Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration.
During mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1)+ vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xt mice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1null mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the nonoverlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Because Kallmann syndrome (KS) is characterized by abnormal GnRH-1ns migration, we examined whole-exome sequencing data from KS subjects. We identified and validated a GLI3 loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that human GLI3 mutations contribute to KS etiology.SIGNIFICANCE STATEMENT The transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl-1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa, and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl-1null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl-1 is necessary for GnRH-1 ontogeny. Analyzing human whole-exome sequencing data, we identified a GLI3 loss-of-function variant in a KS individual. Our data suggest that GLI3 is a candidate gene contributing to KS etiology.


Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells.
Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy.


Severe Persistent Jaundice after the Abuse of an Anabolic Androgenic Steroid Analogue.
Hepatic disorders with prominent cholestasis can be caused by a range of conditions, and anabolic androgenic steroids have been considered a cause of protracted cholestasis. A 29-year-old man who had taken an anabolic androgenic steroid analogue for 2 months visited the hospital complaining of jaundice and indigestion. After stopping the medication, the hyperbilirubinemia tended to decrease, but a transiently elevated aminotransferase level was observed. The endogenous testosterone level also decreased initially but recovered soon after. The liver function profiles were normalized after 2 months of conservative management. This case emphasizes that close drug history taking, including anabolic steroids, is important for identifying the cause of unexplained persistent jaundice.


Assessment of Mouse Liver Histopathology Following Exposure to HFPO-DA With Emphasis on Understanding Mechanisms of Hepatocellular Death.
Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance of histopathological effects seen in livers of mice exposed to HFPO-DA for human health risk assessment, histopathological effects were summarized from hematoxylin and eosin (H&E)-stained sections in several repeat-dose toxicity studies in mice. Findings across studies revealed histopathological changes consistent with peroxisomal proliferation, whereas two reports of steatosis could not be confirmed in the published figures. In addition, mechanisms of hepatocellular death were assessed in H&E sections as well as with the apoptotic marker cleaved caspase-3 (CCasp3) in newly cut sections from archived liver blocks from select studies. A comparison of serially CCasp3 immunolabeled and H&E-stained sections revealed that mechanisms of hepatocellular death cannot be clearly discerned in H&E-stained liver sections alone as several examples of putatively necrotic cells were positive for CCasp3. Published whole genome transcriptomic data were also reevaluated for enrichment of various forms of hepatocellular death in response to HFPO-DA, which revealed enrichment of apoptosis and autophagy, but not ferroptosis, pyroptosis, or necroptosis. These morphological and molecular findings are consistent with transcriptomic evidence for peroxisome proliferator-activated receptor alpha (PPARα) signaling in HFPO-DA exposed mice.


Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty.
The interaction between androgens and GH/IGF-I was studied in male GHR gene disrupted or GHRKO and WT mice during puberty. Androgens stimulate trabecular and cortical bone modeling and increase muscle mass even in the absence of a functional GHR. GHR activation seems to be the main determinant of radial bone expansion, although GH and androgens are both necessary for optimal stimulation of periosteal growth during puberty. Growth hormone (GH) is considered to be a major regulator of postnatal skeletal growth, whereas androgens are considered to be a key regulator of male periosteal bone expansion. Moreover, both androgens and GH are essential for the increase in muscle mass during male puberty. Deficiency or resistance to either GH or androgens impairs bone modeling and decreases muscle mass. The aim of the study was to investigate androgen action on bone and muscle during puberty in the presence and absence of a functional GH/insulin-like growth factor (IGF)-I axis. Dihydrotestosterone (DHT) or testosterone (T) were administered to orchidectomized (ORX) male GH receptor gene knockout (GHRKO) and corresponding wildtype (WT) mice during late puberty (6-10 weeks of age). Trabecular and cortical bone modeling, cortical strength, body composition, IGF-I in serum, and its expression in liver, muscle, and bone were studied by histomorphometry, pQCT, DXA, radioimmunoassay and RT-PCR, respectively. GH receptor (GHR) inactivation and low serum IGF-I did not affect trabecular bone modeling, because trabecular BMD, bone volume, number, width, and bone turnover were similar in GHRKO and WT mice. The normal trabecular phenotype in GHRKO mice was paralleled by a normal expression of skeletal IGF-I mRNA. ORX decreased trabecular bone volume significantly and to a similar extent in GHRKO and WT mice, whereas DHT and T administration fully prevented trabecular bone loss. Moreover, DHT and T stimulated periosteal bone formation, not only in WT (+100% and +100%, respectively, versus ORX + vehicle [V]; p < 0.05), but also in GHRKO mice (+58% and +89%, respectively, versus ORX + V; p < 0.05), initially characterized by very low periosteal growth. This stimulatory action on periosteal bone resulted in an increase in cortical thickness and occurred without any treatment effect on serum IGF-I or skeletal IGF-I expression. GHRKO mice also had reduced lean body mass and quadriceps muscle weight, along with significantly decreased IGF-I mRNA expression in quadriceps muscle. DHT and T equally stimulated muscle mass in GHRKO and WT mice, without any effect on muscle IGF-I expression. Androgens stimulate trabecular and cortical bone modeling and increase muscle weight independently from either systemic or local IGF-I production. GHR activation seems to be the main determinant of radial bone expansion, although GHR signaling and androgens are both necessary for optimal stimulation of periosteal growth during puberty.


dopOSCCI: a functional transcranial Doppler ultrasonography summary suite for the assessment of cerebral lateralization of cognitive function.
We present a description of a new software package, 'dopOSCCI', which summarises data from experimental studies where functional transcranial Doppler ultrasonography (fTCD) is used to compare hemispheric rates of blood flow in order to assess lateralization of a cognitive process. The software provides a graphical user interface to summarise analogue and digital data collected using Multi-Dop Doppler Ultrasound devices (DWL Multidop T2: manufacturer, DWL Elektronische Systeme, Singen, Germany). The unique aspects of dopOSCCI allow multi-file processing, multi-event marker processing, behavioural and multi-session summaries, image file data visualization, and tab-delimited output files which includes split-half, single-trial summaries and data quality variables. The Matlab based software is available under the GNU GPL license and can be accessed online at https://databank.ora.ox.ac.uk/general/datasets/dopOSCCI, the Oxford University DataBank.


Medical tourism in Malaysia: how can we better identify and manage its advantages and disadvantages?
Following the identification of medical tourism as a growth sector by the Malaysian government in 1998, significant government sector and private-sector investments have been channeled into its development over the past 15 years. This is unfolding within the broader context of social services being devolved to for-profit enterprises and 'market-capable' segments of society becoming sites of intensive entrepreneurial investment by both the private sector and the state. Yet, the opacity and paucity of available medical tourism statistics severely limits the extent to which medical tourism's impacts can be reliably assessed, forcing us to consider the real effects that the resulting speculation itself has produced and to reevaluate how the real and potential impacts of medical tourism are--and should be--conceptualized, calculated, distributed, and compensated for. Contemporary debate over the current and potential benefits and adverse effects of medical tourism for destination societies is hamstrung by the scant empirical data currently publicly available. Steps are proposed for overcoming these challenges in order to allow for improved identification, planning, and development of resources appropriate to the needs, demands, and interests of not only medical tourists and big business but also local populations.


Initial management of severe burn injury.
Patients with severe burn injuries pose significant challenges for the intensivist. Though average burn sizes have decreased over time, severe burn injuries involving greater than 20% of the total body surface area still occur. Verified burn centers are limited, making the management of severely burn injured patients at nonspecialized ICUs likely. Current practices in burn care have increased survivability even from massive burns. It is important for intensivists to be aware of the unique complications and therapeutic options in burn critical care management. This review critically discusses current practices and recently published data regarding the evaluation and management of severe burn injury. Burn patients have long, complex ICU stays with accompanying multiorgan dysfunction. Recent advances in burn intensive care have focused on acute respiratory distress syndrome from inhalation injury, acute kidney injury (AKI), and transfusion, resulting in new strategies for organ failure, including renal replacement therapy and extracorporeal life support. Initial evaluation and treatment of acute severe burn injury remains an ongoing area of study. This manuscript reviews current practices and considerations in the acute management of the severely burn injured patient.


Rainfall Enhancement by Dynamic Cloud Modification: Massive silver iodide seeding causes rainfall increases from single clouds over southern Florida.
In summary, the following points are made: 1) There are essentially two approaches to seeding for rain inducement, static and dynamic. 2) The dynamic approach is effective in inducing growth and increasing precipitation from individually seeded convective clouds under specifiable conditions. 3) The static approach to seeding for precipitation increases is apparently not relevant to the summer cumuli of Florida and Missouri. 4) Regional seeding climatologies, including studies of natural freezing processes in convective clouds, should be completed before commencement of a seeding operation. 5) The results of a seeding operation are frequently better understood by stratification of the data, especially with respect to weather conditions. Precipitation increases from seeding are usually found under fair weather regimes with isolated showers, whereas decreases are often noted under naturally rainy conditions.


Use of the sleep clinical record in the follow-up of children with obstructive sleep apnea (OSA) after treatment.
The aim of our study was to evaluate the utility of the sleep clinical record (SCR) in the follow-up of children with obstructive sleep apnea (OSA) after treatment. SCR was completed and overnight polysomnography (PSG) was performed in all enrolled children (T0), with SCR considered positive for scores ≥6.5, as previously validated. Patients underwent adenotonsillectomy (T&A), rapid maxillary expansion (RME), and medical therapy according to severity of OSA and clinical features. Six months after completing therapy, the second overnight PSG and SCR (T1) were performed. For all subjects, both Apnea-Hypopnea Index (AHI) and total SCR score decreased significantly (<0.005) from T0 to T1. For SCR items, clinical examination (item 1) and reported sleep respiratory symptoms (item 2) ameliorated significantly (<0.005). However, hyperactivity or inattention (item 3) decreased significantly (<0.005) after treatment only in T&A group, while no differences in AHI and SCR scores occurred in the medically treated group. At T1, SCR was positive in 95.6 % of children with AHI ≥1, with a concordance of 100 % in the T&A and RME groups, resulting in a positive predictive value of 100 %. A poor concordance (38.3 % in T&A group and 53.4 % in RME group) was found when SCR < 6.5. Children with SCR ≥ 6.5 at T1 showed higher AHI compared to patients with SCR < 6.5 (5.7 ± 5.9 ev/h vs 1.78 ± 1.76 ev/h; p < 0.005). SCR emerges as a potentially useful instrument for follow-up of children with OSA after treatment.


Age-related impairments in object-place associations are not due to hippocampal dysfunction.
Age-associated cognitive decline can reduce an individual's quality of life. As no single neurobiological deficit can account for the wide spectrum of behavioral impairments observed in old age, it is critical to develop an understanding of how interactions between different brain regions change over the life span. The performance of young and aged animals on behaviors that require the hippocampus and cortical regions to interact, however, has not been well characterized. Specifically, the ability to link a spatial location with specific features of a stimulus, such as object identity, relies on the hippocampus, perirhinal and prefrontal cortices. Although aging is associated with dysfunction in each of these brain regions, behavioral measures of functional change within the hippocampus, perirhinal and prefrontal cortices in individual animals are often not correlated. Thus, how dysfunction of a single brain region within this circuit, such as the hippocampus, impacts behaviors that require communication with the perirhinal and prefrontal cortices remains unknown. To address this question, young and aged rats were tested on the interregion dependent object-place paired association task, as well as a hippocampal-dependent test of spatial reference memory. This particular cohort of aged rats did not show deficits on the hippocampal-dependent task, but were significantly impaired at acquiring object-place associations relative to young. These data suggest that behaviors requiring functional connectivity across different regions of the memory network may be particularly sensitive to aging, and can be used to develop models that will clarify the impact of systems-level dysfunction in the elderly.


Vascular intersection detection in retina fundus images using a new hybrid approach.
The use of vascular intersection aberration as one of the signs when monitoring and diagnosing diabetic retinopathy from retina fundus images (FIs) has been widely reported in the literature. In this paper, a new hybrid approach called the combined cross-point number (CCN) method able to detect the vascular bifurcation and intersection points in FIs is proposed. The CCN method makes use of two vascular intersection detection techniques, namely the modified cross-point number (MCN) method and the simple cross-point number (SCN) method. Our proposed approach was tested on images obtained from two different and publicly available fundus image databases. The results show a very high precision, accuracy, sensitivity and low false rate in detecting both bifurcation and crossover points compared with both the MCN and the SCN methods.


Increased osteogenesis in osteoporotic bone marrow stromal cells by overexpression of leptin.
Osteoporosis leads to increased bone fractures and net bone loss, in part because of the dysfunction of bone marrow stromal cells (BMSCs). Leptin is an adipokine that plays important roles in many biological processes, including the regulation of the actions of mesenchymal stem cells. Our aim is to investigate the osteogenic effects of leptin in osteoporotic BMSCs in vitro and in vivo. The leptin gene was transferred into BMSCs isolated from osteoporotic rats by using recombinant adenoviruses. Once the gene and protein expression of leptin had been confirmed, MTT assays were performed; leptin overexpression was confirmed not to affect the viability of osteoporotic BMSCs. However, alkaline phosphatase (ALP) activity measurements, Alizarin red staining and analyses by quantitative real-time reverse transcription with the polymerase chain reaction revealed that leptin upregulated ALP activity, mineral deposition and the mRNA levels of runt-related transcription factor 2, ALP and collagen type І. Lastly, the effects of leptin on osteogenic differentiation were assessed in vivo. Cells transfected with leptin exhibited increased osteogenic differentiation and enhanced formation of bone-like structures. This study thus reveals, for the first time, that the overexpression of leptin in osteoporotic BMSCs (1) enhances their capacity to differentiate into osteoblasts and to form bone-like tissue and (2) might be a useful skeletal regenerative therapy in osteoporotic patients.


Adjuvant radiotherapy and health-related quality of life of patients at intermediate risk of recurrence following primary surgery for oral squamous cell carcinoma.
Controversy surrounds who should receive adjuvant radiotherapy in patients with intermediate risk of recurrence of oral squamous cell carcinoma following primary surgery. The aim of this study was to compare health-related quality of life (HRQOL) outcomes of those who received adjuvant radiotherapy to those who did not in patients at intermediate-risk of recurrence. A total of 765 oral cancer patients were treated at the Regional Maxillofacial Unit, Liverpool from 1995 to 2007. After excluding 124 patients (87 primary radiotherapy, 23 died within 90 days, 14 had insufficient information for determining risk group status), 169 were low-risk, 271 intermediate-risk and 201 were high-risk. In the intermediate-risk group, 33% had adjuvant radiotherapy. Allowing for attrition, more than 70% had University of Washington quality of life data (UW-QOL). Cumulative survival was similar in those with and without adjuvant radiotherapy in a subset of patients at intermediate risk. There was little difference in overall HRQOL scores and in the socio-emotional subscale scores of the UW-QOL. However, there was a significant difference in physical subscale scores and the issue most affected was saliva. These findings support better stratification of risk in the intermediate group, and the plausibility of withholding radiotherapy without compromising survival. This can have dramatic positive benefits on patient physical outcomes, in particular saliva. Where adjuvant radiotherapy is necessary, it is appropriate to minimise adverse effects through measures such as intensity-modulated radiation therapy.


Religion and HIV in Tanzania: influence of religious beliefs on HIV stigma, disclosure, and treatment attitudes.
Religion shapes everyday beliefs and activities, but few studies have examined its associations with attitudes about HIV. This exploratory study in Tanzania probed associations between religious beliefs and HIV stigma, disclosure, and attitudes toward antiretroviral (ARV) treatment. A self-administered survey was distributed to a convenience sample of parishioners (n = 438) attending Catholic, Lutheran, and Pentecostal churches in both urban and rural areas. The survey included questions about religious beliefs, opinions about HIV, and knowledge and attitudes about ARVs. Multivariate logistic regression analysis was performed to assess how religion was associated with perceptions about HIV, HIV treatment, and people living with HIV/AIDS. Results indicate that shame-related HIV stigma is strongly associated with religious beliefs such as the belief that HIV is a punishment from God (p < 0.01) or that people living with HIV/AIDS (PLWHA) have not followed the Word of God (p < 0.001). Most participants (84.2%) said that they would disclose their HIV status to their pastor or congregation if they became infected. Although the majority of respondents (80.8%) believed that prayer could cure HIV, almost all (93.7%) said that they would begin ARV treatment if they became HIV-infected. The multivariate analysis found that respondents' hypothetical willingness to begin ARV treatme was not significantly associated with the belief that prayer could cure HIV or with other religious factors. Refusal of ARV treatment was instead correlated with lack of secondary schooling and lack of knowledge about ARVs. The decision to start ARVs hinged primarily on education-level and knowledge about ARVs rather than on religious factors. Research results highlight the influence of religious beliefs on HIV-related stigma and willingness to disclose, and should help to inform HIV-education outreach for religious groups.


Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders.
This study was designed to determine the effectiveness of a group stress reduction program based on mindfulness meditation for patients with anxiety disorders. The 22 study participants were screened with a structured clinical interview and found to meet the DSM-III-R criteria for generalized anxiety disorder or panic disorder with or without agoraphobia. Assessments, including self-ratings and therapists' ratings, were obtained weekly before and during the meditation-based stress reduction and relaxation program and monthly during the 3-month follow-up period. Repeated measures analyses of variance documented significant reductions in anxiety and depression scores after treatment for 20 of the subjects--changes that were maintained at follow-up. The number of subjects experiencing panic symptoms was also substantially reduced. A comparison of the study subjects with a group of nonstudy participants in the program who met the initial screening criteria for entry into the study showed that both groups achieved similar reductions in anxiety scores on the SCL-90-R and on the Medical Symptom Checklist, suggesting generalizability of the study findings. A group mindfulness meditation training program can effectively reduce symptoms of anxiety and panic and can help maintain these reductions in patients with generalized anxiety disorder, panic disorder, or panic disorder with agoraphobia.


World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria.
Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs.


Effects of age, sex and reproductive status on persistent organic pollutant concentrations in "Southern Resident" killer whales.
"Southern Resident" killer whales (Orcinus orca) that comprise three fish-eating "pods" (J, K and L) were listed as "endangered" in the US and Canada following a 20% population decline between 1996 and 2001. Blubber biopsy samples from Southern Resident juveniles had statistically higher concentrations of certain persistent organic pollutants than were found for adults. Most Southern Resident killer whales, including the four juveniles, exceeded the health-effects threshold for total PCBs in marine mammal blubber. Maternal transfer of contaminants to the juveniles during rapid development of their biological systems may put these young whales at greater risk than adults for adverse health effects (e.g., immune and endocrine system dysfunction). Pollutant ratios and field observations established that two of the pods (K- and L-pod) travel to California to forage. Nitrogen stable isotope values, supported by field observations, indicated possible changes in the diet of L-pod over the last decade.


Fluorescence lifetime measurements using total internal reflection fluorimetry: evidence for a conformational change in albumin adsorbed to quartz.
We have modified the total internal reflectance fluorimetry (TIRF) method to determine, indirectly, quantum fluorescence yield and thus infer structural changes of adsorbed plasma proteins. We employed a frequency multiplied Nd:YAG pulse laser to excite tryptophan residues of bovine serum albumin (BSA), measuring the resulting fluorescence lifetimes. BSA adsorbed on quartz was investigated at normal pH and under acidic (pH 3.8) conditions at which albumin shape change has been established in bulk solution. Albumin adsorbed at pH 7.2 has a slightly lower lifetime than the bulk solution value, reflecting a population of both native and isomerized forms. Gently washing the adsorbate surface significantly reduces fluorescence lifetime, suggesting retention of more tenacious, conformationally altered molecules. Vigorous washing further reduces fluorescence lifetimes to values close to those obtained in bulk under acidic conditions. Similar alterations in fluorescence lifetimes were observed for heat-denatured albumin. These results support the hypothesis that adsorbed albumin exists in the form of a two-layer deposit, each with a possibly different structure. A loosely held layer, consisting of BSA microaggregates and including partially unfolded molecules, exists on the undisturbed surface and is partially removed by gentle washing. Vigorous washing removes all but the most tightly held protein, which exists in a possibly further unfolded configuration. The decrease in fluorescence lifetime of adsorbed BSA implies a corresponding change in quantum yield. A change in quantum yield of BSA tryptophan fluorophors implies that measuring adsorbed protein concentration by intrinsic fluorescence is unreliable.


Astrocytes as an HIV Reservoir: Mechanism of HIV Infection.
If we have any hope of achieving a cure for HIV infection, close attention to the cell types capable of getting infected with HIV is necessary. Of these cell types, astrocytes are the most ideal cell type for the formation of such a reservoir. These are long-lived cells with a very low turnover rate and are found in the brain and the gastrointestinal tract. Although astrocytes are evidently resistant to infection of cell-free HIV in vitro, these cells are efficiently infected via cell-tocell contact by which immature HIV virions bud off lymphocytes and have the ability to directly bind to CXCR4, triggering the process of fusion in the absence of CD4. In this review, we closely examine the evidence for HIV infection of astrocytes in the brain and the mechanisms for viral entry and regulation in this cell type, and discuss an approach for controlling this viral reservoir.


Association Between Dietary Patterns and Fluorosis in Guizhou, China.
Objective: Many studies have explored the effects of individual foods or nutrients on fluorosis, but no studies have focused on dietary patterns. This study examined the relationship between dietary patterns and coal-burning fluorosis in Guizhou, China. Methods: This 1:1 matched case-control study was conducted in Zhijin County of Guizhou province with a sample size of 200 cases of fluorosis and 200 age and gender matched controls. Habitual dietary intake was assessed by face-to-face interviews, using a validated 75-item food frequency questionnaire (FFQ) and various covariates using structured questionnaires. The dietary patterns were identified by factor analysis. Results: The factor analysis identified three major dietary patterns which were labeled healthy, easy-to-roast and high protein. After adjusting for various confounding factors, a decreased risk for fluorosis was observed in the highest tertile of the healthy dietary pattern relative to the lowest tertile (OR = 0.47, 95% CI = 0.27-0.84, P-trend = 0.003) and a positive association was observed between the easy-to-roast dietary pattern and fluorosis risk (OR = 2.05, 95% CI = 1.15-3.66), with a significant linear trend (P = 0.017). We did not find an association between fluorosis risk and the high protein dietary pattern. The relationships remained significant when the analyses were stratified by gender and fluorosis subtypes. Conclusion: The healthy dietary pattern may lower coal-burning fluorosis risk; in contrast, the easy-to-roast dietary pattern significantly increases the risk of coal-burning fluorosis.


Prediction of the Pharmacokinetics, Pharmacodynamics, and Efficacy of a Monoclonal Antibody, Using a Physiologically Based Pharmacokinetic FcRn Model.
Although advantages of physiologically based pharmacokinetic models (PBPK) are now well established, PBPK models that are linked to pharmacodynamic (PD) models to predict pharmacokinetics (PK), PD, and efficacy of monoclonal antibodies (mAbs) in humans are uncommon. The aim of this study was to develop a PD model that could be linked to a physiologically based mechanistic FcRn model to predict PK, PD, and efficacy of efalizumab. The mechanistic FcRn model for mAbs with target-mediated drug disposition within the Simcyp population-based simulator was used to simulate the pharmacokinetic profiles for three different single doses and two multiple doses of efalizumab administered to virtual Caucasian healthy volunteers. The elimination of efalizumab was modeled with both a target-mediated component (specific) and catabolism in the endosome (non-specific). This model accounted for the binding between neonatal Fc receptor (FcRn) and efalizumab (protective against elimination) and for changes in CD11a target concentration. An integrated response model was then developed to predict the changes in mean Psoriasis Area and Severity Index (PASI) scores that were measured in a clinical study as an efficacy marker for efalizumab treatment. PASI scores were approximated as continuous and following a first-order asymptotic progression model. The reported steady state asymptote (Y ss) and baseline score [Y (0)] was applied and parameter estimation was used to determine the half-life of progression (T p) of psoriasis. Results suggested that simulations using this model were able to recover the changes in PASI scores (indicating efficacy) observed during clinical studies. Simulations of both single dose and multiple doses of efalizumab concentration-time profiles as well as suppression of CD11a concentrations recovered clinical data reasonably well. It can be concluded that the developed PBPK FcRn model linked to a PD model adequately predicted PK, PD, and efficacy of efalizumab.


Repetitive task training for improving functional ability after stroke.
Repetitive task training (RTT) involves the active practice of task-specific motor activities and is a component of current therapy approaches in stroke rehabilitation. Primary objective: To determine if RTT improves upper limb function/reach and lower limb function/balance in adults after stroke. Secondary objectives: 1) To determine the effect of RTT on secondary outcome measures including activities of daily living, global motor function, quality of life/health status and adverse events. 2) To determine the factors that could influence primary and secondary outcome measures, including the effect of 'dose' of task practice; type of task (whole therapy, mixed or single task); timing of the intervention and type of intervention. We searched the Cochrane Stroke Group Trials Register (4 March 2016); the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 5: 1 October 2006 to 24 June 2016); MEDLINE (1 October 2006 to 8 March 2016); Embase (1 October 2006 to 8 March 2016); CINAHL (2006 to 23 June 2016); AMED (2006 to 21 June 2016) and SPORTSDiscus (2006 to 21 June 2016). Randomised/quasi-randomised trials in adults after stroke, where the intervention was an active motor sequence performed repetitively within a single training session, aimed towards a clear functional goal. Two review authors independently screened abstracts, extracted data and appraised trials. We determined the quality of evidence within each study and outcome group using the Cochrane 'Risk of bias' tool and GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria. We did not assess follow-up outcome data using GRADE. We contacted trial authors for additional information. We included 33 trials with 36 intervention-control pairs and 1853 participants. The risk of bias present in many studies was unclear due to poor reporting; the evidence has therefore been rated 'moderate' or 'low' when using the GRADE system. There is low-quality evidence that RTT improves arm function (standardised mean difference (SMD) 0.25, 95% confidence interval (CI) 0.01 to 0.49; 11 studies, number of participants analysed = 749), hand function (SMD 0.25, 95% CI 0.00 to 0.51; eight studies, number of participants analysed = 619), and lower limb functional measures (SMD 0.29, 95% CI 0.10 to 0.48; five trials, number of participants analysed = 419). There is moderate-quality evidence that RTT improves walking distance (mean difference (MD) 34.80, 95% CI 18.19 to 51.41; nine studies, number of participants analysed = 610) and functional ambulation (SMD 0.35, 95% CI 0.04 to 0.66; eight studies, number of participants analysed = 525). We found significant differences between groups for both upper-limb (SMD 0.92, 95% CI 0.58 to 1.26; three studies, number of participants analysed = 153) and lower-limb (SMD 0.34, 95% CI 0.16 to 0.52; eight studies, number of participants analysed = 471) outcomes up to six months post treatment but not after six months. Effects were not modified by intervention type, dosage of task practice or time since stroke for upper or lower limb. There was insufficient evidence to be certain about the risk of adverse events. There is low- to moderate-quality evidence that RTT improves upper and lower limb function; improvements were sustained up to six months post treatment. Further research should focus on the type and amount of training, including ways of measuring the number of repetitions actually performed by participants. The definition of RTT will need revisiting prior to further updates of this review in order to ensure it remains clinically meaningful and distinguishable from other interventions.


Tributylphosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP) induced apoptosis and cell cycle arrest in HepG2 cells.
The purpose of this study was to investigate the cytotoxic effects of tributylphosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP) and to explore the underlying molecular mechanism focusing on oxidative stress, apoptosis, and cell cycle arrest. The results showed that TBP and TBEP could inhibit cell proliferation, induce cellular reactive oxidative stress, and suppress the mitochondrial membrane potential in HepG2 cells. TBP and TBEP could induce both mitochondrial and p53 mediated apoptosis through different mitogen-activated protein kinase (MAPK) signal pathways. TBP activated the c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinase (ERK1/2) pathways, while TBEP activated the JNK pathway. Furthermore, TBP and TBEP caused a concentration-dependent decrease of cyclin D1 expression and an increase of cyclin-dependent kinase (CDK) inhibitor proteins such as p21 and p27, resulting in significant cell cycle arrest in the G0/G1 phase. Taken together, the toxicity of TBP and TBEP on the HepG2 cells was associated with apoptosis and cell cycle arrest induced by oxidative stress.


Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension.
Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in in vivo pulmonary arterial hypertension and in vitro pulmonary hypertension models. In the in vivo model, male Sprague Dawley rats received a single subcutaneous injection of Sugen SU5416 (20 mg/kg) prior to two weeks of hypobaric hypoxia (380 mmHg) followed by three weeks normoxia (Sugen/hypoxic), then animals were either maintained for three weeks on control chow or one containing apoptosis signal-regulating kinase 1 inhibitor (100 mg/kg/day). Cardiovascular measurements were carried out. In the in vitro model, primary cultures of rat pulmonary artery fibroblasts and rat pulmonary artery smooth muscle cells were maintained in hypoxia (5% O2) and investigated for proliferation, migration and molecular signalling in the presence or absence of apoptosis signal-regulating kinase 1 inhibitor. Sugen/hypoxic animals displayed significant pulmonary arterial hypertension compared to normoxic controls at eight weeks. Apoptosis signal-regulating kinase 1 inhibitor decreased right ventricular systolic pressure to control levels and reduced muscularised vessels in lung tissue. Apoptosis signal-regulating kinase 1 inhibition was found to prevent hypoxia-induced proliferation, migration and cytokine release in rat pulmonary artery fibroblasts and also prevented rat pulmonary artery fibroblast-induced rat pulmonary artery smooth muscle cell migration and proliferation. Apoptosis signal-regulating kinase 1 inhibition reversed pulmonary arterial hypertension in the Sugen/hypoxic rat model. These effects may be a result of intrinsic changes in the signalling of adventitial fibroblast.


Sclerotium rolfsii Causes White Rot on Taro in Korea.
Taro (Colocasia esculenta L.) is grown throughout the world primarily for its tubers, which become edible after cooking. Taro stems are often used in a traditional soup in South Korea. In September 2012, a suspected white rot of taro occurred in a farmer's fields in Jinju, South Korea. Infected plants gradually withered, a white mycelial mat appeared, and numerous sclerotia developed on the surface of petioles near the soil line. The heavily infected petioles rotted and the entire plant eventually died. The freshly isolated pathogenic fungus was grown on potato dextrose agar (PDA) and examined microscopically. Aerial mycelia usually formed many narrow hyphal strands 4 to 8 μm wide. The white mycelia formed a typical clamp connection structure after 6 days growth at 25°C. The sclerotia were white at first, gradually turned dark brown, and were 1 to 3 mm in diameter. Small globoid sclerotia formed abundantly on PDA after 18 days of growth. Ten 2-month-old potted taro plants were inoculated with S. rolfsii-colonized agar discs directly at the base of each plant and kept at 25°C in a greenhouse to test pathogenicity. Three taro plants were inoculated similarly with uncolonized agar discs as controls. Eight days after inoculation, blight symptoms were observed, and S. rolfsii was reisolated from the artificially inoculated plants. The control taro plants remained healthy. We amplified and sequenced an internal transcribed spacer (ITS) rDNA region of the isolate using the ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-TCCTCCGCTTATTGATATGC-3') primers to confirm the identity of the fungus (2). The resulting 684-bp sequence was deposited in GenBank (Accession No. KC491876). A comparison with other sequences available in the GenBank database revealed that the ITS sequence shared 100% similarity with Sclerotium rolfsii sequences (HQ420816 and JN017199). Based on the symptoms, mycological characteristics, ITS sequence analysis, and host plant pathogenicity, this fungus was identified as S. rolfsii Saccardo (1). To our knowledge, this is the first report of white rot in taro caused by S. rolfsii in Korea. References: (1) J. E. Mordue. CMI Descriptions of Pathogenic Fungi and Bacteria. No. 410, 1974. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, New York, 1990.


Independent evaluation of conflicting microspherule results from different investigations of the Younger Dryas impact hypothesis.
Firestone et al. sampled sedimentary sequences at many sites across North America, Europe, and Asia [Firestone RB, et al. (2007) Proc Natl Acad Sci USA 106:16016-16021]. In sediments dated to the Younger Dryas onset or Boundary (YDB) approximately 12,900 calendar years ago, Firestone et al. reported discovery of markers, including nanodiamonds, aciniform soot, high-temperature melt-glass, and magnetic microspherules attributed to cosmic impacts/airbursts. The microspherules were explained as either cosmic material ablation or terrestrial ejecta from a hypothesized North American impact that initiated the abrupt Younger Dryas cooling, contributed to megafaunal extinctions, and triggered human cultural shifts and population declines. A number of independent groups have confirmed the presence of YDB spherules, but two have not. One of them [Surovell TA, et al. (2009) Proc Natl Acad Sci USA 104:18155-18158] collected and analyzed samples from seven YDB sites, purportedly using the same protocol as Firestone et al., but did not find a single spherule in YDB sediments at two previously reported sites. To examine this discrepancy, we conducted an independent blind investigation of two sites common to both studies, and a third site investigated only by Surovell et al. We found abundant YDB microspherules at all three widely separated sites consistent with the results of Firestone et al. and conclude that the analytical protocol employed by Surovell et al. deviated significantly from that of Firestone et al. Morphological and geochemical analyses of YDB spherules suggest they are not cosmic, volcanic, authigenic, or anthropogenic in origin. Instead, they appear to have formed from abrupt melting and quenching of terrestrial materials.


Ancient carbon from a melting glacier gives high ¹⁴C age in living pioneer invertebrates.
Glaciers are retreating and predatory invertebrates rapidly colonize deglaciated, barren ground. The paradox of establishing predators before plants and herbivores has been explained by wind-driven input of invertebrate prey. Here we present an alternative explanation and a novel glacier foreland food web by showing that pioneer predators eat locally produced midges containing 21,000 years old ancient carbon released by the melting glacier. Ancient carbon was assimilated by aquatic midge larvae, and terrestrial adults achieved a radiocarbon age of 1040 years. Terrestrial spiders, harvestmen and beetles feeding on adult midges had radiocarbon ages of 340-1100 years. Water beetles assumed to eat midge larvae reached radiocarbon ages of 1100-1200 years. Because both aquatic and terrestrial pioneer communities use ancient carbon, the term "primary succession" is questionable in glacier forelands. If our "old" invertebrates had been collected as subfossils and radiocarbon dated, their age would have been overestimated by up to 1100 years.


New Guideline for the Reporting of Studies Developing, Validating, or Updating a Multivariable Clinical Prediction Model: The TRIPOD Statement.
Prediction models are developed to aid health care providers in estimating the probability that a specific outcome or disease is present (diagnostic prediction models) or will occur in the future (prognostic prediction models), to inform their decision making. Prognostic models here also include models to predict treatment outcomes or responses; in the cancer literature often referred to as predictive models. Clinical prediction models have become abundant. Pathology measurement or results are frequently included as predictors in such prediction models, certainly in the cancer domain. Only when full information on all aspects of a prediction modeling study are clearly reported, risk of bias and potential usefulness of the prediction model can be adequately assessed. Many reviews have illustrated that the quality of reports on the development, validation, and/or adjusting (updating) of prediction models, is very poor. Hence, the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) initiative has developed a comprehensive and user-friendly checklist for the reporting of studies on, both diagnostic and prognostic, prediction models. The TRIPOD Statement intends to improve the transparency and completeness of reporting of studies that report solely on development, both development and validation, and solely on the validation (with or without updating) of diagnostic or prognostic, including predictive, models.


Hibiscus sabdariffa extract protects against cadmium-induced ovarian toxicity in adult Wistar rats.
Hibiscus sabdariffa (HS) is native to tropical and subtropical regions, and its enrichment as a source of antioxidants and phytoestrogen has been documented. The present study investigated effects of HS on ovarian toxicity induced by cadmium. Adult female Wistar rats were grouped into 4 (n=5/group): Group A received HS (100 mg/kg), group B received cadmium sulphate (5 mg/kg), group C received cadmium sulphate and HS, and group D (control) received 1 ml of distilled water. Cadmium sulphate was administered for five days (i.p) followed by oral administration of HS for 28 days. Results showed distortion in the cytoarchitecture of the follicular cells in the ovary of cadmium-treated rats while there was mild or no distortion recorded for the ovary of the rats treated with cadmium and HS. There was also a significant reduction in the serum level of Luteinizing and follicle stimulating hormone of the rats treated with cadmium (group B) when compared with control rats. However, these alterations were attenuated when treated with HS. We concluded that HS has an ovarian protective effect in cadmium-treated adult female rats. Hence the present results suggest that HS extract would be a potential therapeutic agent in ovarian dysfunction.


Species-specific responses to community density in an unproductive perennial plant community.
Most studies of density dependent regulation in plants consider a single target species, but regulation may also occur at the level of the entire community. Knowing whether a community is at carrying capacity is essential for understanding its behaviour because low density plant communities may behave quite differently than their high density counterparts. Also, because the intensity of density dependence may differ considerably between species and physical environments, generalizations about its effects on community structure requires comparisons under a range of conditions. We tested if: (1) density dependent regulation occurs at the level of an entire plant community as well as within individual species; (2) the intensity (effect of increasing community density on mean plant mass) and importance (the effect of increasing density, relative to other factors, on mean plant mass) of competition increases, decreases or remains unchanged with increasing fertilization; (3) there are species-specific responses to changes in community density and productivity. In 63 1 m2 plots, we manipulated the abundance of the nine most common species by transplanting or removing them to create a series of Initial Community Densities above and below the average natural field density, such that the relative proportion of species was consistent for all densities. Plots were randomly assigned to one of three fertilizer levels. At the community level, negative density dependence of mean plant size was observed for each of the 4 years of the study and both the intensity and importance of competition increased each year. At the species level, most species' mean plant mass were negatively density dependent. Fertilizer had a significant effect only in the final year when it had a negative effect on mean plant mass. Our data demonstrate a yield-density response at the entire community-level using perennial plant species in a multi-year experiment.


Experiences of renal transplants from donors with renal cell carcinoma after ex vivo partial nephrectomy.
Routine evaluation of kidney donors occasionally reveals an incidental renal mass with an otherwise satisfactory kidney function. The use of such a kidney with an enhancing mass for transplantation is a matter of debate owing to a possible risk of transmission of donor malignancies. We report our experience of kidney transplants from donors with renal cell carcinoma, after ex vivo resection of the renal mass. Two women aged 44 and 56 years were diagnosed with enhancing renal masses measuring 0.9 cm and 0.7 cm, respectively, during donor evaluation for kidney transplantation. Both patients and their families were informed of a potential risk of recurrent renal cell carcinoma following transplantation. Renal function test results of both donors satisfied the living donor selection criteria. Laparoscopic live donor nephrectomy was performed with ex vivo resection of renal masses on the bench table. Immediate pathological analysis revealed a renal cell carcinoma with a margin of normal renal parenchyma before transplantation. Regimens based on mammalian target of rapamycin inhibitors, which are known for their antitumoral properties, were used for immunosuppression in both recipients. None of the recipients showed recurrence or metastasis during the follow-up period, which was longer than 3 years after transplantation. In light of the ongoing shortage of kidney donors, kidneys with small renal cell carcinoma could be considered for transplantation after appropriate removal of the lesion, with a very low risk of recurrent disease.


Convulxin binding to platelet receptor GPVI: competition with collagen related peptides.
Convulxin (CVX), a potent platelet aggregating protein from the venom of the snake Crotalus durissus terrificus, is known to bind to the platelet collagen receptor, glycoprotein VI (GPVI). CVX binding to human platelets was investigated by flow cytometry, using fluorescein labeled convulxin (FITC-CVX). Scatchard analysis indicated high and low affinity binding sites with Kd values of 0.6 and 4 nM and Bmax values of 1200 and 2000 binding sites per platelet. FITC-CVX binding was inhibited by collagen related peptides (CRPs) comprising a repeated GPO sequence, namely GCO(GPO)(10)GCOGNH(2) and GKO(GPO)(10)GKOGNH(2), which also bind to receptor GPVI. These peptides (monomeric or cross-linked forms) gave a high affinity inhibition of 10-20% for concentrations between 10 ng/ml and 5 microg/ml, followed by a second phase of inhibition at concentrations greater than 5 microg/ml. It was shown also that the inhibition of FITC-CVX binding by CRPs was independent on the time of preincubation of platelets with CRPs, and the same percentage of inhibition was seen with various concentrations of convulxin. Confocal microscopy of the distribution of FITC-CVX binding sites on platelets showed an homogeneous distribution of FITC-CVX bound to GPVI, although some limited clustering may exist.


Use of a Removable Mandibular Neuroprosthesis for the Reduction of Posttraumatic Stress Disorder (PTSD) and Mild Traumatic Brain Injury/PTSD/Associated Nightmares, Headaches, and Sleep Disturbances.
Posttraumatic stress disorder (PTSD) has been associated with nighttime headaches (HAs), nightmares (NMs), and difficulty falling or staying asleep (sleep disturbances [SD]). The authors of the current study evaluated the correlative elements of using a removable mandibular neuroprosthesis (RMN) and the reduction of these symptoms in participants diagnosed with PTSD or mild traumatic brain injury (mTBI)/PTSD. The RMN device is a form of specialized dental splint that has a potential to reduce the painful stimuli of bruxing and potential upregulation of threat response systems that may occur during sleep. A sample of 32 individuals was selected through random assignment from a volunteer base of 200 volunteers for examination by self-report according to an A-B-A-B design. The sample included 25 men and 7 women between the ages of 21 and 65; 21 had military experience and 11 were civilians. Participants were asked to rate the frequency and intensity of their HAs, NMs, and SD during each phase. Their responses were scored using a custom survey (equivalent forms reliability) that provides ratio-scaled results for symptom frequency and intensity. The original number of participants was 35 with three participants dropping out before the conclusion of the study. Survey scores for PTSD-related sleep symptoms were relatively high at baseline (x̄=0.52) and significantly lower in the first experimental phase (x̄=0.20). Scores in the second experimental phase were likewise lower (x̄=0.38). Significant reductions in symptoms were reported across all three dimensions. All participants reported some improvement in symptoms while using the device. No participants reported worsening of any symptoms as a result of using the RMN. Participants commonly reported that improvements in symptoms were immediate and did not diminish over time. Data indicate that there is a negative correlation between the use of an RMN and the reduction of HAs, NMs, and SD in persons diagnosed with PTSD or mTBI/PTSD.


Clonal diversity impacts coral cover in Acropora cervicornisthickets: Potential relationships between density, growth, and polymorphisms.
As coral reefs decline, cryptic sources of resistance and resilience to stress may be increasingly important for the persistence of these communities. Among these sources, inter- and intraspecific diversity remain understudied on coral reefs but extensively impact a variety of traits in other ecosystems. We use a combination of field and sequencing data at two sites in Florida and two in the Dominican Republic to examine clonal diversity and genetic differentiation of high- and low-density aggregations of the threatened coral Acropora cervicornisin the Caribbean. We find that high-density aggregations called thickets are composed of up to 30 genotypes at a single site, but 47% of genotypes are also found as isolated, discrete colonies outside these aggregations. Genet-ramet ratios are comparable for thickets (0.636) and isolated colonies after rarefaction (0.569), suggesting the composition of each aggregation is not substantially different and highlighting interactions between colonies as a potential influence on structure. There are no differences in growth rate, but a significant positive correlation between genotypic diversity and coral cover, which may be due to the influence of interactions between colonies on survivorship or fragment retention during asexual reproduction. Many polymorphisms distinguish isolated colonies from thickets despite the shared genotypes found here, including putative nonsynonymous mutations that change amino acid sequence in 25 loci. These results highlight intraspecific diversity as a density-dependent factor that may impact traits important for the structure and function of coral reefs.


Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain.
Excitotoxic damage may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected at birth, the glutamatergic analog ibotenate induces mouse brain lesions that strikingly mimic human microgyria. When ibotenate is injected at postnatal day 5, it produces transcortical necrosis and white matter cysts that mimic human perinatal hypoxic-like lesions. Vasoactive intestinal peptide (VIP) has potent growth-related actions and neuroprotective properties that influence mitosis and neuronal survival in culture. The goal of this study was to assess the protective role of VIP against excitotoxic lesions induced by ibotenate in developing mouse brain. VIP cotreatment reduced ibotenate-induced microgyric-like cortical lesions and white matter cysts by up to 77 and 85%, respectively. VIP protective effects were reproduced by a peptide derived from activity-dependent neurotrophic factor (ADNF), a trophic factor released by VIP-stimulated astrocytes, and by stearyl norleucine VIP, a specific VIP agonist that does not activate adenylate cyclase. Neither forskolin, an adenylate cyclase activator, nor pituitary adenylate cyclase-activating peptide, provided VIP-like protection. VIP and neurotrophic analogs, acting through a cAMP-independent mechanism and inducing ADNF release, could represent new avenues in the understanding and prevention of human cerebral palsy.


Metabolic Modulation of Immunity: A New Concept in Cancer Immunotherapy.
Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations.


Barriers to and Facilitators of Delivering Brief Tobacco and Alcohol Interventions in Integrated Primary Care Settings.
Tobacco and excessive alcohol use are 2 of the top 3 preventable causes of death in the United States, yet most patients using these substances do not pursue treatment. Most patients do visit their primary care provider (PCP) annually, but PCPs report that they are not very effective in addressing behavior change with patients. Brief interventions for alcohol and tobacco use are effective and can be delivered by behavioral health providers (BHPs) embedded in the primary care setting. However, BHPs do not report frequent use of these interventions. The aim of the current study was to conduct the first examination of barriers to and facilitators of implementing brief interventions for at-risk drinking and tobacco use among integrated BHPs. BHPs (N = 285) working in a primary care setting for at least 6 months with at least 10% effort allocated to clinical activities were recruited through professional listservs (August-September 2016) and completed an online survey that assessed barriers to and facilitators of delivering brief tobacco and alcohol interventions in routine clinical practice. BHPs were primarily psychologists (48%) and social workers (33%) with cognitive-behavioral orientation (51%). The primary barriers to addressing tobacco use and at-risk drinking reported by BHPs was the perception that patients did not want to discuss or did not want to change these behaviors. The primary facilitators of addressing tobacco use and at-risk drinking were patients identifying cessation or reduction as a treatment goal, positive provider-patient relationship, and receiving referrals specifically for tobacco or alcohol use. Clinicians, researchers, and administrators should focus on strategies to increase the regularity with which BHPs assess and provide intervention for smoking and alcohol use in the context of other primary presenting concerns.


Cardiovascular risk factors after conversion from cyclosporine to tacrolimus in children after liver transplantation.
Calcineurin inhibitors (CNI) may increase the risk of cardiovascular (CV) events. This prospective study aimed to determine cardiovascular risk factors in pediatric patients after living related liver transplantation (LRLTx) 12 months after the conversion from cyclosporine (CS) to tacrolimus (TAC). The study group consisted of 7 children (5 females and 2 males) after LRLTx performed at the median age of 3 years (range 0.8-7.2), who received CS monotherapy for at least 5 years before it was switched to TAC. The median age at conversion was years 13.1 years (range 10.1-18). Weight BMI Z-score, 24-h ABPM (ambulatory blood pressure monitoring), renal function assessment, and fasting lipid and oxidative stress profiles were performed before and 12 months after conversion. Within 1-year follow-up, TAC was well tolerated and we did not observe any drug-related adverse effects or severe infections. Renal function, blood pressure, and lipid parameters did not differ after the conversion. Before the conversion, there was lower median glutathione (GSH) levels (748 vs. 776 [µmol/l]) and glutathione peroxidase (GPx) activity (31.4 vs. 32.4 [U/gHb]), but statistical significance was not reached (p>0.05). Asymmetric dimethylarginine (ADMA) levels were higher before conversion to TAC (0.93 vs. 0.69 [µmol/l], p=0.01), as were oxidized LDL (oxyLDL) levels (317 vs. 264 [mU/ml], p=0.04). There was no significant difference between CS and TAC in risk factors for CV events. Potential benefits in oxidative stress profile resulting from CS to TAC conversion may add another important area for further research.


The legacy of early attachments.
The impact of early close relationships on psychological development is one of the enduring questions of developmental psychology that is addressed by attachment theory and research. This essay evaluates what has been learned, and offers ideas for future research, by examining the origins of continuity and change in the security of attachment early in life, and its prediction of later behavior. The discussion evaluates research on the impact of changing family circumstances and quality of care on changes in attachment security, and offers new hypotheses for future study. Considering the representations (or internal working models) associated with attachment security as developing representations, the discussion proposes that (1) attachment security may be developmentally most influential when the working models with which it is associated have sufficiently matured to influence other emerging features of psychosocial functioning; (2) changes in attachment security are more likely during periods of representational advance; and (3) parent-child discourse and other relational influences shape these developing representations after infancy. Finally, other features of early parent-child relationships that develop concurrently with attachment security, including negotiating conflict and establishing cooperation, also must be considered in understanding the legacy of early attachments.


A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain.
To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities. Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored. The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients. Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function.


Astragaloside IV prevents damage to human mesangial cells through the inhibition of the NADPH oxidase/ROS/Akt/NF‑κB pathway under high glucose conditions.
Glomerular hypertrophy and hyperfiltration are the two major pathological characteristics of the early stages of diabetic nephropathy (DN), which are respectively related to mesangial cell (MC) proliferation and a decrease in calcium influx conducted by canonical transient receptor potential cation channel 6 (TRPC6). The marked increase in the production of reactive oxygen species (ROS) induced by hyperglycemia is the main sponsor of multiple pathological pathways in DN. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of ROS production in MCs. Astragaloside IV (AS‑IV) is an active ingredient of Radix Astragali which has a potent antioxidative effect. In this study, we aimed to investigate whether high glucose (HG)‑induced NADPH oxidase activation and ROS production contribute to MC proliferation and the downregulation of TRPC6 expression; we also wished to determine the effects of AS‑IV on MCs under HG conditions. Using a human glomerular mesangial cell line, we found that treatment with AS‑IV for 48 h markedly attenuated HG‑induced proliferation and the hypertrophy of MCs in a dose‑dependent manner. The intracellular ROS level was also markedly reduced following treatment with AS‑IV. In addition, the enhanced activity of NADPH oxidase and the expression level of NADPH oxidase 4 (Nox4) protein were decreased. Treatment with AS‑IV also inhibited the phosphorylation level of Akt and IκBα in the MCs. In addition, TRPC6 protein expression and the intracellular free calcium concentration were also markedly reduced following treatment with AS‑IV under HG conditions. These results suggest that AS‑IV inhibits HG‑induced mesangial cell proliferation and glomerular contractile dysfunction through the NADPH oxidase/ROS/Akt/nuclear factor‑κB (NF‑κB) pathway, providing a new perspective for the clinical treatment of DN.


Coding of Experimental Conditions in Microfluidic Droplet Assays Using Colored Beads and Machine Learning Supported Image Analysis.
To efficiently exploit the potential of several millions of droplets that can be considered as individual bioreactors in microfluidic experiments, methods to encode different experimental conditions in droplets are needed. The approach presented here is based on coencapsulation of colored polystyrene beads with biological samples. The decoding of the droplets, as well as content quantification, are performed by automated analysis of triggered images of individual droplets in-flow using bright-field microscopy. The decoding strategy combines bead classification using a random forest classifier and Bayesian inference to identify different codes and thus experimental conditions. Antibiotic susceptibility testing of nine different antibiotics and the determination of the minimal inhibitory concentration of a specific antibiotic against a laboratory strain of Escherichia coli are presented as a proof-of-principle. It is demonstrated that this method allows successful encoding and decoding of 20 different experimental conditions within a large droplet population of more than 105 droplets per condition. The decoding strategy correctly assigns 99.6% of droplets to the correct condition and a method for the determination of minimal inhibitory concentration using droplet microfluidics is established. The current encoding and decoding pipeline can readily be extended to more codes by adding more bead colors or color combinations.


Complete chloroplast genome sequence of Carthamus tinctorius L. from PacBio Sequel Platform.
Carthamus tinctorius L, also known as safflower, is an important oil crop planted worldwide. The complete chloroplast (cp) genome was reported in this study using the PacBio Sequel Platform. The cp genome with a total size of 152,963 bp consisted of two inverted repeats (25,128 bp) separated by a large single-copy region (84,124 bp) and a small single-copy region (18,583 bp). Further annotation revealed the cp genome contains 112 genes, including 79 protein-coding genes, 29 tRNA genes, and 4 rRNA genes. The information of the cp genome will be useful for investigation of evolution and molecular breeding of safflower in the future.


Rapid and direct effects of pH on connexins revealed by the connexin46 hemichannel preparation.
pH is a potent modulator of gap junction (GJ) mediated cell-cell communication. Mechanisms proposed for closure of GJ channels by acidification include direct actions of H+ on GJ proteins and indirect actions mediated by soluble intermediates. Here we report on the effects of acidification on connexin (Cx)46 cell-cell channels expressed in Neuro-2a cells and Cx46 hemichannels expressed in Xenopus oocytes. Effects of acidification on hemichannels were examined macroscopically and in excised patches that permitted rapid (<1 ms) and uniform pH changes at the exposed hemichannel face. Both types of Cx46 channel were found to be sensitive to cytoplasmic pH, and two effects were evident. A rapid and reversible closure was reproducibly elicited with short exposures to low pH, and a poorly reversible or irreversible loss occurred with longer exposures. We attribute the former to pH gating and the latter to pH inactivation. Half-maximal reduction of open probability for pH gating in hemichannels occurs at pH 6.4. Hemichannels remained sensitive to cytoplasmic pH when excised and when cytoplasmic [Ca2+] was maintained near resting ( approximately 10(-7) M) levels. Thus, Cx46 hemichannel pH gating does not depend on cytoplasmic intermediates or a rise in [Ca2+]. Rapid application of low pH to the cytoplasmic face of open hemichannels resulted in a minimum latency to closure near zero, indicating that Cx46 hemichannels directly sense pH. Application to closed hemichannels extended their closed time, suggesting that the pH sensor is accessible from the cytoplasmic side of a closed hemichannel. Rapid closure with significantly reduced sensitivity was observed with low pH application to the extracellular face, but could be explained by H+ permeation through the pore to reach an internal site. Closure by pH is voltage dependent and has the same polarity with low pH applied to either side. These data suggest that the pH sensor is located directly on Cx46 near the pore entrance on the cytoplasmic side.


Post Vaccination Guillain Barre Syndrome: A Case Report.
Guillain-Barre syndrome is a rare but fatal autoimmune disease. The exact cause of Guillain-Barre syndrome is still unknown. The most common known etiology of Guillain-Barre syndrome is infectious disease notably caused by Campylobacter jejuni. A very small fraction of people can develop Guillain-Barre syndrome due to vaccines and vaccinations like a meningococcal vaccine, poliovirus vaccine, influenza vaccine, and rabies vaccine. Of all these, rabies is fatal invariably. It can be preventable if diagnosed early and post-exposure treatment is followed according to the World Health Organization guidelines. Older formulations of rabies vaccines are cultured in the neural tissues and have been found to have an increased risk of Guillain-Barre syndrome. Although less immunogenic older formulations of rabies vaccines are more commonly used in Asian and South American countries due to their cost-effective nature. There is little to no data available on the incidence of Guillain-Barre syndrome due to vaccinations in Pakistan. Most of the cases of Guillain-Barre syndrome due to vaccination are either undiagnosed or misdiagnosed. In this case report, we are presenting a case of vaccine-associated Guillain-Barre syndrome due to neural tissue anti-rabies vaccine in a young girl, who presented with lower limb weakness, inability to pass urine and abdominal pain.


Quantum entanglement in plasmonic waveguides with near-zero mode indices.
We investigate the quantum entanglement between two quantum dots (QDs) in a plasmonic waveguide with a near-zero mode index, considering the dependence of concurrence on interdot distance, QD waveguide frequency detuning, and coupling strength ratio. High concurrence is achieved for a wide range of interdot distances due to the near-zero mode index, which largely relaxes the strict requirement of interdot distance in conventional dielectric waveguides or metal nanowires. The proposed QD waveguide system with near-zero phase variation along the waveguide near the mode cutoff frequency shows very promising potential in quantum optics and quantum information processing.


Nonpharmacological Treatment of Army Service Members with Chronic Pain Is Associated with Fewer Adverse Outcomes After Transition to the Veterans Health Administration.
Potential protective effects of nonpharmacological treatments (NPT) against long-term pain-related adverse outcomes have not been examined. To compare active duty U.S. Army service members with chronic pain who did/did not receive NPT in the Military Health System (MHS) and describe the association between receiving NPT and adverse outcomes after transitioning to the Veterans Health Administration (VHA). A longitudinal cohort study of active duty Army service members whose MHS healthcare records indicated presence of chronic pain after an index deployment to Iraq or Afghanistan in the years 2008-2014 (N = 142,539). Propensity score-weighted multivariable Cox proportional hazard models tested for differences in adverse outcomes between the NPT group and No-NPT group. NPT received in the MHS included acupuncture/dry needling, biofeedback, chiropractic care, massage, exercise therapy, cold laser therapy, osteopathic spinal manipulation, transcutaneous electrical nerve stimulation and other electrical manipulation, ultrasonography, superficial heat treatment, traction, and lumbar supports. Primary outcomes were propensity score-weighted proportional hazards for the following adverse outcomes: (a) diagnoses of alcohol and/or drug disorders; (b) poisoning with opioids, related narcotics, barbiturates, or sedatives; (c) suicide ideation; and (d) self-inflicted injuries including suicide attempts. Outcomes were determined based on ICD-9 and ICD-10 diagnoses recorded in VHA healthcare records from the start of utilization until fiscal year 2018. The propensity score-weighted proportional hazards for the NPT group compared to the No-NPT group were 0.92 (95% CI 0.90-0.94, P < 0.001) for alcohol and/or drug use disorders; 0.65 (95% CI 0.51-0.83, P < 0.001) for accidental poisoning with opioids, related narcotics, barbiturates, or sedatives; 0.88 (95% CI 0.84-0.91, P < 0.001) for suicide ideation; and 0.83 (95% CI 0.77-0.90, P < 0.001) for self-inflicted injuries including suicide attempts. NPT provided in the MHS to service members with chronic pain may reduce risk of long-term adverse outcomes.


Pre-analytical sample quality: metabolite ratios as an intrinsic marker for prolonged room temperature exposure of serum samples.
Advances in the "omics" field bring about the need for a high number of good quality samples. Many omics studies take advantage of biobanked samples to meet this need. Most of the laboratory errors occur in the pre-analytical phase. Therefore evidence-based standard operating procedures for the pre-analytical phase as well as markers to distinguish between 'good' and 'bad' quality samples taking into account the desired downstream analysis are urgently needed. We studied concentration changes of metabolites in serum samples due to pre-storage handling conditions as well as due to repeated freeze-thaw cycles. We collected fasting serum samples and subjected aliquots to up to four freeze-thaw cycles and to pre-storage handling delays of 12, 24 and 36 hours at room temperature (RT) and on wet and dry ice. For each treated aliquot, we quantified 127 metabolites through a targeted metabolomics approach. We found a clear signature of degradation in samples kept at RT. Storage on wet ice led to less pronounced concentration changes. 24 metabolites showed significant concentration changes at RT. In 22 of these, changes were already visible after only 12 hours of storage delay. Especially pronounced were increases in lysophosphatidylcholines and decreases in phosphatidylcholines. We showed that the ratio between the concentrations of these molecule classes could serve as a measure to distinguish between 'good' and 'bad' quality samples in our study. In contrast, we found quite stable metabolite concentrations during up to four freeze-thaw cycles. We concluded that pre-analytical RT handling of serum samples should be strictly avoided and serum samples should always be handled on wet ice or in cooling devices after centrifugation. Moreover, serum samples should be frozen at or below -80°C as soon as possible after centrifugation.


Akathisia variants and tardive dyskinesia.
Eighty-two schizophrenic outpatients receiving maintenance antipsychotic medication were assessed for akathisia and tardive dyskinesia. Thirty-nine (48%) manifested patterns of nondyskinetic, restless movement characteristic of akathisia. On the basis of their clinical features, these patients were divided into three groups: "acute" akathisia (recent onset, related to an increase in antipsychotic drug dose); "pseudoakathisia" (motor signs but no subjective symptoms); and "chronic" akathisia (a mixed category including persistent acute akathisia and "tardive" akathisia with the pharmacologic characteristics of tardive dyskinesia). Coarse, jerky foot tremor was observed as an invariable accompaniment of acute akathisia. A significant association was found between choreoathetoid limb dyskinesias, orofacial dyskinesias, and the presence of chronic akathisia. Also, the findings suggested a possible relationship between pseudoakathisia, orofacial and limb dyskinesia, and the severity of negative schizophrenic symptoms.


How many valid measurements are necessary to assess liver fibrosis using FibroScan® in patients with chronic viral hepatitis? An analysis of subjects with at least 10 valid measurements.
Using FibroScan® to obtain a reliable liver stiffness measurement (LSM) may require more than 10 valid measurements (VMs), according to the manufacturer's recommendations. However, this requirement lacks scientific evidence in support thereof. We investigated the minimal number of VMs required to assess liver fibrosis without significant loss of accuracy in patients with chronic hepatitis B (CHB) and C (CHC) and predictors of discordance between LSM and liver biopsy (LB). Between January 2005 and December 2009, we prospectively enrolled 182 patients with CHB and 68 patients with CHC who were to undergo LB and LSM before starting antiviral treatment. Only LSMs with at least 10 VMs were considered reliable. The Batts and Ludwig scoring system was used for histologic assessment. The mean age and body mass index were 46.0 years and 23.4 kg/m² in patients with CHB and 49.7 years and 23.1 kg/m² in those with CHC, respectively. The median elasticity scores from the first 3, first 5, and all VMs taken significantly predicted fibrosis stages ≥F2 and F4 (all p<0.05) without significant differences (all p>0.05 by DeLong's method). Alanine aminotransferase (ALT) was the only predictor of discordance in fibrosis stage as estimated by the median elasticity score from the first 3 VMs and by LB in patients with CHB, whereas no significant predictor was identified in those with CHC. After comparison of patients who had more than 10 valid measurements for LSM, three VMs may be enough to assess liver fibrosis using LSM without significant loss of accuracy in patients with CHC and patients with CHB. However, ALT should be considered when interpreting LSM for patients with CHB.


Cold-activated brown adipose tissue in healthy men.
Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. We studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], < 25) and 14 who were overweight or obese (BMI, > or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry. Brown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation. The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.


Computed Tomography-guided Radiofrequency Ablation for Sub-diaphragm Hepatocellular Carcinoma: Safety and Efficacy of Inducing an Artificial Pneumothorax.
We retrospectively evaluated the safety and efficacy of artificial pneumothorax induction to perform computed tomography (CT)-guided radiofrequency ablation (RFA) for sub-diaphragm hepatocellular carcinomas (HCCs). From June 2008 to October 2010 at our institution, 19 HCCs (16 patients) were treated using CT-guided RFA after artificial pneumothorax induction. A 23-G needle was inserted into the liver surface at a site of 2 connected pleurae without lung tissue. After a small amount of air was injected, the pleural space widened, creating a small pneumothorax. Additional air was insufflated via a newly inserted 18-G cannula to raise the lung away from the planned puncture line for RFA. The electrode was then advanced transthoracically. Ablation was performed using a cool-tip electrode with manual impedance control mode. The injected air was then aspirated as much as possible. Artificial pneumothorax was successfully induced in all cases. The average total volume of injected air in each case was 238ml. No artificial pneumothorax-related complication occurred; lung injury occurred in one case during RF electrode insertion. No local progression occurred during follow-up. Recurring HCCs were observed in eight patients. Artificial pneumothorax induction is safe and effective for CT-guided RFA of sub-diaphragm HCCs, which are difficult to locate on US.


Determining Selection across Heterogeneous Landscapes: A Perturbation-Based Method and Its Application to Modeling Evolution in Space.
Spatial structure can decisively influence the way evolutionary processes unfold. To date, several methods have been used to study evolution in spatial systems, including population genetics, quantitative genetics, moment-closure approximations, and individual-based models. Here we extend the study of spatial evolutionary dynamics to eco-evolutionary models based on reaction-diffusion equations and adaptive dynamics. Specifically, we derive expressions for the strength of directional and stabilizing/disruptive selection that apply both in continuous space and to metacommunities with symmetrical dispersal between patches. For directional selection on a quantitative trait, this yields a way to integrate local directional selection across space and determine whether the trait value will increase or decrease. The robustness of this prediction is validated against quantitative genetics. For stabilizing/disruptive selection, we show that spatial heterogeneity always contributes to disruptive selection and hence always promotes evolutionary branching. The expression for directional selection is numerically very efficient and hence lends itself to simulation studies of evolutionary community assembly. We illustrate the application and utility of the expressions for this purpose with two examples of the evolution of resource utilization. Finally, we outline the domain of applicability of reaction-diffusion equations as a modeling framework and discuss their limitations.


A novel link between FMR gene and the JNK pathway provides clues to possible role in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is an aggressive form of thoracic cancer with poor prognosis. While some studies have identified the molecular alterations associated with MPM, little is known about their role in MPM. For example, fragile X mental retardation (FMR) gene is up-regulated in MPM but its role in MPM is unknown. Here, utilizing Drosophila genetics, I investigate the possible role FMR may be playing in MPM. I provide evidence which suggests that FMR may contribute to tumorigenesis by up-regulating a matrix metalloprotease (MMP) and by degrading the basement membrane (BM), both important for tumor metastasis. I also demonstrate a novel link between FMR and the JNK pathway and suggest that the effects of FMR in MPM could in part be mediated by up-regulation of the JNK pathway.


Ngi and Internet2: accelerating the creation of tomorrow's internet.
Internet2 is a consortium of leading U.S. universities working in partnership with industry and the U.S. government's Next Generation Internet (NGI) initiative to develop a faster, more reliable Internet for research and education including enhanced, high-performance networking services and the advanced applications that are enabled by those services [1]. By facilitating and coordinating the development, deployment, operation, and technology transfer of advanced, network-based applications and network services, Internet2 and NGI are working together to fundamentally change the way scientists, engineers, clinicians, and others work together. [http://www.internet2.edu] The NGI Program has three tracks: research, network testbeds, and applications. The aim of the research track is to promote experimentation with the next generation of network technologies. The network testbed track aims to develop next generation network testbeds to connect universities and federal research institutions at speeds that are sufficient to demonstrate new technologies and support future research. The aim of the applications track is to demonstrate new applications, enabled by the NGI networks, to meet important national goals and missions [2]. [http://www.ngi.gov/] The Internet2/NGI backbone networks, Abilene and vBNS (very high performance Backbone Network Service), provide the basis of collaboration and development for a new breed of advanced medical applications. Academic medical centers leverage the resources available throughout the Internet2 high-performance networking community for high-capacity broadband and selectable quality of service to make effective use of national repositories. The Internet2 Health Sciences Initiative enables a new generation of emerging medical applications whose architecture and development have been restricted by or are beyond the constraints of traditional Internet environments. These initiatives facilitate a variety of activities to foster the development and deployment of emerging applications that meet the requirements of clinical practice, medical and related biological research, education, and medical awareness throughout the public sector. Medical applications that work with high performance networks and supercomputing capabilities offer exciting new solutions for the medical industry. Internet2 and NGI,strive to combine the expertise of their constituents to establish a distributed knowledge system for achieving innovation in research, teaching, learning, and clinical care.


Assessment of EGFR/HER2 dimerization by FRET-FLIM utilizing Alexa-conjugated secondary antibodies in relation to targeted therapies in cancers.
The expression level of the HER family is unreliable as a predictive marker for targeted therapies in cancer. Thus, there is a need to develop other biomarkers, which can be used to accurately select responsive patients for targeted therapies. The HER dimerization status may be more important than HER receptor expression per se in determining sensitivity or resistance to a given therapeutic agent. The aim of the study is to develop a FRET assay using dye conjugated secondary antibodies to assess HER receptor dimerization. Using primary antibodies from different species in conjunction with Alexa488 and Alexa546 conjugated secondary antibodies, we validated our EGFR/HER2 dimerization assay in three cell lines, EGFR positive A431 cells as well as HER2 positive breast cell lines BT474 and SKBR3 cells. Finally, we applied our assay to assess EGFR/HER2 dimerization in paraffin embedded cell pellets. Our results show promise for the assay to be applied to tumor samples in order to assess the prognostic significance and predictive value of HER receptor dimerization in various cancers.


Diet Quality Profile of Track-and-Field Paralympic Athletes.
This study aimed to assess the diet quality of Brazilian Paralympic track-and-field team sprinters and its variation between days. All sprinters (n = 28) were invited, and 20 (13 men and seven women) accepted the invitation consisting of 13 athletes with visual impairment, four with cerebral palsy, and three with limb deficiency. The dietary intake was recorded by photographic register on four consecutive days, and diet quality was determined using a revised version of the Healthy Eating Index for the Brazilian population. Physical activity was assessed using an accelerometer, and metabolic unit information was used to classify exercise intensity. Variance Analysis Model and Bonferroni multiple comparisons were used to assess relationships between variables. The correlations between variables used Pearson linear correlation coefficient. The results show that revised version of the Healthy Eating Index score was classified as "needs to be modified" for all athletes. The maximum score for the components "Whole fruits," "Total vegetables," and "Dark green and orange vegetables and legumes" was achieved by 23.1% and 14.3%, 7.7% and 14.3%, and 46.2% and 57.8% of male and female athletes, respectively. Only 38.5% of the male athletes achieved the maximum score for the "Total cereal" component. Female athletes achieved higher scores than male athletes for the "Milk and dairy products" component (p = .03). Intake of whole grain cereals, dairy products, vegetables, and whole fruits needs modifications to improve adequate intake of vitamins and antioxidants, highlighting the need of continuous actions of nutrition education for this population.