y chromosome. From a dosing experiment using various amounts of the cloned repeat, we estimate that there are 5,000-7,500 copies of the 2.0 kb BamHI repeat per haploid genome. Since the vast majority, if not all, of these are confined to the X chromosome, this repeated DNA family must account for 5-10% of all X chromosome DNA and must constitute the major sequence component of the pericentromeric region of the X.


A method for identifying satiation versus extinction effects under noncontingent reinforcement schedules.
We evaluated one method for determining whether response suppression under noncontingent reinforcement (NCR) is a function of satiation or extinction. Three individuals with developmental disabilities who engaged in self-injurious behavior (SIB) or aggression participated. Results of functional analyses indicated that their problem behavior was maintained by social-positive reinforcement. NCR procedures, individualized for each participant, were implemented in a multiple baseline across subjects design and were associated with decreases in all participants' problem behavior. Identification of the mechanism by which NCR produced these effects was based on examination of cumulative records showing response patterns during and immediately following each NCR session. Satiation during NCR should lead to a temporary increase in responding during the post-NCR (extinction) period due to a transition from the availability to the unavailability of reinforcement (satiation to deprivation). Alternatively, extinction during NCR should reveal no increase in responding during the extinction period because the contingency for the problem behavior would remain unchanged and the transition from satiation to deprivation conditions would be irrelevant. Results suggested that the operative mechanisms of NCR were idiosyncratic across the 3 participants and appeared to change during treatment for 1 of the participants.


Pulmonary inflammatory myofibroblastic tumor associated with nephrotic syndrome.
Inflammatory myofibroblastic tumor (IMT) of the lung is a benign, non-metastasizing tumor with the possibility of local infiltration, recurrence or persistent local growth. This kind of tumor arises due to an unregulated growth of inflammatory cells. To our knowledge, IMT associated with nephrotic syndrome has not yet been recognized. Therefore, we present the case of a 14-year-old girl with lung IMT associated with secondary nephrotic syndrome (NS), which was cured after tumor removal.


Telomere length and outcomes in ischaemic heart failure: data from the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA).
Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth. We measured leucocyte telomere length in 3275 patients with chronic ischaemic systolic heart failure participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) study. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, which occurred in 575 patients during follow-up. We observed a significant association of leucocyte telomere lengths with the primary endpoint (hazard ratio 1.10; 95% confidence interval 1.01-1.20; P=0.03). However, this observation was not superior to age as defined by date of birth. The neutral effect of rosuvastatin treatment on clinical outcomes was not modified by baseline telomere length. Biological age as defined by leucocyte telomere length was associated with clinical outcomes in patients with ischaemic heart failure, but this association did not add prognostic information above age as defined by date of birth.


THC (Δ9-Tetrahydrocannabinol) Exerts Neuroprotective Effect in Glutamate-affected Murine Primary Mesencephalic Cultures Through Restoring Mitochondrial Membrane Potential and Anti-apoptosis Involving CB1 Receptor-dependent Mechanism.
Aging-related neurodegenerative diseases, such as Parkinson's disease (PD) or related disorders, are an increasing societal and economic burden worldwide. Δ9-Tetrahydrocannabinol (THC) is discussed as a neuroprotective agent in several in vitro and in vivo models of brain injury. However, the mechanisms by which THC exhibits neuroprotective properties are not completely understood. In the present study, we investigated neuroprotective mechanisms of THC in glutamate-induced neurotoxicity in primary murine mesencephalic cultures, as a culture model for PD. Glutamate was administered for 48 h with or without concomitant THC treatment. Immunocytochemistry staining and resazurin assay were used to evaluate cell viability. Furthermore, superoxide levels, caspase-3 activity, and mitochondrial membrane potential were determined to explore the mode of action of this compound. THC protected dopaminergic neurons and other cell types of primary dissociated cultures from glutamate-induced neurotoxicity. Moreover, THC significantly counteracted the glutamate-induced mitochondrial membrane depolarization and apoptosis. SR141716A, a CB1 receptor antagonist, concentration-dependently blocked the protective effect of THC in primary mesencephalic cultures. In conclusion, THC exerts anti-apoptotic and restores mitochondrial membrane potential via a mechanism dependent on CB1 receptor. It strengthens the fact that THC has a benefit on degenerative cellular processes occurring, among others, in PD and other neurodegenerative diseases by slowing down the progression of neuronal cell death. Copyright © 2016 John Wiley & Sons, Ltd.


[Characteristics of adolescent pregnancy in São Luís, Maranhão, Brazil].
To identify the main socioeconomic, demographic, anthropometric and behavioral characteristics, and pregnancy outcomes of adolescent pregnancy and to assess health services used by pregnant adolescents. Data were collected from a cross-section of 2,429 deliveries by women residing in the municipality of São Luís, Brazil, of which 94% were hospital births. Women were categorized into six age groups. The two groups of teenagers (under 18 and 18-19 years) were compared to four groups of older women. Comparison was also made between the two teenage groups. The chi-square test was used to compare proportions and prevalence ratio was used as an effect measure. Of 2,429 women, 714 (29.4%) were adolescents. Their specific fertility coefficient was higher than in other regions of the country. Adolescents showed lower socioeconomic and reproductive conditions than older women and a higher proportion of inadequate prenatal care. The majority had no partner. They had the lowest percentages of caesarean section and smokers. Despite their equally unfavorable socioeconomic situation, 18-19 year-old adolescents had pregnancy outcomes comparable to the age group 25-29, whereas those under 18 had the highest proportions of low birth weight, preterm birth, and infant mortality rate. This suggests that biologic immaturity may be associated with adverse pregnancy outcomes.


Muscle quantity is not synonymous with muscle quality.
Greater muscle mass can generally produce greater muscle strength. However, whether higher muscle mass is associated with higher muscle quality (muscle strength relative to muscle mass) remains unknown. Furthermore, the nature of this relationship, and how their interaction determines the presence of functional impairments are unknown. This article aims to address these issues. Secondary data analysis including 1219 women aged 75 years and older of the Toulouse ÉPIDemiologie de l'OSteoporose cohort study. Body composition (dual energy X-ray absorptiometry), handgrip, and knee extension strength were assessed. Physical function was measured using the chair stand test as well as the usual and fast gait speed tests. Participants were also asked if they experienced any difficulty in performing functional tasks. Upper- and lower-body muscle quality (r = -0.42, P < .001 and r = -0.16, P < .001, respectively) were significantly and negatively correlated with appendicular skeletal muscle mass index (ASMI). Independently of ASMI, individuals with high muscle quality had low risks of functional impairments (odds ratio <0.74), whereas individuals with high ASMI but low muscle quality had high risks of impairments (odds ratio >1.27). This inverse relationship between muscle mass and quality implies that sarcopenic individuals have better muscle quality than nonsarcopenic individuals. Results also suggest that high muscle quality may compensate for low ASMI with respect to functional impairments. Physical activity may potentially be involved in this relationship.


Developmental dysplasia of the hip. Prevention and real incidence.
The controversy over the incidence of developmental dysplasia of the hip (DDH) stems mainly from an ambiguity of criteria for defining a genuinely pathologic neonatal hip. The aim of this study was to identify those neonatal hips which, if left untreated, would develop any kind of dysplasia and, therefore, are to be included in the determination of DDH incidence. Clinical and ultrasonographic examinations for DDH were performed on 4356 neonatal hips. Newborns with skeletal deformities, neurologic/muscular disorders, and neural tube defects were excluded. Hips that featured any type of sonographic pathology were reexamined at 2 or 6 weeks, depending on the severity of the findings. Only hips in which the initial pathology was not improved or had deteriorated were treated; all others were examined periodically until the age of 12 months. Sonographic screening of 4356 hips detected 301 instances of deviation from normal, indicating a sonographic DDH incidence of 69.5 per 1000. However, only 21 hips remained abnormal and required treatment, indicating a true DDH incidence of 4.8 per 1000 hips. All the others evolved into normal hips, and no additional instances of DDH were found on follow-up throughout the 12 months. These findings enables us to distinguish two categories of neonatal hip pathology: one that eventually develops into a normal hip (essentially sonographic DDH); and another that will deteriorate into a hip with some kind of dysplasia, including full dislocation (true DDH). This approach seems to allow for a better-founded definition of DDH, for an appropriate determination of its incidence, for decision-making regarding treatment, and for assessment of the cost-effectiveness of screening programs for the early detection of DDH (Tab. 2, Ref. 15).


Multidrug resistance in ocular melanoma.
Metastatic disease in patients with ocular melanoma is resistant to chemotherapy. One of the main mechanisms of modulating multidrug resistance is the expression of the multidrug resistance gene 1 (MDR1) product (p-glycoprotein) by tumour cells. The purpose of this study was to evaluate the frequency of expression of the MDR1 gene in ocular melanoma whose primary treatment was surgical excision or enucleation. Twelve recent ocular melanomas were received fresh, snap frozen and cryostat sections of tumour were analysed for expression of MDR1 by immunohistochemistry using a well characterised monoclonal antibody to MDR1. Tumour explants were established in short term tissue culture from four tumours and cell blocks were examined by immunohistochemistry. MDR1 expression was present in five of 12 ocular melanomas. Upregulation of protein expression was found in four cell lines established in short term culture from tumour explants. A recurrent tumour, initially treated by local excision and radioactive plaque, showed overexpression of MDR1 mRNA. These results suggest that significant level of MDR1 may be intrinsically present in ocular melanomas before exposure to drugs involved in multidrug resistance, and indicate the possible importance of MDR1 in modulating chemoresistance in ocular melanoma. Chemosensitisation may be of potential value in planning adjuvant chemotherapy for patients with metastatic disease.


Little evidence for Cope's rule from Bayesian phylogenetic analysis of extant mammals.
According to Cope's rule, lineages tend to evolve towards larger body size, possibly because of selective advantages of being large. The status of Cope's 'rule' remains controversial as it is supported in some but not all large-scale fossil studies. Here, we test for Cope's rule by Bayesian analyses of average body masses of 3253 extant mammal species on a dated phylogenetic tree. The data favour a model that does not assume Cope's rule. When Cope's rule is assumed, the best estimate of its strength is an average ancestor-descendant increase in body size of only 0.4%, which sharply contrasts with the 9% bias estimated from fossil mammals. Thus, we find no evidence for Cope's rule from extant mammals, in agreement with earlier analyses of existing species, which also did not find support for Cope's rule.


Image registration using adaptive polar transform.
Image registration is an essential step in many image processing applications that need visual information from multiple images for comparison, integration, or analysis. Recently, researchers have introduced image registration techniques using the log-polar transform (LPT) for its rotation and scale invariant properties. However, it suffers from nonuniform sampling which makes it not suitable for applications in which the registered images are altered or occluded. Inspired by LPT, this paper presents a new registration algorithm that addresses the problems of the conventional LPT while maintaining the robustness to scale and rotation. We introduce a novel adaptive polar transform (APT) technique that evenly and effectively samples the image in the Cartesian coordinates. Combining APT with an innovative projection transform along with a matching mechanism, the proposed method yields less computational load and more accurate registration than that of the conventional LPT. Translation between the registered images is recovered with the new search scheme using Gabor feature extraction to accelerate the localization procedure. Moreover an image comparison scheme is proposed for locating the area where the image pairs differ. Experiments on real images demonstrate the effectiveness and robustness of the proposed approach for registering images that are subjected to occlusion and alteration in addition to scale, rotation, and translation.


The dopamine transporter gene, a spectrum of most common risky behaviors, and the legal status of the behaviors.
This study tests the specific hypothesis that the 9R/9R genotype in the VNTR of the dopamine transporter gene (DAT1) exerts a general protective effect against a spectrum of risky behaviors in comparison to the 10R/9R and 10R/10R genotypes, drawing on three-time repeated measures of risky behaviors in adolescence and young adulthood on about 822 non-Hispanic white males from the Add Health study. Our data have established two empirical findings. The first is a protective main effect in the DAT1 gene against risky behaviors. The second finding is that the protective effect varies over age, with the effect prominent at ages when a behavior is illegal and the effect largely vanished at ages when the behavior becomes legal or more socially tolerated. Both the protective main effect and the gene-lifecourse interaction effect are replicated across a spectrum of most common risky behaviors: delinquency, variety of sexual partners, binge drinking, drinking quantity, smoking quantity, smoking frequency, marijuana use, cocaine use, other illegal drug use, and seatbelt non-wearing. We also compared individuals with the protective genotype and individuals without it in terms of age, physical maturity, verbal IQ, GPA, received popularity, sent popularity, church attendance, two biological parents, and parental education. These comparisons indicate that the protective effect of DAT1*9R/9R cannot be explained away by these background characteristics. Our work demonstrates how legal/social contexts can enhance or reduce a genetic effect on risky behaviors.


Differences between men and women in dietary intakes and metabolic profile in response to a 12-week nutritional intervention promoting the Mediterranean diet.
Few studies have compared men and women in response to nutritional interventions but none has assessed differences between men and women in the response to a nutritional intervention programme based on the self-determination theory (SDT) and using the Mediterranean diet (MedDiet) as a model of healthy eating, in a context of CVD prevention and within a non-Mediterranean population. The present study aimed to document differences between men and women in changes in dietary, anthropometric and metabolic variables, in response to a nutritional intervention programme promoting the adoption of the MedDiet and based on the SDT. A total of sixty-four men and fifty-nine premenopausal women presenting risk factors for CVD were recruited through different media advertisements in the Québec City Metropolitan area (Canada). The 12-week nutritional programme used a motivational interviewing approach and included individual and group sessions. A validated FFQ was administered to evaluate dietary intakes from which a Mediterranean score (Medscore) was derived. Both men and women significantly increased their Medscore in response to the intervention (P < 0·0001). Men showed a significantly greater decrease in red and processed meat (-0·4 (95 % CI -0·7, -0·1) portions per d) and a greater increase in fruit (0·9 (95 % CI 0·2, 1·6) portions per d) intakes than women. Significant decreases were observed for BMI and waist circumference in both men and women (P ≤ 0·04). Significant greater decreases were found for total cholesterol (total-C):HDL-cholesterol (HDL-C) (-0·2; 95 % CI -0·4, -0·03) and TAG:HDL-C (-0·2; 95 % CI -0·4, -0·04) ratios in men than in women. When adjusting for the baseline value of the response variable, differences between men and women became non-significant for red and processed meat and fruit intakes whereas significant differences between men and women (i.e. larger increases in men than women) were observed for legumes, nuts and seeds (0·6 (95 % CI 0·2, 1·0) portions per d) and whole-grain products (0·5 (95 % CI 0·01, 1·0) portions per d) intakes. For metabolic variables, differences between men and women became non-significant for total-C:HDL-C and TAG:HDL-C ratios when adjusted for the baseline value of the response variable. The present results suggest that the nutritional intervention promoting the adoption of the Mediterranean diet and based on the SDT led to greater improvements in dietary intakes in men than in women, which appear to have contributed to beneficial anthropometric and metabolic changes, more particularly in men. However, the more deteriorated metabolic profile found in men at baseline seems to contribute to a large extent to the more beneficial changes in CVD risk factors observed in men as compared with women.


Adaptation Duration Dissociates Category-, Image-, and Person-Specific Processes on Face-Evoked Event-Related Potentials.
Several studies demonstrated that face perception is biased by the prior presentation of another face, a phenomenon termed as face-related after-effect (FAE). FAE is linked to a neural signal-reduction at occipito-temporal areas and it can be observed in the amplitude modulation of the early event-related potential (ERP) components. Recently, macaque single-cell recording studies suggested that manipulating the duration of the adaptor makes the selective adaptation of different visual motion processing steps possible. To date, however, only a few studies tested the effects of adaptor duration on the electrophysiological correlates of human face processing directly. The goal of the current study was to test the effect of adaptor duration on the image-, identity-, and generic category-specific face processing steps. To this end, in a two-alternative forced choice familiarity decision task we used five adaptor durations (ranging from 200-5000 ms) and four adaptor categories: adaptor and test were identical images-Repetition Suppression (RS); adaptor and test were different images of the Same Identity (SameID); adaptor and test images depicted Different Identities (DiffID); the adaptor was a Fourier phase-randomized image (No). Behaviorally, a strong priming effect was observed in both accuracy and response times for RS compared with both DiffID and No. The electrophysiological results suggest that rapid adaptation leads to a category-specific modulation of P100, N170, and N250. In addition, both identity and image-specific processes affected the N250 component during rapid adaptation. On the other hand, prolonged (5000 ms) adaptation enhanced, and extended category-specific adaptation processes over all tested ERP components. Additionally, prolonged adaptation led to the emergence of image-, and identity-specific modulations on the N170 and P2 components as well. In other words, there was a clear dissociation among category, identity-, and image-specific processing steps in the case of longer (3500 and 5000 ms) but not for shorter durations (< 3500 ms), reflected in the gradual reduction of N170 and enhancement of P2 in the No, DiffID, SameID, and RS conditions. Our findings imply that by manipulating adaptation duration one can dissociate the various steps of human face processing, reflected in the ERP response.


Overexpression of Tyrosine hydroxylase and Dopa decarboxylase associated with pupal melanization in Spodoptera exigua.
Melanism has been found in a wide range of species, but the molecular mechanisms involved remain largely elusive. In this study, we studied the molecular mechanisms of the pupal melanism in Spodoptera exigua. The full length cDNA sequences of tyrosine hydroxylase (TH) and dopa decarboxylase (DDC), two key enzymes in the biosynthesis pathway of melanin, were cloned, and their temporal expression patterns in the integument were compared during the larval-pupal metamorphosis process of the S. exigua wild type (SEW) and melanic mutant (SEM) strains. No amino acid change in the protein sequence of TH and DDC was found between the two strains. Both DDC and TH were significantly over-expressed in the integument of the SEM strain at late-prepupa and 0 h pupa, respectively, compared with those of the SEW strain. Feeding 5(th) instar larvae of SEM with diets incorporated with 1 mg/g of the DDC inhibitor L-α-Methyl-DOPA and 0.75 mg/g of the TH inhibitor 3-iodo-tyrosine (3-IT) resulted in 20% pupae with partially-rescued phenotype and 68.2% of pupae with partially- or fully-rescued phenotype, respectively. These results indicate that overexpressions of TH and DDC are involved in the pupal melanization of S. exigua.


Prevalence of intracranial aneurysms in first-degree relatives of patients with aneurysms.
A familial predisposition toward cerebral aneurysms has been previously described in patients with two or more affected family members. In the present study the familial incidence of unruptured intracranial aneurysms was studied in 96 patients with at least one first-degree relative (parent, sibling, or child) in whom a cerebral aneurysm was diagnosed. All patients were between 20 and 70 years of age and underwent three-dimensional fast-spin echo magnetic resonance imaging. Sixty-one patients (63.5%) were women. The majority of patients (84%) were caucasian and the remainder were Hispanic (13%) or African-American (3%). No patient suffered a medical condition (excluding hypertension and smoking) known to be associated with cerebral aneurysm formation. In four patients at least one aneurysm was found (two harbored multiple aneurysms). Three of the four patients were women. Two of the patients were siblings. The estimated prevalence in first-degree relatives was 4.2% (95% confidence interval 1.2-10.1). Of note, the mean age in the current study population was 39 years. The authors of recent metaanalyses have suggested that the prevalence of nonfamilial aneurysms is approximately 2%, despite earlier reports in which higher figures were cited. The authors conclude that first-degree relatives of patients with aneurysms are at higher risk for harboring an intracranial aneurysm.


Some features of traffic accidents.
Some aspects of urban and rural traffic accidents have been studied at the scene of some accidents in Birmingham and the county of Worcestershire. Accidents to pedestrians are essentially an urban problem, occur mainly at low speed, and most of the serious injury comes from the initial contact with the vehicle, rather than from secondary impacts with the road surface. The characteristics of motor-cycle accidents are more varied; in urban areas there are many side impacts, with consequent injury to the lower limbs, while rural collisions are predominantly front on, with a high incidence of head injury. Accidents to car occupants vary according to the environment.


The Effects of Active Warming on Core Body Temperature and Thermal Comfort in Patients After Transurethral Resection of the Prostate: A Randomized Clinical Trial.
Prevention and treatment of hypothermia by active warming in perioperative period care is recommended but scientific evidence of its effectiveness in a clinical setting is scarce. The purpose of this study was to determine the effects of warmed intravenous fluids (WIVF) on the core body temperature and the patients' thermal comfort. Baseline data of 105 male patients undergoing TUR-P surgery and bladder irrigation were analyzed. The experimental group was warmed using active WIVF, and the control group's routine care was conducted using a cotton blanket. Body temperature was higher in patients in the experimental group than those in the control group. Repeated measures Manova revealed significantly different core temperature changes between groups (F = 34.446, p = .001). The thermal comfort scores were also higher in the experimental group than in the control group (x2 = 203.552, p = .001). The findings indicated that WIVF can enhance body temperature and improve the thermal comfort of patients.


The solvent dynamics at pore surfaces in molecular gels studied by field-cycling magnetic resonance relaxometry.
The molecular dynamics of the solvent molecules at liquid-solid interfaces in low molecular mass gels and in bulk solvents have been identified and characterized with the aid of field-cycling NMR relaxometry. The gels are formed using ethylene glycol (EG) and 1,3-propanediol (PG) with different concentrations of 4,6,4',6'-O-terephthalylidene-bis(methyl α-D-glucopyranoside) (gelator 1). The spin-lattice relaxation times of bulk solvents measured in the function of Larmor frequency were analyzed assuming the intramolecular and intermolecular dipole-dipole interactions. For analysis of the relaxation data for confined solvents the two-phase fast-exchange model was assumed. It was found that in a low-frequency range a dominating NMR relaxation mechanism of solvent interacting with internal surfaces of pores in studied molecular gels is reorientation mediated by translational displacements (RMTD). This dynamic process allows us to explain a very long correlation time of the order of 10(-5) s calculated for confined EG molecules and an even longer one for PG. The RMTD contribution to the relaxation is described by power-law frequency dependence. In the 1/EG gels the exponent is equal to 0.5 for all gelator concentrations suggesting the equipartition of the diffusion modes with different wavelengths. In this gel the relaxation dispersion data were transformed to a susceptibility representation and a "master-like" curve was constructed. In the 1/PG gel the exponent varies in the function of gelator concentration. Different behavior of the relaxation dispersion shape is due to the relative sizes of the ordered (at surface) and bulk-like phase. In the 1/EG gel the surface layer of the ordered molecules is always much smaller than the dimensions of the gel cavities whereas it differs in the 1/PG gel as a consequence of the disruption of the PG aggregates due to the solvent-gelator interaction.


MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat.
HIV-1 protease (PR) cleavage of the Gag polyprotein triggers the assembly of mature, infectious particles. Final cleavage of Gag occurs at the junction helix between the capsid protein CA and the SP1 spacer peptide. Here we used MicroED to delineate the binding interactions of the maturation inhibitor bevirimat (BVM) using very thin frozen-hydrated, 3D microcrystals of a CTD-SP1 Gag construct with and without bound BVM. The 2.9-Å MicroED structure revealed that a single BVM molecule stabilizes the six-helix bundle via both electrostatic interactions with the dimethylsuccinyl moiety and hydrophobic interactions with the pentacyclic triterpenoid ring. These results provide insight into the mechanism of action of BVM and related maturation inhibitors that will inform further drug discovery efforts. This study also demonstrates the capabilities of MicroED for structure-based drug design.


Control of microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis.
Oncoprotein 18 (Op18; also termed p19, 19K, metablastin, stathmin, and prosolin) is a conserved protein that regulates microtubule (MT) dynamics. Op18 is multisite phosphorylated on four Ser residues during mitosis; two of these Ser residues, Ser-25 and Ser-38, are targets for cyclin-dependent protein kinases (CDKs), and the other two Ser residues, Ser-16 and Ser-63, are targets for an unidentified protein kinase. Mutations of the two CDK sites have recently been shown to result in a mitotic block caused by destabilization of MTs. To understand the role of Op18 in regulation of MT dynamics during mitosis, in this study we dissected the functions of all four phosphorylation sites of Op18 by combining genetic, morphological, and biochemical analyses. The data show that all four phosphorylation sites are involved in switching off Op18 activity during mitosis, an event that appears to be essential for formation of the spindle during metaphase. However, the mechanisms by which specific sites down-regulate Op18 activity differ. Hence, dual phosphorylation on the CDK sites Ser-25 and Ser-38 appears to be required for phosphorylation of Ser-16 and Ser-63; however, by themselves, the CDK sites are of only minor importance in direct regulation of Op18 activity. Subsequent phosphorylation of either Ser-16, Ser-63, or both efficiently switches off Op18 activity.


Adjustment of Born-Oppenheimer electronic wave functions to simplify close coupling calculations.
Technical problems connected with use of the Born-Oppenheimer clamped-nuclei approximation to generate electronic wave functions, potential energy surfaces (PES), and associated properties are discussed. A computational procedure for adjusting the phases of the wave functions, as well as their order when potential crossings occur, is presented which is based on the calculation of overlaps between sets of molecular orbitals and configuration interaction eigenfunctions obtained at neighboring nuclear conformations. This approach has significant advantages for theoretical treatments describing atomic collisions and photo-dissociation processes by means of ab initio PES, electronic transition moments, and nonadiabatic radial and rotational coupling matrix elements. It ensures that the electronic wave functions are continuous over the entire range of nuclear conformations considered, thereby greatly simplifying the process of obtaining the above quantities from the results of single-point Born-Oppenheimer calculations. The overlap results are also used to define a diabatic transformation of the wave functions obtained for conical intersections that greatly simplifies the computation of off-diagonal matrix elements by eliminating the need for complex phase factors.


AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis.
Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer due to its highly metastatic nature. Melanomas harboring oncogenic BRAFV600E mutations combined with PTEN loss exhibit unrestrained PI3K/AKT signaling and increased invasiveness. However, the contribution of different AKT isoforms to melanoma initiation, progression, and metastasis has not been comprehensively explored, and questions remain about whether individual isoforms play distinct or redundant roles in each step. We investigate the contribution of individual AKT isoforms to melanoma initiation using a novel mouse model of AKT isoform-specific loss in a murine melanoma model, and we investigate tumor progression, maintenance, and metastasis among a panel of human metastatic melanoma cell lines using AKT isoform-specific knockdown studies. We elucidate that AKT2 is dispensable for primary tumor formation but promotes migration and invasion in vitro and metastatic seeding in vivo, whereas AKT1 is uniquely important for melanoma initiation and cell proliferation. We propose a mechanism whereby the inhibition of AKT2 impairs glycolysis and reduces an EMT-related gene expression signature in PTEN-null BRAF-mutant human melanoma cells to limit metastatic spread. Our data suggest that the elucidation of AKT2-specific functions in metastasis might inform therapeutic strategies to improve treatment options for melanoma patients.


[The role of the peripheral nervous system damage in clinical picture of multiple sclerosis].
Multiple sclerosis (MS) was believed to be an autoimmune disease of central nervous system (CNS). Recently, several studies showing early involvement of peripheral nervous system (PNS) in MS pathological process have been published. This review own analyzer and published clinical and paraclinical data on PNS pathology in MS patients and CNS damage in patients with chronic inflammatory demyelinating polyneuropathy. Different mechanisms of the damage of PNS may explain different clinical manifestation of PNS involvement in MS.


Brain surgery in a stereoscopic virtual reality environment: a single institution's experience with 100 cases.
A comprehensive understanding of the spatial relationships between intracranial anatomy and pathological features is a crucial element in neurosurgical planning. To assess our clinical experiences using a novel approach, stereoscopic virtual reality environment, to help neurosurgeons with both surgical training and surgical strategic planning purposes. Patient-specific digital imaging data obtained from a variety of different diagnostic sources (computed tomography, computed tomographic angiography, magnetic resonance, functional magnetic resonance, magnetic resonance-diffusion tensor imaging) were collected and then transferred to a workstation setting. These clinical data were obtained from 100 patients who were suffering from either brain vascular malformations or tumors that were located in difficult brain sites. A 3-dimensional volume rendering was produced for each of the 100 clinical cases, which were then subjected to data coregistration and fusion. By using different head positioning systems and craniotomy options, we simulated microscopic visualizations of the lesion through numerous surgical approaches and from various angles of view. This simulation strategy enabled us to carry out an approach selection and eventually to identify the optimum angle of lesion visualization. These virtual craniotomies successfully simulated a sampling of different operative environments that have the potential to play a significant role in neurosurgical training and operative planning worthy of further exploration and development.


Integrated programs for mothers with substance abuse issues: A systematic review of studies reporting on parenting outcomes.
Integrated treatment programs (those that include on-site pregnancy-, parenting-, or child-related services with addiction services) were developed to break the intergenerational cycle of addiction, dysfunctional parenting, and poor outcomes for mothers and children, yet there has been no systematic review of studies of parenting outcomes. As part of larger systematic review to examine the effectiveness of integrated programs for mothers with substance abuse issues, we performed a systematic review of studies published from 1990 to 2011 with data on parenting outcomes. Literature search strategies included online bibliographic database searches, checking printed sources, and requests to researchers. Studies were included if all participants were mothers with substance abuse problems at baseline, the treatment program included at least one specific substance use treatment and at least one parenting or child service, and there were quantitative data on parenting outcomes. We summarized data on parenting skills and capacity outcomes. There were 24 cohort studies, 3 quasi-experimental studies, and 4 randomized trials. In the three randomized trials comparing integrated programs to addiction treatment-as-usual (N = 419), most improvements in parenting skills favored integrated programs and most effect sizes indicated that this advantage was small, ds = -0.02 to 0.94. Results for child protection services involvement did not differ by group. In the three studies that examined factors associated with treatment effects, parenting improvements were associated with attachment-based parenting interventions, children residing in the treatment facility, and improvements in maternal mental health. This is the first systematic review of studies evaluating the effectiveness of integrated programs on parenting. The limited available evidence supports integrated programs, as findings suggest that they are associated with improvements in parenting skills. However, more research is required comparing integrated programs to addiction treatment-as-usual. This review highlights the need for improved methodology, study quality, and reporting to improve our understanding of how best to meet the parenting needs of women with substance abuse issues.


Newly Identified Electrically Coupled Neurons Support Development of the Drosophila Giant Fiber Model Circuit.
The Drosophila giant fiber (GF) escape circuit is an extensively studied model for neuron connectivity and function. Researchers have long taken advantage of the simple linear neuronal pathway, which begins at peripheral sensory modalities, travels through the central GF interneuron (GFI) to motor neurons, and terminates on wing/leg muscles. This circuit is more complex than it seems, however, as there exists a complex web of coupled neurons connected to the GFI that widely innervates the thoracic ganglion. Here, we define four new neuron clusters dye coupled to the central GFI, which we name GF coupled (GFC) 1-4. We identify new transgenic Gal4 drivers that express specifically in these neurons, and map both neuronal architecture and synaptic polarity. GFC1-4 share a central site of GFI connectivity, the inframedial bridge, where the neurons each form electrical synapses. Targeted apoptotic ablation of GFC1 reveals a key role for the proper development of the GF circuit, including the maintenance of GFI connectivity with upstream and downstream synaptic partners. GFC1 ablation frequently results in the loss of one GFI, which is always compensated for by contralateral innervation from a branch of the persisting GFI axon. Overall, this work reveals extensively coupled interconnectivity within the GF circuit, and the requirement of coupled neurons for circuit development. Identification of this large population of electrically coupled neurons in this classic model, and the ability to genetically manipulate these electrically synapsed neurons, expands the GF system capabilities for the nuanced, sophisticated circuit dissection necessary for deeper investigations into brain formation.


RECONSTRUCTING THE HISTORY OF HOST-PARASITE ASSOCIATIONS USING GENERALISED PARSIMONY.
- In reconstructing the history of host-parasite associations, it is necessary to consider several different processes, such as cospeciation and host switching, that may affect an association. A simple reconstruction method is to maximise the number of host-parasite cospeciations. However, maximum cospeciation reconstruction may require the postulation of a large number of other kinds of events, such as parasite extinction or exclusion from certain hosts. A more sophisticated method associates each kind of event with a cost or weight which is inversely related to the likelihood of that kind of event occurring. I present a method of the latter type that distinguishes between two different processes: host tracking, of which cospeciation is a special case, and host switching. Given a relative weight for these two types of events, it is possible to convert the host phytogeny into a cost matrix, allowing for host switching, and use generalised-parsimony algorithms to find minimum-cost reconstructions of the history of the host-parasite association. Different relative switch weights give different minimum-cost reconstructions; the optimal switch weight can be found by maximising the fit between the tracking events and the parasite phytogeny, controlling for the number of postulated switches. As an empirical application of the method, data on an association between pocket gophers and their parasitic chewing lice were re-examined. Although these data have been extensively analysed previously, the generalised parsimony approach throws new light on the history of the association.


The Relationship of Socio-Demographic Factors, Fertility Behavior and Child's Perceived Value with Fertility.
Fertility intention is one of the strongest predictors of couple's fertility behavior that is affected by many variables. This study aimed to identify the relationship of socio-demographic factors, fertility behavior, and child's perceived value with fertility intention of women in a region in the east Iran. In this descriptive cross-sectional study, 241 married women aged between 15 and 49 years of Torbat Heydariyeh City in 2015, were studied. The data collection scales included a demographic information form, fertility information questionnaire and Trommsdorff's child value questionnaire. Data were analyzed using SPSS 16 by Chi-square, Kruskal-Wallis, t-independent test and logistic regression. The significance level of P<0.05 was considered. Most of the subjects (52.7%) had no fertility intention. Independent-samples test and Kruskal-Wallis revealed significant differences in fertility intention with the subject's age, mate's age, number of children and costs of children (P=0.001). In addition, in subjects with children of both sexes, intention for childbearing was significantly lower when compared to subjects with only one sex in children (P=0.001). However, when the logistic regression test was performed, being housewife, number of children, having children of both sexes, benefit and costs of children showed statistical significance (P<0.05). The results indicate that being housewife, number of current children, having children of both sexes, and perceived childbearing costs are important in determining the odds that a woman will intend to have a child. These findings can contribute to the realization of new population programs towards higher fertility rate in the country.


HIV-associated nephropathy: pathogenesis.
HIV-associated nephropathy (HIVAN) is characterized histologically by a collapsing form of focal segmental glomerulosclerosis (FSGS), microcystic tubular dilation, interstitial inflammation and fibrosis. In this review, we provide a summary of the current state of knowledge about the mechanisms involved in the pathogenesis of HIVAN. Two variants in the ApoL1 gene have been identified as the susceptibility alleles that account for a majority of the increased risk of FSGS and nondiabetic end-stage renal disease in blacks. HIVAN1 and HIVAN2 are the other host susceptibility genes that have been identified in animal models for HIVAN. HIV infects renal tubular epithelial cells likely through direct cell-cell transmission. Both in-vivo and in-vitro evidence suggests that Nef and Vpr are the key viral genes mediating HIVAN. Nef induces podocyte dysfunction, whereas Vpr induces renal tubular epithelial cell apoptosis. HIVAN results from direct infection by HIV-1 and expression of viral genes, especially Nef and Vpr, in renal epithelial cells in a genetically susceptible host. The infected renal epithelium acts as a separate viral compartment from the blood and facilitates evolution of strains distant from blood. Dysregulation of several host cellular pathways, including those involved in cell cycle and apoptosis, ultimately results in the unique histopathological syndrome of HIVAN.


Targeting protein-protein interfaces using macrocyclic peptides.
Protein-protein interactions (PPIs) are critical in numerous biological processes including signaling transduction, function regulations, and disease development. To regulate PPIs has been thought to be challenging due to their highly dynamic and expansive interfacial areas. Nonetheless, successful examples have been reported of targeting PPIs using small molecules, peptides, and proteins. Peptides, especially macrocyclic peptides have proven to be a particularly useful tool to inhibit PPIs for their exquisite potency, stability and selectivity. Herein we review the recent developments of this area of research, focusing on the macrocyclic peptides isolated from natural products, identified from library screening, and rationally designed based on structures, as PPI regulators.


Manifestations of Parkinson disease differ in association with REM sleep behavior disorder.
REM sleep behavior disorder (RBD) is commonly associated with Parkinson disease (PD), but it is unclear whether this association has implications for disease manifestations. We evaluated 36 PD patients for the presence of RBD by polysomnography. Patients underwent an extensive evaluation by a movement disorders specialist blinded to polysomnography results. Severity of motor manifestations, autonomic, visual, psychiatric, and olfactory dysfunctions and quality of life (QOL) were assessed, and compared using regression analysis that adjusted for disease duration, age and sex. Severity of motor manifestations did not differ between groups. However, the presence of RBD in PD was strongly associated with symptoms and signs of orthostatic hypotension (systolic blood pressure lying to standing = -25.7 +/- 13.0 mmHg vs. -4.9 +/-14.1, P < 0.001); and orthostatic symptom prevalence = 71% vs. 27%, P = 0.0076). There was no association between RBD and other autonomic symptoms. Color vision was worse in patients with RBD, but olfactory dysfunction did not differ between groups. The prevalence of depression, hallucinations, paranoia, and impulse disorders did not differ between groups. Emotional functioning and general health QOL measures were lower in those with RBD, but there were no differences between groups on disease-specific indices or on measures of overall physical QOL. These findings suggest that the pathophysiology of RBD and nonmotor manifestations of PD, particularly autonomic dysfunction, are linked.


Analysis of scar tissue distribution on rat palates: a laser Doppler flowmetric study.
The aim of this study was to evaluate the effectiveness of laser Doppler flowmetry (LDF) to discriminate postoperative scar tissue distribution on the palate. Nineteen male Wistar rats at the 20th postnatal day were divided into experimental and control groups. In the experimental group, lateral palatal mucoperiosteum was excised to form scar tissue on the palate. At the 11th postnatal week, changes in the palatal blood flow were recorded with LDF in both groups by occluding exposed common carotid arteries. Perfusion values of nonoccluded (stable) and occluded states and the ratio of occluded to stable states were compared for scar tissue and normal tissue areas, and also for the normal tissue areas. After the LDF measurements, India ink-injected specimens and tissue sections were prepared for histological observations. Scar tissue areas showed lower perfusion values both in the stable and occluded states, reflecting a lower vascular density in the scar tissue. The ratio of the occluded to stable states was higher in the scar tissue than in the normal tissue areas. In normal tissue areas, perfusion values of both the stable and occluded states appeared to vary, but the ratio did not vary among the areas. In the LDF study, the ratio of the occluded to stable states was considered to be the better parameter for discriminating scar tissue from normal tissue.