Effect of microcirculatory resistance on coronary blood flow and instantaneous wave-free ratio: A computational study.
The instantaneous wave-free ratio (iFR) has been proposed to estimate the hemodynamic severity of atherosclerotic stenosis in coronary arteries. The atherosclerotic stenosis in a proximal coronary artery could change its distal microcirculatory resistance (MR). However, there is a lack of investigation about the effect of MR variation on the blood flow and iFR of stenotic coronary arteries. We aim to investigate the changes of blood flow and iFR caused by distal MR variation. Four three-dimensional models of coronary arteries were reconstructed from the computed tomography images of two normal cases and two cases with 74.9% and 96.4% (in area) stenoses in a large branch of left anterior descending artery (LAD). Computational fluid dynamics simulation was performed on each model under 6 MR situations: hyperemia as the reference situation, resting when MR was multiplied by 8/3 in all outlet branches, h-one-1.5 and h-one-2 when MR was multiplied by 1.5 and 2.0 in one branch (the stenotic, or the corresponding branch in normal case) of LAD, h-branches-1.5 and h-branches-2 when MR was multiplied by 1.5 and 2.0 in the stenotic/corresponding and its cognate branches. Flow rate and iFR of each outlet branch were then calculated and compared between different MR situations to investigate the effect of MR variation on flow rate and iFR. In the 74.9% stenosed and normal cases, referring to the hyperemia situation, the increase of MR in any branch significantly decreased its flow rate and increased its iFR, with limited effect on the flow rate (<3%) and iFR (<0.01) of other branches. However, in the 96.4% stenosed case, the doubled MR in the stenosed branch (h-one-2) significantly increased the flow rate (>10%) and iFR (>0.05) of its cognate branches. The increase of MR in a normal or mildly stenosed branch of coronary artery decreases its blood flow and increases its iFR, with limited effect on other branches. Whereas, the increase of MR in a severely stenotic large branch could significantly increase the flow velocity and iFR of its cognate branches.


Impaired Retinal Capillary Function in Patients With Alzheimer Disease.
Extensive evidence indicates that vasculopathy, especially the level of microcirculation, contributes to neurodegeneration in Alzheimer disease (AD). However, it is not easy to directly monitor cerebral microcirculation. The retinal microvasculature has been proposed as a surrogate measure to study cerebral vascular changes. Indeed, decreased retinal microvascular network densities were reported in patients with AD. We sought to determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) in patients with AD. Twenty patients (age 60-84 years, mean ± SD: 72.8 ± 7.7 years) with AD and 14 age-matched cognitively normal controls (CN, age 62-81 years, mean ± SD: 68.6 ± 6.7 years.) were recruited. There were no differences in vascular risk factors, including smoking, hypertension, hyperlipidemia, Type 2 diabetes, and cardiovascular disease, between the groups. One eye of each subject in both groups was imaged. Retinal blood flow (RBF) was measured using a retinal function imager, and retinal capillary density (RCD, expressed as fractal dimension Dbox) was measured using optical coherence tomography angiography. RCF was defined as the ratio of RBF to RCD. RCF was 1.62 ± 0.56 nl/s/Dbox (mean ± SD) in the AD group, which was significantly lower than that (2.56 ± 0.25 nl/s/Dbox, P < 0.01) in the CN group. The change of RCF in the AD group represented 28% lower than in the CN group. RCF was significantly and positively correlated with RBF in the AD group (r = 0.98, P < 0.05) and in the CN group (r = 0.65, P < 0.05). Our study is the first to demonstrate impaired retinal capillary function in patients with AD. The alteration of RCF was mainly due to decreased retinal blood flow, which is transferred by the capillary network. The RCF may be developed as a biomarker of impaired cerebral microcirculation in patients with AD.


β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice.
Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3-expressing regulatory T cells (Foxp3(+)Tregs). Dysregulation of the IL-2-IL-2 receptor axis is associated with aberrant Foxp3(+)Tregs and T cell-mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3(+)Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3(+)Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3(+)Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3(+)Tregs in dsAAVmIP-IL2-treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell-specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell-specific IL-2 expands an islet-resident Foxp3(+)Tregs pool that effectively suppresses ongoing type 1 diabetes long term.


Surgical technique for the management of corneal perforation in brittle cornea.
Brittle cornea syndrome is among the few special scenarios in ophthalmology that are a nightmare not only for the operating surgeon but also for the patient. Here, the thin and fragile corneas are unable to maintain the shape and structural integrity of the globe and are more prone to minor traumatic or spontaneous corneal perforations. Suturing a brittle cornea and closure of the corneal perforation in a brittle cornea are very challenging requiring the utmost care and special precautions. If proper measures are not taken during the surgery, it may be difficult to salvage the eye. Hence, it is imperative to diagnose appropriately, suture effectively, taking necessary preventive measures in salvaging these corneas. This manuscript aims at providing tips for handling brittle corneal perforations. It will also discuss the problems encountered during surgery, highlight the suturing techniques that can be customized, and finally give an insight into postoperative care.


Rectal stricture: a rare presentation of primary amyloidosis.
Amyloidosis is a process were an abnormal protein deposits in tissues. This deposit accumulates and may eventually cause a variety of nonspecific symptoms. Primary amyloidosis refers to amyloidosis caused by an underlying plasma cell disorder. Protein electrophoresis showing a monoclonal band is suggestive of the disease but in order to make the diagnosis, the presence of amyloid deposition on tissues must be shown by biopsy. We present a woman in whom primary amyloid is manifested as a rectal stricture. She came to the gastroenterology clinics complaining of hematochezia, weight loss, decreased appetite and abdominal pain. Her only sign of organ damage was mild to moderate proteinuria (80mg per day). The patient also had an unusual retroperitoneal infiltration with encasement of the abdominal aorta.


Effectiveness of cleaning-disinfection wipes and sprays against multidrug-resistant outbreak strains.
Hospital rooms play an important role in the transmission of several health care-associated pathogens. During the last few years, a number of innovative cleaning-disinfecting products have been brought to market. In this study, commercially available products combining cleaning and disinfection were compared, using 2 different application methods. The aim was to determine which product was most effective in simultaneous cleaning and disinfection of surfaces. Seven cleaning-disinfecting wipes and sprays based on different active ingredients were tested for their efficacy in removal of microbial burden and proteins. Efficacy was tested with known Dutch outbreak strains: vancomycin-resistant enterococci (VRE), Klebsiella pneumoniae OXA-48, or Acinetobacter baumannii. For all bacteria, ready-to-use cleaning-disinfecting products reduced the microbial count with a log10 reduction >5 with a 5-minute exposure time, with the exception of a spray based on hydrogen peroxide. Omitting the aforementioned hydrogen peroxide spray, there were no significant differences between use of a wipe or spray in bacterial load reduction. Using adenosine triphosphate (ATP) measurements, a significant difference in log10 relative light units (RLU) reduction between various bacteria (P ≤ .001) was observed. In general, a >5 log10 reduction of colony forming units (CFU) for tested wipes and sprays was obtained for all tested bacteria strains, with exception of hydrogen peroxide spray and VRE. Although ATP may show a difference between pre- and postcleaning, RLU reduction does not correlate with actual CFU reductions.


CpG island-mediated global gene regulatory modes in mouse embryonic stem cells.
Both transcriptional and epigenetic regulations are fundamental for the control of eukaryotic gene expression. Here we perform a compendium analysis of >200 large sequencing data sets to elucidate the regulatory logic of global gene expression programs in mouse embryonic stem (ES) cells. We define four major classes of DNA-binding proteins (Core, PRC, MYC and CTCF) based on their target co-occupancy, and discover reciprocal regulation between the MYC and PRC classes for the activity of nearly all genes under the control of the CpG island (CGI)-containing promoters. This CGI-dependent regulatory mode explains the functional segregation between CGI-containing and CGI-less genes during early development. By defining active enhancers based on the co-occupancy of the Core class, we further demonstrate their additive roles in CGI-containing gene expression and cell type-specific roles in CGI-less gene expression. Altogether, our analyses provide novel insights into previously unknown CGI-dependent global gene regulatory modes.


Validation of thwaites' diagnostic scoring system for the differential diagnosis of tuberculous meningitis and bacterial meningitis.
To compare the clinical features of patients with tuberculous meningitis (TBM) and bacterial meningitis (BM) and to validate Thwaites' diagnostic scoring system for the differential diagnosis of TBM and BM, a retrospective review of 211 patients with TBM or BM who were admitted to Huashan Hospital, Fudan University, from 2007 to 2012 was conducted. The clinical characteristics and laboratory data were compared, and Thwaites' diagnostic scores were assessed at the time of admission for the differential diagnosis of TBM and BM. Significant differences were observed between the 2 groups in general information, clinical features, and cerebrospinal fluid characteristics. The sensitivity and specificity of Thwaites' diagnostic scoring system for the differential diagnosis of TBM and BM were found to be 98.2% and 43.6%, respectively, with positive and negative predictive values being 65.9% and 95.8%, respectively. The sensitivity and specificity for the differential diagnosis of TBM and initially treated BM were 98.2% and 82.9%, respectively, but were only 98.2% and 24.2% for that of TBM and partially treated BM, respectively. Thus, Thwaites' diagnostic scoring system was found to be highly effective for the differential diagnosis of TBM and initially treated BM but was found to be less effective for that of TBM and partially treated BM.


Sigma-1 Receptor Antagonist (BD1047) Decreases Cathepsin B Secretion in HIV-Infected Macrophages Exposed to Cocaine.
Pathogenesis of HIV-associated neurocognitive disorders (HAND) is mediated through the infiltration of perivascular macrophages into the brain with the secretion of viral, neurotoxic and inflammatory proteins. One of these proteins is cathepsin B (CATB), a lysosomal cysteine protease that induces neuronal apoptosis, and increases in plasma and cerebrospinal fluid from HIV-1 infected patients (Cantres-Rosario et al. AIDS 27(3):347-356, 2013). Cocaine further potentiates CATB neurotoxicity in vitro and in vivo (Zenón et al. J NeuroImmune Pharmacol 9(5):703-715, 2014). Modulation of sigma-1 (Sig1R) by cocaine increases oxidative species, cytokines and other factors that promote lysosomal disruption. However, the role of Sig1R in CATB secretion and HIV-1 replication in macrophages exposed to cocaine is unknown. We hypothesized that pharmacological modulation of Sig1R would alter CATB secretion from HIV-1 infected macrophages in vitro and in vivo. To test our hypothesis, monocyte derived-macrophages (MDM) from HIV-1 seronegative donors were isolated, infected with HIV-1ADA, and pretreated with Sig1R antagonist (BD1047) or Sig1R agonist (PRE-084) prior to cocaine exposure and followed for 3,6,9 and 11 days post-infection (dpi). Experiments in vivo were conducted using the HIV encephalitis mouse model (HIVE) with BD1047 treatments prior to cocaine for 14 days. Results demonstrate that in presence of cocaine, BD1047 decreases CATB secretion at 11 dpi, while PRE-084 did not have an effect. In the mouse model, BD1047 treatment prior to cocaine decreased CATB expression, cleaved caspase-3 an p24 antigen levels, reduced astrocytosis, but did not increase MAP-2 or synaptophysin. Results demonstrate that Sig1R plays a role in the modulation of CATB levels in HIV-1 infected MDM exposed to cocaine in vitro and in vivo. Graphical Abstract .


Fast axonal transport of foreign transmitters in an identified serotonergic neurone of Aplysia californica.
1. Radioactively labelled compounds, several of which are neurotransmitters, were injected with pressure into the soma of the serotonergic giant cerebral neurone (g.c.n.) of Aplysia californica. The compounds injected were [3H]dopamine, [3H]DL-octopamine, [3H]histamine, [3H]gamma-aminobutyric acid and [3H]choline. 2. Substantial amounts of radioactivity appeared in the axons of the g.c.n. with all of the injected compounds. Except for [3H]choline, the amounts were similar to the amount appearing when [3H]serotonin is injected. 3. The biogenic amines, [3H]dopamine, DL-[3H]octopamine and [3H]histamine, all moved in the axon at velocities similar to that of [3H]serotonin. In contrast, the radioactivity in axons of cells injected with [3H]gamma-aminobutyric acid and [3H]choline moved much more slowly. In addition, the shapes of the spatial distributions of radioactivity in the axons of cells injected with the biogenic amines resembled that obtained when [3H]serotonin is injected. This distribution is characteristic of fast axonal transport. The spatial distributions of radioactivity in the axons of cells injected with [3H]gamma-aminobutyric acid and [3H]choline were markedly different. We thus conclude that [3H]dopamine, DL-[3H]octopamine and [3H]histamine move by fast axonal transport, whereas the radioactivity in the axons of cells injected with [3H]gamma-aminobutyric acid and [3H]choline does not. 4. Injection of large amounts of dopamine and octopamine reduced the export into the axon of [3H]serotonin injected into the same cell. Large amounts of choline did not reduce export of [3H]serotonin. We conclude that the biogenic amines compete with serotonin for the vesicular storage site and that they move by fast transport because they are sequestered by the serotonergic storage vesicle. 5. The specificity of uptake into the storage vesicle as assayed with this in vivo system is similar to the specificity of uptake into aminergic vesicles as previously studied in vitro.


Combined use of cyclophosphamide and Chalone 19-peptide in experimental breast cancer.
Cyclophosphamide is a potent anticancer drug, but its clinical utility is limited because of its severe side effects, in particular liver damage. Chalone 19-peptide induces apoptosis of tumor cells and inhibits tumor growth. The present study investigated the antitumor effects of a combination of cyclophosphamide and Chalone 19-peptide in experimental breast cancer. An animal model of breast cancer was developed, consisting of an MDA-MB-231 cell line implanted in the nude mouse. Eight doses of a combination of cyclophosphamide 50 mg/kg or 100 mg/kg and Chalone 19-peptide 6.6 mg/kg were administered, and the mice were euthanized 28 days after the final drug injection. Histopathologic analysis of tumor size, metastasis, and apoptosis of cancer cells was performed. Control mice were injected intraperitoneally with either cyclophosphamide alone or the same volume of solvent. Tumor sizes in the treatment groups were smaller than in the controls. No metastasis was found in the groups treated with cyclophosphamide and Chalone 19-peptide, but lung metastasis was found in controls. Liver damage in the groups treated with cyclophosphamide was more serious than in the other groups. Addition of Chalone 19-peptide can improve the ability of cyclophosphamide to inhibit tumor growth and also reduces side effects.


Network-Level Control of Frequency Tuning in Auditory Cortex.
Lateral inhibition is a fundamental circuit operation that sharpens the tuning properties of cortical neurons. This operation is classically attributed to an increase in GABAergic synaptic input triggered by non-preferred stimuli. Here we use in vivo whole-cell recording and two-photon Ca2+ imaging in awake mice to show that lateral inhibition shapes frequency tuning in primary auditory cortex via an unconventional mechanism: non-preferred tones suppress both excitatory and inhibitory synaptic inputs onto layer 2/3 cells ("network suppression"). Moreover, optogenetic inactivation of inhibitory interneurons elicits a paradoxical increase in inhibitory synaptic input. These results indicate that GABAergic interneurons regulate cortical activity indirectly via the suppression of recurrent excitation. Furthermore, the network suppression underlying lateral inhibition was blocked by inactivation of somatostatin-expressing interneurons (SOM cells), but not parvalbumin-expressing interneurons (PV cells). Together, these findings reveal that SOM cells govern lateral inhibition and control cortical frequency tuning through the regulation of reverberating recurrent circuits.


Bosnian study of APOE distribution (BOSAD): a comparison with other European populations.
The ε2, ε3 and ε4 alleles of APOE gene have been associated with several diseases in different populations. Data on the frequency of alleles are used in both a clinical and evolutionary context. Although the data on frequency of these alleles are numerous, there are no reports for the population of Bosnia and Herzegovina. To estimate the frequency of APOE alleles in a healthy Bosnian population and compare it to data for other European populations. Overall, 170 unrelated Bosnian subjects (108 female and 62 male), aged 53.0 (±5.0) years were included in this study. Genotypes were determined by real-time PCR. In our group the prevalence of heterozygotes E2/E3, E2/E4 and E3/E4 was 20.6%, 3.5% and 12.9%, respectively, while the prevalence of homozygotes E2/E2, E3/E3, E4/E4 was 0.6%, 61.2% and 1.2%, respectively, with a mean frequency of ε2, ε3 and ε4 alleles of 12.6%, 78.0% and 9.4%, respectively. In studied European populations we observed a linear, gradually increasing trend in the frequency of ε4 allele from South to North (Pearson's test 0,7656, p value <0.00001), and the Bosnian population fits into this pattern perfectly.


Role of androgen receptor splice variants, their clinical relevance and treatment options.
In this review, we summarize the importance of AR variants with a particular focus on clinically relevant members of this family. A non-systematic literature review was performed based on Medline and PubMed. Endocrine therapy represents the central paradigm for the management of prostate cancer. Eventually, in response to androgen ablation therapy, several resistance mechanisms against the endocrine therapy might develop that can circumvent the therapy approaches. One specific resistance mechanism that has gained increasing attention is the generation of alternatively spliced variants of the androgen receptor, with AR-V7 being the most prominent. More broadly, AR-V7 is one member of a group of alternatively spliced AR variants that share a common feature, the missing ligand-binding domain. These ΔLBD androgen receptor variants have shown the capability to induce androgen receptor-mediated gene transcription even under conditions of androgen deprivation and to drive cancer progression. The methods used for detecting AR-Vs, at least on the mRNA level, are well-advanced and harbor the potential to be introduced into clinical diagnostics. It is important to note, that the testing, especially of AR-V7 has its limitations in predicting treatment response. More promising is the great number of active clinical trials aimed at reducing the AR-Vs, and using this to re-sensitize CRPC towards endocrine treatment might provide additional treatment options for CRPC patients in the future.


Types and functions of heterogeneity in mycobacteria.
The remarkable ability of Mycobacterium tuberculosis to survive attacks from the host immune response and drug treatment is due to the resilience of a few bacilli rather than a result of survival of the entire population. Maintenance of mycobacterial subpopulations with distinct phenotypic characteristics is key for survival in the face of dynamic and variable stressors encountered during infection. Mycobacterial populations develop a wide range of phenotypes through an innate asymmetric growth pattern and adaptation to fluctuating microenvironments during infection that point to heterogeneity being a vital survival strategy. In this Review, we describe different types of mycobacterial heterogeneity and discuss how heterogeneity is generated and regulated in response to environmental cues. We discuss how this heterogeneity may have a key role in recording memory of their environment at both the single-cell level and the population level to give mycobacterial populations plasticity to withstand complex stressors.


[Primary distal renal tubular acidosis coexisting with malabsorption syndrome].
The authors present the case of 54-old man primary tubular acidosis coexisting with malabsorption syndrome. Deviation were: extension of QT interval, low level of potassium and calcium in the blood, perturbations of calcium metabolism and high level of PTH. Glucose, lactose and iron absorption curves were flat. The final diagnosis was given as a result of analysis of findings and literature. The patient underwent the vitamin D3, calcium and potassium preparations, hydrochlorotiazyd treatment. Megaloblastic anaemia was treated with vitamin B12 and folic acid. Such therapy gave considerable improvement in patient's general condition and normalisation of lab tests results. The authors try explain the etiopathogenesis of bones changes and high level of parathormone. They assume the attitude towards methods of therapy and necessary medicaments doses. Relationship between described syndromes remains inextricable. Roentgen image of ileum which suggests occlusion is still unexplainable. Described case seemed to be very interesting considering rarity of primary tubular acidosis and its coexistence with malabsorption syndrome.


Impact of tenofovir alafenamide vs. entecavir on hepatocellular carcinoma risk in patients with chronic hepatitis B.
Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method. In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.


Evaluation of Family Planning Counselling in North Jordan.
Counselling plays a key role in enhancing reproductive services, providing contraception-related information and supporting long-term family planning for women of childbearing age. This study aimed to evaluate family planning counselling sessions in selected governmental and private clinics in northern Jordan. This cross-sectional study was conducted between January and June 2016 in Irbid, Jordan. A total of 200 women attending two private clinics affiliated with the Jordanian Association for Family Planning and Protection (JAFPP) and six governmental clinics were invited to participate in the study. Counselling sessions were attended by an independent observer and evaluated with regards to their compliance with the standard Greet, Ask, Tell, Help, Explain, Return (GATHER) framework. A total of 198 women participated in the study (response rate: 99.0%), including 80 women (40.4%) from JAFPP clinics and 118 (59.6%) from governmental clinics. In total, 42.9% of the counselling sessions were deemed adequate, with providers applying 80% or more of the GATHER framework, while 26.8% of the sessions were deemed semi-adequate and 30.3% were considered inadequate. Counselling services provided in the governmental clinics were significantly less adequate than those provided in JAFPP clinics (P <0.001). The quality of counselling services in governmental family planning centres in Jordan needs to be improved to ensure that women receive the highest possible level of care. Healthcare policymakers should therefore focus on developing and supporting effective family planning counselling services in northern Jordan.


Development of Novel Polymeric Prodrugs Synthesized by Mechanochemical Solid-State Copolymerization of Hydroxyethylcellulose and Vinyl Monomers.
Novel polymeric prodrugs were synthesized by mechanochemical solid-state copolymerization of hydroxyethylcellulose and the methacryloyloxy derivative of 5-fluorouracil (5-FU). Copolymerization was about 94% complete after 4 h, and the polymeric prodrug was quantitatively obtained after 14 h of reaction. The number average molecular weight (Mn) and polydispersity (H) of the polymeric prodrug were 39000 g/mol and 6.20, respectively. Mechanical fracturing of the polymer in a stainless steel twin-shell blender improved these properties (Mn=16000 g/mol and H=1.94). 5-FU was sustainably released from the polymeric prodrugs, and the rate was not affected by the molecular weight or molecular weight distribution of the prodrug under the experimental conditions used. These results suggest that novel polymeric prodrugs composed of a polysaccharide and a synthetic polymer can be fabricated by mechanochemical solid-state copolymerization under anaerobic conditions.


An evaluation of the performance of three semantic background knowledge sources in comparative anatomy.
In this paper we evaluate the performance and usefulness of three semantic background knowledge sources for predicting synonymous anatomical terms across species boundaries. The reference sources under evaluation are UMLS, FMA-OBO and WordNet, which are applied to the anatomical ontologies of mouse and zebrafish. Our results show that the use of specialized knowledge sources leads to highly accurate predictions, verified through complete manual curation, which can be further improved by combining multiple of said sources. We argue that these three references complement each other in terms of granularity and specificity. From our results we conclude that these references can be used to create reliable ontology mappings with minimal human supervision.


Whole body, regional fat accumulation, and appetite-related hormonal response after hypoxic training.
The present study was conducted to determine change in regional fat accumulation and appetite-related hormonal response following hypoxic training. Twenty sedentary subjects underwent hypoxic (n = 9, HYPO, FiO(2) = 15%) or normoxic training (n = 11, NOR, FiO(2) = 20·9%) during a 4-week period (3 days per week). They performed a 4-week training at 55% of maximal oxygen uptake (V·O(2max)) for each condition. Before and after the training period, V·O(2max), whole body fat mass, abdominal fat area, intramyocellular lipid content (IMCL), fasting and postprandial appetite-related hormonal responses were determined. Both groups showed a significant increase in V·O(2max) following training (P<0·05). Whole body and segmental fat mass, abdominal fat area, IMCL did not change in either group. Fasting glucose and insulin concentrations significantly reduced in both groups (P<0·05). Although area under the curve for the postprandial blood glucose concentrations significantly decreased in both groups (P<0·05), the change was significantly greater in the HYPO group than in the NOR group (P<0·05). Changes in postprandial plasma ghrelin were similar in both groups. A significant reduction of postprandial leptin response was observed in both groups (P<0·05), while postprandial glucagon-like peptide-1 (GLP-1) concentrations increased significantly in the NOR group only (P<0·05). In conclusion, hypoxic training for 4 weeks resulted in greater improvement in glucose tolerance without loss of whole body fat mass, abdominal fat area or IMCL. However, hypoxic training did not have synergistic effect on the regulation of appetite-related hormones.


[Clinical observation of iron sucrose combined with recombinant human erythropoietin in the treatment of anemia of hip fracture in elderly patients].
To explore the clinical efficacy of iron sucrose combined with recombinant human erythropoietin(EPO) for the treatment of anemia in elderly patients with hip fracture. From February 2016 to April 2018, 96 elderly anemia patients who underwent hip fracture surgery were divided into three groups according to the treatment methods. All the three groups received anti-anemia treatment 3 days before operation. Among them, 32 cases in group A were treated with iron sucrose alone, 32 cases in group B were treated with recombinant human erythropoietin alone, and 32 cases in group C were treated with iron sucrose combined with recombinant human erythropoietin. The therapeutic effects of the three groups were observed and compared. The clinical effective rate in group C was significantly higher than that in group A and B (P<0.05). There was no significant difference in perioperative blood loss among the three groups(P>0.05), but the transfusion rate in group C was significantly lower than that in group A and B (P<0.05). There was no significant difference in hemoglobin and erythrocyte counts among the three groups before treatment(P>0.05), but the above indexes in group C were significantly higher than those in group A and B(P<0.05) at 1, 3 and 5 days after operation. There was no significant difference in the incidence of adverse drug reactions among the three groups(P>0.05). Compared with single drug, the combined use of sucrose and iron and recombinant human erythropoietin in the treatment of elderly hip fracture anemia has a definite effect. It can not only effectively improve the level of hemoglobin, ensure the smooth operation, but also reduce the blood transfusion rate of patients and promote their recovery after operation.


Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias.
Coordinated electrical activation of the heart is essential for the maintenance of a regular cardiac rhythm and effective contractions. Action potentials spread from one cell to the next via gap junction channels. Because of the elongated shape of cardiomyocytes, longitudinal resistivity is lower than transverse resistivity causing electrical anisotropy. Moreover, non-uniformity is created by clustering of gap junction channels at cell poles and by non-excitable structures such as collagenous strands, vessels or fibroblasts. Structural changes in cardiac disease often affect passive electrical properties by increasing non-uniformity and altering anisotropy. This disturbs normal electrical impulse propagation and is, consequently, a substrate for arrhythmia. However, to investigate how these structural changes lead to arrhythmias remains a challenge. One important mechanism, which may both cause and prevent arrhythmia, is the mismatch between current sources and sinks. Propagation of the electrical impulse requires a sufficient source of depolarizing current. In the case of a mismatch, the activated tissue (source) is not able to deliver enough depolarizing current to trigger an action potential in the non-activated tissue (sink). This eventually leads to conduction block. It has been suggested that in this situation a balanced geometrical distribution of gap junctions and reduced gap junction conductance may allow successful propagation. In contrast, source-sink mismatch can prevent spontaneous arrhythmogenic activity in a small number of cells from spreading over the ventricle, especially if gap junction conductance is enhanced. Beside gap junctions, cell geometry and non-cellular structures strongly modulate arrhythmogenic mechanisms. The present review elucidates these and other implications of passive electrical properties for cardiac rhythm and arrhythmogenesis.


Development of Improved Tumor-Residualizing, GRPR-Targeted Agents: Preclinical Comparison of an Endolysosomal Trapping Approach in Agonistic and Antagonistic Constructs.
Receptor-targeted radiopharmaceuticals based on low-molecular-weight carriers offer many clinically advantageous attributes relative to macromolecules but have generally been hampered by their rapid clearance from tumors, thus diminishing tumor-to-nontarget tissue ratios. Herein, we present a strategy using irreversible inhibitors (E-64 derivative) of cysteine cathepsins (CCs) as trapping agents to increase the tumor retention of receptor-targeted agents. Methods: We incorporated these CC-trapping agents into agonistic and antagonistic pharmacophores targeting the gastrin-releasing peptide receptor (GRPR). The synthesized radioconjugates with either an incorporated CC inhibitor or a matching control were examined using in vitro and in vivo models of the GRPR-positive, PC-3 human prostate cancer cell line. Results: From the in vitro studies, multiple techniques confirmed that the CC-trapping, GRPR-targeted constructs were able to increase cellular retention by forming intracellular macromolecule adducts. In PC-3 tumor-bearing xenograft mice, the CC-trapping, GRPR-targeted agonistic and antagonistic constructs led to an approximately 2-fold increase in tumor retention with a corresponding improvement in most tumor-to-nontarget tissue ratios over 72 h. Conclusion: CC endolysosomal trapping provides a pathway to increase the efficacy and clinical potential of low-molecular-weight, receptor-targeted agents.


Core-Level Binding Energies from GW: An Efficient Full-Frequency Approach within a Localized Basis.
The GW method is routinely used to predict charged valence excitations in molecules and solids. However, the numerical techniques employed in the most efficient GW algorithms break down when computing core excitations as measured by X-ray photoelectron spectroscopy (XPS). We present a full-frequency approach on the real axis using a localized basis to enable the treatment of core levels in GW. Our scheme is based on the contour deformation technique and allows for a precise and efficient calculation of the self-energy, which has a complicated pole structure for core states. The accuracy of our method is validated by comparing to a fully analytic GW algorithm. Furthermore, we report the obtained core-level binding energies and their deviations from experiment for a set of small molecules and large polycyclic hydrocarbons. The core-level excitations computed with our GW approach deviate by less than 0.5 eV from the experimental reference. For comparison, we also report core-level binding energies calculated by density functional theory (DFT)-based approaches such as the popular delta self-consistent field (ΔSCF) method. Our implementation is optimized for massively parallel execution, enabling the computation of systems up to 100 atoms.


Visualization of methylglyoxal in living cells and diabetic mice model with a 1,8-naphthalimide-based two-photon fluorescent probe.
Methylglyoxal (MGO), a dicarbonyl metabolite, is the most studied precursor of advanced glycation end-products (AGEs) and its elevated levels have also been associated with various pathologies. Hence, the development of effective methods for monitoring MGO in live cells and in vivo is of great importance for ascertaining the onset and progress of related diseases. Herein, we designed and synthesized an endoplasmic reticulum-targeting two-photon fluorescent probe called NI-OPD for the detection of MGO with high selectivity, sensitivity, and hypotoxicity. The probe was successfully applied for monitoring MGO in living cells and a diabetic mice model. The two-photon fluorescence images confirmed that the endogenous MGO in the liver and kidney tissues of diabetic mice is higher than that of normal mice. Furthermore, it revealed that after treatment with metformin, a widely used hypoglycemia drug, the diabetic mice showed a decreased concentration of MGO in liver and kidney tissues. Thus, NI-OPD may serve as a useful tool for the detection of MGO and for studying the relationships between MGO and pathological and biological processes in biosystems.


Studies on the histogenesis of the tunica mucosa of the stomach of the Egyptian water buffalo (Bos bubalus L.). V. Histogenesis of the abomasal mucosa.
The primordia of the mucosal longitudinal folds are already prominent in the fetus with 9 cm CRL. In the fetus with 9 cm CRL the epithelium is stratified and becomes mixtured of simple and pseudostratified columnar in the fetus with 16 cm CRL in which the primordia of the abomasal glands are firstly seen but finally in the fetus with 17 cm CRL the whole epithelium becomes simple columnar. Although some few parietal cells are evident in the fetus with 73 cm among some fundic glands, but the complete-establishment of their cellular elements is completed postnatally. The Lamina muscularis mucosae is firstly seen in the fetus with 16 cm in the terminal portion of the abomasum.


Alginate dressing and polyurethane film versus paraffin gauze in the treatment of split-thickness skin graft donor sites: a randomized controlled pilot study.
To compare postoperative healing of split-thickness skin graft (STSG) donor sites using traditional dressings (paraffin gauze) or modern wound dressings (alginate dressing and polyurethane film) in a randomized controlled trial. Thirty patients were randomly assigned to treatment of an STSG donor site with an alginate dressing and a polyurethane film or nonadherent paraffin gauze. Outcome variables were pain (measured with a visual analog scale), amount of dressing changes, healing time, cosmetic outcome, treatment costs, and overall satisfaction with the procedure. There was no significant difference in pain (postoperative day 1: 2.1 vs 1.2, P = .26; postoperative days 5-7: 1.0 vs 0.9, P = .47; final removal: 1.9 vs 1.0, P = .19) and time to healing (18.1 vs 15.4 days, P = .29) between alginate/polyurethane film dressing and nonadherent paraffin gauze. The semiocclusive dressings with polyurethane film required multiple dressing changes, whereas the nonadherent paraffin gauze could be left in place until complete epithelialization. Treatment costs were substantially lower for paraffin gauze. Semiocclusive dressings with alginate dressings and polyurethane film showed no advantages over treatment with paraffin gauze. With lower costs and better patient acceptance, paraffin gauze dressings were the preferred treatment for STSG donor sites.


Prediction of B cell and T-helper cell epitopes candidates of bovine leukaemia virus (BLV) by in silico approach.
The bovine leukaemia virus (BLV) is a retrovirus responsible for enzootic bovine leukaemia (EBL) disease, the most common cattle disease leading to high annual economic losses to the cattle breeding industry. Virus monitoring among the sheep and cattle herds is usually done by vaccination. Inactivated virus vaccines can partially protect the livestock from viral challenge. However, vaccinated animals are likely to be infected. So, there is an essential need for producing vaccine by other methods. Gp60 SU, encoded by Env gene, is the surface glycoprotein of BLV detected to be the major target for the host immunity against the virus. Different stages were performed to predict the potential B and T-helper cell epitopes. The general framework of the method includes retrieving the amino acid sequence of gp60 SU, conducting the sequence alignment, getting the entropy plot, retrieving the previously found epitopes, predicting the hydropathy parameters, modelling the tertiary structure of the glycoprotein, minimizing the structure energy, validating the model by Ramachandran plot, predicting the linear and discontinuous epitopes by various servers and eventually choosing the consensus immunogenic regions. Ramachandran plot scrutiny has demonstrated that the modelled prediction is accurate and suitable. By surveying overlaps of various results, 4 and 2 immunogenic regions were selected as linear and conformational epitopes respectively. Amino acids 35-53, 67-97, 288-302 and 410-421 and those of numbers 37-58 and 72-100 were the regions selected as linear and conformational epitopes respectively. The tertiary structure of the final epitope was modelled as well. A comparison of the predicted epitopes structure with that of gp60 SU envelope, illustrated that the tertiary structure of these epitopes does not change after being separated from the primary complete one. The present achievements will lead to a better interpretation of the antigen-antibody interactions against gp60 in the designing process of safe and efficient vaccines.


Effects of starch concentration on calcium-enhanced black bullhead catfish protein gels.
Calcium-enhanced protein recovered from black bullhead catfish was used to develop gels containing increasing amounts of potato starch (0-20 g/kg protein paste) and the effects of starch on functional, textural, and color properties were tested. Energy required to unfold protein groups was greater with the addition of 5 g starch/kg protein paste. Gels containing starch were harder, chewier, and less springy (p < .05) than gels without starch. For most measurements, regression analysis showed that increasing the starch concentration beyond 5 g/kg did not contribute to further significant textural changes. Torsional shear stress and strain along with Kramer shear force increased as the concentration of starch increased (R2 = .79, .79, and .53, respectively). The addition of ≥10 g starch/kg protein paste resulted in darker gels and gels got darker as more starch was added (R2 = .71). Results showed no benefit to increasing starch concentration in gels beyond 5 g starch/kg protein paste.


Diabetes and postcataract extraction endophthalmitis.
This paper reports the results of an exploratory analysis among patients in the Endophthalmitis Vitrectomy Study to determine if there was a different response to treatment in diabetes and whether the signs and symptoms of endophthalmitis differ between diabetic and nondiabetic patients. Patients in this multicenter clinical trial were followed for 9 months after random assignment to either vitrectomy or tap/biopsy. Outcome measures included visual acuity assessed in standardized fashion. Fifty-eight of 420 study patients were diabetic. Diabetics presented with slightly worse vision and ocular media. Only 39% of diabetics compared with 55% of nondiabetics achieved 20/40 final vision. Both diabetic and nondiabetic patients who presented with vision of only light perception (LP) had better visual results with immediate vitrectomy. For those who presented with better than LP vision, diabetics achieved 20/40 more often with vitrectomy (57%) than with tap/biopsy (40%), but non diabetics did equally well with vitrectomy or tap/biopsy. In the diabetic group, small numbers did not allow adequate statistical power to test treatment difference. A new clinical trial is needed to determine if in fact there is a difference in response to treatment among diabetic and nondiabetic patients who present with better than LP vision.


Rapidly synthesized ZnO nanowires by ultraviolet decomposition process in ambient air for flexible photodetector.
We are the first group to use a simple direct ultraviolet light (UV, λ=365 nm, I=76 mW cm(-2)) in a decomposition process to fabricate ZnO nanowires on a flexible substrate using a zinc acetylacetonate hydrate precursor in ambient air. ZnO nanocrystal (or nanowire) production only requires three to ten minutes. A field emission scanning electron microscopy (FESEM) image reveals a high aspect ratio of the ZnO nanowires, which are grown on a substrate with a diameter of ∼50-100 nm, and a length of up to several hundred microns. High resolution transmission electron microscopy (HRTEM) images reveal that the nanowires consist of many single crystalline ZnO nanoparticles that grow along the c axis, which suggests an oriented attachment process. A potential application for flexible UV photodetectors was investigated using a UV lamp (λ=365 nm, I=2.34 mW cm(-2)). A significant ratio of photocurrent to dark current--around 11,300%--was achieved.


Dynamic topography of visual evoked potentials and extrageniculate projection in case of Riddoch phenomenon.
A 34-year-old woman showing the Riddoch phenomenon was studied by the technique of dynamic topography of visual evoked potential (VEP). This case had cortical blindness which developed during the process of massive intestinal hemorrhage, shock and surgery. The visual acuity was limited to hand movement, and perception of white and colored light was present, but there was no form recognition. Tracking eye movement for a flashlight was possible and optokinetic nystagmus (OKN) also appeared. CT-scan showed a diffuse low density area in the white matter of the occipital lobe. The VEPs by flash and a checkerboard of 60'-100' were detectable. Dynamic topography of the VEP showed that a strong negative deflection from the brainstem appeared at around 30 msec and this deflection expanded to the parietal region at about 90 msec. Subsequently, a positive deflection extending from the frontal region to the occipital region continued at 100 msec to 150 msec. Such a process of reaction is not observed in the normal subject. These findings suggest that the visual reaction was conducted abnormally through the extrageniculate system; from the brainstem to the parietal area and then to the occipital area.


Bumblebees Use Sequential Scanning of Countable Items in Visual Patterns to Solve Numerosity Tasks.
Most research in comparative cognition focuses on measuring if animals manage certain tasks; fewer studies explore how animals might solve them. We investigated bumblebees' scanning strategies in a numerosity task, distinguishing patterns with two items from four and one from three, and subsequently transferring numerical information to novel numbers, shapes, and colors. Video analyses of flight paths indicate that bees do not determine the number of items by using a rapid assessment of number (as mammals do in "subitizing"); instead, they rely on sequential enumeration even when items are presented simultaneously and in small quantities. This process, equivalent to the motor tagging ("pointing") found for large number tasks in some primates, results in longer scanning times for patterns containing larger numbers of items. Bees used a highly accurate working memory, remembering which items have already been scanned, resulting in fewer than 1% of re-inspections of items before making a decision. Our results indicate that the small brain of bees, with less parallel processing capacity than mammals, might constrain them to use sequential pattern evaluation even for low quantities.


Child maltreatment, youth violence, and intimate partner violence: developmental relationships.
Understanding the cycle of violence, from victimization to perpetration across the life span, is critical for designing successful prevention interventions. This study uses a nationally representative sample to examine the developmental relationships among three forms of child maltreatment, youth violence perpetration or victimization, and young adult intimate partner violence (IPV) perpetration or victimization. Data describing self-reported youth violence perpetration (or victimization) from Wave I of the National Longitudinal Study of Adolescent Health (1994-1995) were matched with self-reported IPV perpetration (or victimization) in young adult sexual relationships and retrospective reports of child maltreatment collected during Wave III (2001-2002). Bivariate probit regression models were used to analyze the developmental relationships between child maltreatment, youth violence, and IPV. Analyses were completed in September 2006. Compared to nonvictims of child maltreatment, victims of child maltreatment are more likely to perpetrate youth violence (a likelihood increase ranging from -1.2% to 6.6% for females and 3.7% to 11.9% for males) and young adult IPV (an increase from 8.7% to 10.4% for females and from 1.3% to 17.2% for males), although the direct and indirect effects vary by type of child maltreatment experienced. Gender differences exist in the links between child maltreatment, youth violence and IPV, and in the effects of socioeconomic factors on youth violence and IPV. Results suggest that it may be important to account for gender differences when designing violence prevention programs, and an integrative approach is critical for stopping the developmental trajectory of violence.


DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms.
Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.


Field measurements of light exposures and circadian disruption in two populations of older adults.
The absence of daily robust light-dark exposure patterns may contribute to sleep disturbances in persons with Alzheimer's disease and related dementias (ADRD). Personal light-dark and activity-rest patterns were measured for healthy older adults and for persons with ADRD. Persons with ADRD experienced lower light levels, exhibited lower activity levels, and had greater levels of circadian disruption than healthy older adults during winter. Seasonal differences were observed for persons with ADRD; lower levels of light exposure and greater levels of circadian disruption were seen during the winter than during the summer, although activity levels did not differ for the two seasons.


General practice nursing: who is cherishing this workforce?
The remodelling of the NHS requires a strong general practice nurse (GPN) workforce within general practice. The challenges facing general practice nursing are set within the current policy context and recent available evidence and illustrated by drawing upon the experience of a current GPN working in London. It is argued that there is a need to support the professional development of GPNs and nurture the next generation of potential GPNs if the current shortage of GPNs is to be addressed.


Exploiting the difference between intrinsic and extrinsic kinases: implications for regulation of signaling by immunoreceptors.
When receptors must interact with an extrinsic kinase to initiate signaling, the kinase can play a regulatory role that is not available to intrinsic receptor kinases. Whether control is exercised at this level depends critically on the amount of kinase available to the receptors and on the potential for redistribution of the kinase during signaling. This study demonstrates that the high affinity receptor for IgE (Fc epsilonRI) on rat basophilic leukemia cells is regulated by its initiating kinase. We present a mathematical model that allows for the reversible recruitment of extrinsic kinases to phosphorylated immunoreceptor tyrosine-based activation motifs. By comparing model predictions to experimental time courses of phosphorylation, we infer that Lyn is limiting, that redistribution occurs after receptors are aggregated, and that the redistribution makes the relationship between tyrosine phosphorylation and receptor aggregation nonlinear.


Heterogeneous nuclear ribonucleoprotein K is overexpressed and associated with poor prognosis in gastric cancer.
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is one of the major pre-mRNA-binding proteins, that is involved in translational modifications. In our previous studies, we found that hnRNP K is associated with human gastric cancer. The protein levels of hnRNP K were detected in cell lines and tissue microarrays. The correlation between hnRNP K expression and patient survival rate was evaluated by Kaplan-Meier survival analysis. In addition, we also detected hnRNP K expression in preoperative and postoperative serum samples from patients with gastric cancer, and serum samples from healthy volunteers. We found that hnRNP K was overexpressed in the gastric cancer cell lines. The levels of hnRNP K were significantly elevated in the gastric cancer tissues compared with that noted in the tumor-adjacent gastric mucosal and normal gastric mucosal sampes, and hnRNP K expression was found to correlate with tumor stage and lymph node metastasis. However, the level of serum hnRNP K did not differ significantly between gastric cancer patients and healthy volunteers. We also found that patients whose tumors showed elevated expression of hnRNP K had poor survival. The present study suggests that hnRNP K is a promising tissue biomarker for diagnosing gastric cancer and is a prognostic indicator for patients with gastric cancer.


[A case of urinary retention due to a female paraurethral leiomyoma].
A case of urinary retention due to a female paraurethral leiomyoma is reported. The patient was a 67-year-old female who visited our clinic complaining of urinary retention. Urinary sediment and infravenous pyelography revealed no abnormal findings. An oval-shaped mass was palpated at the anterior vaginal wall. The tumor was 7 X 6 cm in size, elastic hard in consistency, irregular surfaced and well movable. Computed tomography revealed a calcified tumor in the urethrovaginal septum extending over all the urethral length from the bladder neck to the urethral meatus. Cystourethroscopic examination revealed a bladder neck elevation. Transvaginal needle biopsy was performed and the pathological diagnosis was benign leiomyoma. Transvaginal removal of the tumor was performed under the diagnosis of female paraurethral leiomyoma. The tumor was easily dissected from the vaginal wall but was adhered rather firmly to the urethra. The origin of the tumor could not be identified. Postoperatively, urination was improved. Female paraurethral leiomyoma is rare but must be considered as a cause of urinary retention.


General Stress Signaling in the Alphaproteobacteria.
The Alphaproteobacteria uniquely integrate features of two-component signal transduction and alternative σ factor regulation to control transcription of genes that ensure growth and survival across a range of stress conditions. Research over the past decade has led to the discovery of the key molecular players of this general stress response (GSR) system, including the sigma factor σ(EcfG), its anti-σ factor NepR, and the anti-anti-σ factor PhyR. The central molecular event of GSR activation entails aspartyl phosphorylation of PhyR, which promotes its binding to NepR and thereby releases σ(EcfG) to associate with RNAP and direct transcription. Recent studies are providing a new understanding of complex, multilayered sensory networks that activate and repress this central protein partner switch. This review synthesizes our structural and functional understanding of the core GSR regulatory proteins and highlights emerging data that are defining the systems that regulate GSR transcription in a variety of species.


The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study.
Pregnancy is accompanied by dramatic physiological changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age and determine biological processes that are perturbed in normal pregnancy. A longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age without maternal or neonatal complications. For each pregnancy, 3 to 6 maternal plasma samples (median, 5) were profiled to measure the abundance of 1125 proteins using multiplex assays. Linear mixed-effects models with polynomial splines were used to model protein abundance as a function of gestational age, and the significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having the following: (1) >1.5-fold change between 8 and 40 weeks of gestation; and (2) a false discovery rate-adjusted value of P < .1. Gene ontology enrichment analysis was used to identify biological processes overrepresented among the proteins that changed with advancing gestation. The following results were found: (1) Ten percent (112 of 1125) of the profiled proteins changed in abundance as a function of gestational age; (2) of the 1125 proteins analyzed, glypican-3, sialic acid-binding immunoglobulin-type lectin-6, placental growth factor, C-C motif-28, carbonic anhydrase 6, prolactin, interleukin-1 receptor 4, dual-specificity mitogen-activated protein kinase 4, and pregnancy-associated plasma protein-A had more than a 5-fold change in abundance across gestation (these 9 proteins are known to be involved in a wide range of both physiological and pathological processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc); and (3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis, and leukocyte migration (false discovery rate, 10%). The plasma proteome of normal pregnancy demonstrates dramatic changes in both the magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy and the development of biomarkers to differentiate normal vs abnormal pregnancy and determine the response to interventions.


The effect of solasodine on the body temperature.
The action of solasodine, the steroid-structure alcaloid of Solanum laciniatum Ait., was studied on normal and pyretic body temperature of rats and mice. In rats a single dosage of 3 mg/kg depressed by an average of --1.5+/-0.3 degrees C the normal temperature for 24 h. With larger dosages or longer treatment the effect could not be intensified and tolerance was also not observed. In mice the temperature decrease was even more explicit, --2.0+/-0.2 degrees C lasting 48 h. The effect was reproducible by repeated treatment. In mice fever provoked by a suspension of killed bacteria, Pyrago¿, or by 2,4-dinitrophenol (DNP) could be counteracted with 1 mmole/kg solasodine. Body temperature depressed with solasodine was not raised by Pyrago but became higher after administration of DNP, in part of the animals even comparable to normal initial averages. Following solasodine treatment the body temperature of normothermic rats and mice decreased to subnormal values. Pyrexia produced either with centrally acting Pyrago or with the peripherally acting DNP was depressed with small solasodine dosages. Previous administration of the alcaloid counteracted Pyrago effect but could not inhibit the development of DNP action. These data are pertaining to the possible central effect of solasodine.


Immunomodulators.
Cytokine immunomodulators have received considerable attention. Interferon-alpha has broad clinical application for treatment of a number of viruses. The neutrophil-stimulatory effects of interferon-gamma are useful in neutrophil disorders. TNF antagonists are useful in rheumatoid arthritis but carry the risk of activating intracellular organisms. Hemopoietic growth factors have considerable clinical effect in patients receiving immunosuppressive chemotherapy. A number of cytokines and cytokine antagonists are undergoing research development.


Finding a nonlinear lattice with improved integrability using Lie transform perturbation theory.
A condition for improved dynamic aperture for nonlinear, alternating gradient transport systems is derived using Lie transform perturbation theory. The Lie transform perturbation method is used here to perform averaging over fast oscillations by canonically transforming to slowly oscillating variables. This is first demonstrated for a linear sinusoidal focusing system. This method is then employed to average the dynamics over a lattice period for a nonlinear focusing system, provided by the use of higher order poles such as sextupoles and octupoles along with alternate gradient quadrupoles. Unlike the traditional approach, the higher order focusing is not treated as a perturbation. The Lie transform method is particularly advantageous for such a system where the form of the Hamiltonian is complex. This is because the method exploits the property of canonical invariance of Poisson brackets so that the change of variables is accomplished by just replacing the old ones with the new. The analysis shows the existence of a condition in which the system is azimuthally symmetric in the transformed, slowly oscillating frame. Such a symmetry in the time averaged frame renders the system nearly integrable in the laboratory frame. This condition leads to reduced chaos and improved confinement when compared to a system that is not close to integrability. Numerical calculations of single-particle trajectories and phase space projections of the dynamic aperture performed for a lattice with quadrupoles and sextupoles confirm that this is indeed the case.


The viability of cryopreserved PBPC depends on the DMSO concentration and the concentration of nucleated cells in the graft.
DMSO is widely used as a cryoprotectant for PBPC. It is desirable to reduce the amount of DMSO without jeopardizing the quality of the stem cell product. The present study was undertaken to investigate whether recovery and survival of CD34+ cells would be significantly altered when PBPC used for autologous transplantations were cryopreserved with four different DMSO concentrations. Apheresis samples of PBPC from 20 consecutive patients were mixed in parallel with 2%, 4%, 5% and 10% DMSO, frozen with identical cell concentrations at a controlled rate, and stored in liquid nitrogen for 6-8 weeks. PBPC samples from 11 consecutive patients were also cryopreserved with two different cell concentrations (150 and 300 x 10(6) nucleated cells/mL) to investigate the effect of increasing the cell concentrations while decreasing the DMSO concentration. The flow cytometric absolute count method, based on ISHAGE guidelines, was used to measure the absolute count of total and viable CD34+ cells in the post-thaw samples. PBPC cryopreserved at 150 x 10(6) cells/mL with 2% DMSO yielded significantly inferior CD34+ cell recovery (P < 0.001) and survival (P < 0.001) compared with cryopreservation with 4% and 5% DMSO. This was also observed when comparing higher cell concentrations. However, a reduced cell survival (P = 0.02) was observed when the nucleated cell concentration was increased from 150 to 300 x 10(6) cells/mL in samples cryopreserved with 5% DMSO. We conclude that 5% DMSO may be the optimal dose for cryopreserving PBPC as long as the cells have not been concentrated at much more than 200 x 10(6) nucleated cells/mL.


Effects of clopidogrel on inflammatory cytokines and adhesion molecules in human endothelial cells: Role of nitric oxide mediating pleiotropic effects.
Clopidogrel is commonly used in prevention and treatment of atherothrombosis. Some previous studies have suggested a pleiotropic effect of clopidogrel; however, when this drug causes platelet-independent effects on endothelial function remains unclear. To evaluate the influence of clopidogrel on inflammatory biomarkers and adhesion molecules in human endothelial cells and the role of nitric oxide (NO) in this process. TNF-α-induced human umbilical vein endothelial cells (HUVEC) were exposed to clopidogrel. Gene expression and protein expression of ICAM-1, P-selectin, IL-8, IL-6, and MCP-1 were evaluated by qPCR, flux cytometry, or milliplex technology. Expression of endothelial nitric oxide synthase (NOS3) and NO release were also evaluated. Influence of clopidogrel was further evaluated in NOS3 downregulated HUVEC by RNAi. Clopidogrel at 20 μmol/L induced NO release in HUVEC after 24-hours treatment. Gene expressions of inflammatory markers IL-8 and MCP1 were reduced after clopidogrel treatment (P<.05); however, only MCP-1 remained reduced at protein level. IL-6 was not modified by clopidogrel treatment. Gene expression and protein expression of ICAM-1 were diminished by 24-hours clopidogrel exposure, whereas P-selectin was not modified. NOS3 downregulated HUVEC model revealed that ICAM-1 modification by clopidogrel is dependent of this via, whereas MCP-1 is modulated in an NO-independent form. Our results support new evidence for pleiotropic effects of clopidogrel on inflammation and endothelial function. Reduction in ICAM-1 and MCP-1 in human endothelium is an important extent of the use of this drug for treatment of cardiovascular diseases, and NO has an important role in this process.


Effectiveness of the use of the Vytelle system in evaluating bulls in Kazakhstan.
This article presents the results of the introduction of Canadian digital technologies Vytelle GrowSafe in the beef cattle breeding of Kazakhstan to assess Residual Feed Intake (RFI). The experiments were carried out with Qazaq Aqbas Breed in the Privet Farms of North Kazakhstan (Akmola and Pavlodar farms). As part of the ration in Akmola farm for a bull of 350 kg of weight, are contained 77 MJ or 7.6 kg of DM, in Pavlodar farm for a bull weighing 290 kg contains 65 MJ or 6.5 kg of DM. Studies have shown that in the Akmola farm the RFI index ranged from -2.08 to +2.88, in the Pavlodar farm from -1.89 to +2.06. According to the results of research in the Akmola farm, the RFI assessment show, 7 out of 26 bulls are suitable for breeding sale, in the Pavlodar farm out of 55 bulls 18. The assessment of the productive effect of feed on RFI, mainly (by 80%), coincided with the assessment of the ratio of gain to consumed dry matter, and some bulls showed deviations in terms of residual average daily live weight gain and the corrected value of the ratio of feed costs to live weight gain, which led to incomplete manifestation of the productive potential of the consumed feed.


[SIGNIFICANCE OF IgG4 IN IDIOPATHIC RETROPERITONEAL FIBROSIS].
(Objective)Retroperitoneal fibrosis is largely divided into the idiopathic and secondary types. Some idiopathic cases include IgG4-related diseases, which are often similar to malignant diseases, such as lymphoma and sarcoma. The diagnostic criteria for IgG4-related disease are used and pathologic examination is necessary for a definitive diagnosis of IgG4-related retroperitoneal fibrosis. The first choice of treatment for IgG4-related retroperitoneal fibrosis is steroid administration, but no consensus has been established regarding its dose and tapering schedule. We investigated the significance of IgG4 in diagnosis and treatment of idiopathic retroperitoneal fibrosis. (Patients and methods)We examined 14 cases diagnosed as idiopathic retroperitoneal fibrosis between April 2013 and March 2019. Serum IgG4 was measured at the time of diagnosis in 13 cases, and changes over time in serum IgG4 before and after the induction of steroid therapy were measured in 6 cases. Computed tomography-guided biopsy was performed on 4 cases. (Results)Of all cases, 1 patient was diagnosed as IgG4-related retroperitoneal fibrosis and 5 patients were classified as possible group. Ten patients were administered steroid therapy. Percutaneous nephrostomy tube was placed in 3 patients and was removed in 2 of these patients after steroid therapy. The serum high levels of IgG4 were confirmed in all 4 patients who were classified into the possible group and who were treated with steroids. (Conclusion)Although histologic examination is necessary for the diagnosis of retroperitoneal fibrosis, tissue collection by open or laparoscopic surgery is highly invasive. CT-guided biopsy may be useful in high-risk cases, such as elderly patients on anticoagulation. After excluding other diseases in high-risk cases, response to empiric steroid therapy may be diagnostic. In the possible group, changes in serum IgG4 levels may reflect the disease condition and might be useful in determining the maintenance dose of steroids.


Capillary electrophoretic determination of main components of natural dyes with MS detection.
CE with UV-Vis and MS detections was investigated as a technique for detection of main components of selected natural dyes of plant and insect origin. The BGE giving the best separation of the investigated flavonoids and anthraquinoids, suitable for MS detection consisted of 40 mM ammonium acetate solution of pH 9.5 with 40% ACN. LODs obtained with MS detection were even one order of magnitude lower than the ones obtained with UV-Vis detection. Application of MS detection enabled determination of eleven dye compounds from three different chemical groups in 15 min. and proved to be more satisfactory than diode-array detection in the electrophoretic analysis of main classes of natural dyes both in terms of selectivity and sensitivity of analysis.


In vitro polyadenylation is stimulated by the presence of an upstream intron.
The majority of vertebrate pre-mRNAs are both spliced and polyadenylated. To investigate the mechanism whereby processing factors recognize last exons containing both splicing and polyadenylation consensus elements, chimeric precursor RNAs containing a single intron and a poly(A) site were constructed and assayed for in vitro splicing and polyadenylation. Chimeric RNAs underwent splicing and polyadenylation. Both reactions occurred in a single RNA. The presence of an intron enhanced the rate of polyadenylation at a downstream poly(A) site. The extent of stimulation varied from two- to fivefold, depending on the magnesium concentration. Maximal stimulation of polyadenylation by an upstream intron required a 3' splice site but not a 5' splice site, suggesting that the structure of the terminal exon was more important than the presence of a complete upstream intron. We suggest that splicing and polyadenylation factors interact to recognize terminal, poly(A) site-containing exons. Such interaction may explain why all known intron-containing eukaryotic pre-mRNAs generate their 3' ends by polyadenylation.


Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease.
Graft-versus-host disease (GVHD) is the major complication after allogeneic stem cell transplantation (SCT). Emerging evidence indicates that GVHD leads to injury of intestinal stem cells. However, it remains to be investigated whether skin stem cells could be targeted in skin GVHD. Lgr5+ hair follicle stem cells (HFSCs) contribute to folliculogenesis and have a multipotent capacity to regenerate all epithelial cells in repair. We studied the fate of Lgr5+ HFSCs after SCT and explored the novel treatment to protect Lgr5+ HFSCs against GVHD using murine models of SCT. We found that GVHD reduced Lgr5+ HFSCs in association with impaired hair regeneration and wound healing in the skin after SCT. Topical corticosteroids, a standard of care for a wide range of skin disorders including GVHD, damaged HFSCs and failed to improve skin homeostasis, despite of their anti-inflammatory effects. In contrast, JAK1/2 inhibitor ruxolitinib significantly ameliorated skin GVHD, protected Lgr5+ HFSCs, and restored hair regeneration and wound healing after SCT. We, for the first time, found that GVHD targets Lgr5+ HFSCs and that topical ruxolitinib represents a novel strategy to protect skin stem cells and maintain skin homeostasis in GVHD.


The efficacy and safety of simple-needling for the treatment of primary dysmenorrhea compared with ibuprofen: A systematic review and meta-analysis.
Needling and ibuprofen are often used clinically to treat primary dysmenorrhea (PD). However, the difference between the efficacy and safety of the treatment of PD is not clear. This study evaluates the efficacy and safety of simple-needling for PD patients through a comparison with ibuprofen. A comprehensive search of 7 electronic databases and relevant medical journals, from the establishment of the publication to December 2020. The Cochrane risk of bias tool was used to evaluate the methodological quality of randomized clinical trials (RCTs) that met the inclusion criteria, and a meta-analysis was performed with the Review Manager version (RevMan version 5.3). Twenty three RCTs were included. The meta-analysis reported that simple-needling groups had better than ibuprofen groups on cure rate (relative risk = 2.29, 95% CI [1.96, 2.68], P < .00001) and total effective rate (relative risk = 1.24, 95% CI [1.19, 1.29], P < .00001) and VAS score (MD = -1.24, 95% CI [-1.92, -0.55], P = .0004). Seven studies reported adverse events, of which 4 studies had mild adverse events. Simple-needling is superior to ibuprofen treatment in terms of clinical efficacy and improvement of pain symptoms. A small number of studies reported whether simple-needling produced adverse events, so there is not enough evidence to support the safety of simple-needling in the treatment of PD. CRD42021233403.


A COPI coat subunit interacts directly with an early-Golgi localized Arf exchange factor.
Arf (ADP-ribosylation factor) family small G proteins are crucial regulators of intracellular transport. The active GTP-bound form of Arf interacts with a set of proteins--effectors--which mediate the downstream signalling events of Arf activation. A well-studied class of Arf1 effectors comprises the coat complexes, such as the cis-Golgi-localized COPI (coat protein complex I) coat, and trans-Golgi network-endosomal clathrin coats. At least five different coats require Arf1-GTP to localize to organelle membranes. How a single Arf protein recruits different coat complexes to distinct membrane sites raises the question of how specificity is achieved. Here, we propose a molecular mechanism of this specificity for the COPI coat by showing a direct and specific interaction between a COPI subunit and a cis-Golgi localized subfamily of Arf guanine nucleotide exchange factors (GEFs) that takes place independently of Arf1 activation. In this way, a specific output on Arf1 activation can be programmed before the exchange reaction by the GEF itself.


Potential Role of Lysine Acetylation in Antibiotic Resistance of Escherichia coli.
Antibiotic resistance is increasingly becoming a challenge to public health. The regulation of bacterial metabolism by post-translational modifications (PTMs) has been widely studied. However, the mechanism underlying the regulation of acetylation in bacterial resistance to antibiotics is still unknown. Here, we performed a quantitative analysis of the acetylated proteome of a wild-type (WT) Escherichia coli (E. coli) sensitive strain and ampicillin- (Re-Amp), kanamycin- (Re-Kan), and polymyxin B-resistant (Re-Pol) strains. Based on bioinformatics analysis combined with biochemical validations, we found a common regulatory mechanism between the different resistant strains. Our results showed that protein acetylation negatively regulates bacterial metabolism to regulate antibiotic resistance and positively regulates bacterial motility. Further analyses revealed that key enzymes in various metabolic pathways were differentially acetylated. In particular, pyruvate kinase (PykF), a glycolytic enzyme that regulates bacterial metabolism, and its acetylated form were highly expressed in the three resistant strains and were identified as reversibly acetylated by the deacetylase CobB and the acetyl-transferase PatZ (peptidyl-lysine N-acetyltransferase). Results showed that PykF also could be acetylated by nonenzymatic acetyl phosphatase (AcP) in vitro. Furthermore, the deacetylation of Lys413 in PykF increased PykF enzymatic activity by changing the conformation of its ATP binding site, resulting in an increase in energy production which, in turn, increased the sensitivity of drug-resistant strains to antibiotics. This study provides novel insights for understanding bacterial resistance and lays the foundation for future research on the regulation of acetylation in antibiotic-resistant strains. IMPORTANCE The misuse of antibiotics has resulted in the emergence of many antibiotic-resistant strains which seriously threaten human health. Protein post-translational modifications, especially acetylation, tightly control bacterial metabolism. However, the comprehensive mechanism underlying the regulation of acetylation in bacterial resistance remains unexplored. Here, acetylation was found to positively regulate bacterial motility and negatively regulate energy metabolism, which was common in all antibiotic-resistant strains. Moreover, the acetylation and deacetylation process of PykF was uncovered, and deacetylation of the Lys 413 in PykF was found to contribute to bacterial sensitivity to antibiotics. This study provides a new direction for research on the development of bacterial resistance through post-translational modifications and a theoretical basis for developing antibacterial drugs.


Combining human antisera to human leukocyte antigens, HIVgp120 and 70 kDa heat shock protein results in broadly neutralizing activity to HIV-1.
To elicit broadly neutralizing antibody activity by combining polyclonal human serum IgG antibodies with HIVgp120, human leukocyte antigen (HLA) class I or class II and 70 kDa heat shock protein. : In addition to HIV antigens, HIV-1 virions express HLA class I, HLA class II and 70 kDa heat shock protein molecules, which have quantitative and functional significance. The complementary effect of combining human polyclonal IgG antibodies with these antigens may result in effective broad spectrum neutralizing activity. Polyclonal human sera with IgG antibodies and monoclonal antibody to HLA class I or class II, HIVgp120 and 70 kDa heat shock protein were selected and used in single, double or triple combinations. Dose-dependent inhibition studies of HIV-1 clades A, B, C and D were carried out using human CD4 T cells treated with the combinations of human sera and with monoclonal antibodies for clade B. The results are presented as half maximal (IC50) inhibitory concentration and maximum inhibition by these sera. The half maximal (IC50) inhibitory concentration of clade B HIV-1 infection with single or a combination of two antisera was higher than those with three antisera, which also showed maximum inhibition of HIV-1. Further investigations of human sera with HIV-1 clades C and D also showed lower half maximal (IC50) inhibitory concentrations and higher maximum inhibition with combinations of the three antisera, but this was not seen with clade A. A novel vaccination strategy eliciting broadly neutralizing antibody activity to the CCR5-using HIV-1 clades B, C and D has been demonstrated by the trimolecular complex of human antisera with HLA class II or class I, HIVgp120 and 70 kDa heat shock protein.


Frequency and surgical difficulties associated with pseudoexfoliation syndrome among Indian rural population scheduled for cataract surgery: Hospital-based data.
To study the frequency and intraoperative difficulties associated with pseudoexfoliation (PXF) syndrome at a tertiary eye care center in a rural central India. This study included patients scheduled for cataract surgery who were diagnosed with PXF syndrome. All patients underwent a complete ophthalmologic evaluation, including slit-lamp examination, tonometry, gonioscopy, and ophthalmoscopy before the surgery. Cataract surgeries were performed by a single surgeon who reported the intraoperative difficulties. In total, 1022 phakic eyes of 1823 patients were evaluated, 226 of whom (22.1%) were diagnosed with PXF syndrome. Most eyes (n = 81, 35.8%) with PXF syndrome were ≥81 years old. Eighty-six eyes (38.1%) had bilateral involvement, whereas 70 (30.9%) had right or left eye involvement. Further, PXF material was distributed on the iris, pupil, and lens in 70 eyes (30.9%) and on the pupillary margin in 36 eyes (15.9%). The mean pupillary dilation was 5.1 (±1.4) mm in patients with PXF syndrome compared with 7.2 (±1.6) mm in those without it (P = 0.03). Grade VI cataract was observed in 93 eyes (41.2%) and hypermature cataract was the most commonly observed cataract stage. Twenty-one eyes (9.3%) had increased intraocular pressure. Intraoperative difficulties were encountered in 62 eyes (27.4%) with poor pupillary dilation being the most common problem (32 eyes, 14.2%), followed by zonular dehiscence (18 eyes, 8%). This hospital-based study showed that PXF syndrome is common in Indian rural population and that the intraoperative complication rate in these patients is high.


TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics.
The TASK-3 channel is an acid-sensitive two-pore-domain K+ channel, widely expressed in the brain and probably involved in regulating numerous neuronal populations. Here, we characterized the behavioral and pharmacological phenotypes of TASK-3 knockout (KO) mice. Circadian locomotor activity measurements revealed that the nocturnal activity of the TASK-3 KO mice was increased by 38% (P < 0.01) compared with wild-type littermate controls, light phase activity being similar. Although TASK-3 channels are abundant in cerebellar granule cells, the KO mice performed as well as the wild-type mice in walking on a rotating rod or along a 1.2-cm-diameter beam. However, they fell more frequently from a narrower 0.8-cm beam. The KO mice showed impaired working memory in the spontaneous alternation task, with the alternation percentage being 62 +/- 3% for the wild-type mice and 48 +/- 4% (P < 0.05) for the KO mice. Likewise, during training for the Morris water-maze spatial memory task, the KO mice were slower to find the hidden platform, and in the probe trial, the female KO mice visited fewer times the platform quadrant than the male KO and wild-type mice. In pharmacological tests, the TASK-3 KO mice showed reduced sensitivity to the inhalation anesthetic halothane and the cannabinoid receptor agonist WIN55212-2 mesylate [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] but unaltered responses to the alpha2 adrenoceptor agonist dexmedetomidine, the i.v. anesthetic propofol, the opioid receptor agonist morphine, and the local anesthetic lidocaine. Overall, our results suggest important contributions of TASK-3 channels in the neuronal circuits regulating circadian rhythms, cognitive functions, and mediating specific pharmacological effects.


[Clinical aspects of hypophyseal metastases].
Metastatic tumors within the pituitary gland are rare. The incidence--reported by series of autopsies--differs from 1.8-12% of metastatic tumors. Most of the primary tumors are breast cancers, followed by cancers of the gastro-intestinal system. Only 20% of these metastases are clinically diagnosed. Diabetes insipidus is the main symptom, correlating with the greater incidence of metastatic lesions in the posterior lobe. The unusual features of a reported case are discussed. In this case the dysfunction of cranial nerves passing the sella turcica led to the diagnosis. Therapy with Flutamid initiated a remission. Survival of 18 months is remarkably long.


Single-Cell Transcriptomics Reveals Regulators of Neuronal Migration and Maturation During Brain Development.
The correct establishment of inhibitory circuits is crucial for cortical functionality and defects during the development of γ-aminobutyric acid-expressing cortical interneurons contribute to the pathophysiology of psychiatric disorders. A critical developmental step is the migration of cortical interneurons from their site of origin within the subpallium to the cerebral cortex, orchestrated by intrinsic and extrinsic signals. In addition to genetic networks, epigenetic mechanisms such as DNA methylation by DNA methyltransferases (DNMTs) are suggested to drive stage-specific gene expression underlying developmental processes. The mosaic structure of the interneuron generating domains producing a variety of interneurons for diverse destinations complicates research on regulatory instances of cortical interneuron migration. To this end, we performed single-cell transcriptome analysis revealing Dnmt1 expression in subsets of migrating interneurons. We found that DNMT1 preserves the migratory morphology in part through transcriptional control over Pak6 that promotes neurite complexity in postmigratory cells. In addition, we identified Ccdc184, a gene of unknown function, to be highly expressed in postmitotic interneurons. Single-cell mRNA sequencing revealed a positive correlation of Ccdc184 with cell adhesion-associated genes pointing to potential implications of CCDC184 in processes relying on cell-cell adhesion-like migration or morphological differentiation of interneurons that deserves further investigations.


Clinical and angiographic outcomes in diabetic patients following single or multivessel stenting in the COSTAR II randomized trial.
Percutaneous coronary intervention (PCI) is associated with increased clinical and angiographic restenosis in diabetic patients. Stent-based elution of paclitaxel from a biostable polymer reduces restenosis and major adverse cardiovascular events (MACE) when compared with bare-metal stent deployment. The safety and efficacy of paclitaxel elution from a bioresorbable polymer has not been studied in diabetic patients. Patients (n = 1700) with single- or multivessel coronary disease were randomized (3:2) to receive the CoStar or Taxus stent. All patients had glycolated hemoglobin (HbA1c) obtained at enrollment. Medically-treated diabetes was present in 469 patients (117 insulin-treated) and 77 patients had elevated HbA1c > 6.5% in the absence of previously diagnosed diabetes. MACE were increased in diabetics and were greatest in those requiring insulin. Elevated HbA1c, in the absence of diagnosed diabetes, was not associated with adverse outcomes. MACE (8 months) in the diabetic cohort trended lower with Taxus versus CoStar (10.9 vs. 14.4%, respectively; p = 0.271) due to a reduction in target vessel revascularization. Late lumen loss in-segment (9 months) was reduced by Taxus compared to CoStar (0.20 vs. 0.52 mm, respectively; p < 0.05). Diabetes is associated with adverse outcomes following stent deployment. Taxus stents improved angiographic outcomes with a trend toward improved clinical outcomes when compared with CoStar stents following PCI in diabetic patients. As a measure of preprocedural glycemic control, the HbA1c level was weakly correlated with outcomes.


Rethinking the central dogma of palliative care.
Palliative care defines itself as complementary to life-prolonging therapy. Consideration should be given instead to viewing palliative care as the gold standard for all patients with progressive, life-threatening illness. The dichotomy between cure on the one hand and palliation on the other reflects the oncologic roots of palliative medicine, as well as the widespread societal view of medical treatment as overwhelmingly focused on cure. Because the treatment of patients with serious and complex illness is seldom curative, it makes more sense to think of the care of such patients as inherently palliative. Patients must choose among various forms of potentially life-prolonging therapies, each with its own side-effect profile and likelihood of success, depending on how they prioritize their goals of care. From this perspective, palliative care, an interdisciplinary approach that attends to advance care planning, psychosocial issues, and management of symptoms, should be the standard of care for these patients. Palliative care physicians can either provide primary care to patients with serious illness or can serve as consultants in the care of particularly challenging cases.


Surface roughness of nanofill and nanohybrid resin composites after polishing and brushing.
The purpose of this study was to compare the surface roughness of nanofill (Filtek Supreme XT dentin shade and transparent shade, Filtek Z350, and Estelite Sigma), nanohybrid (Tetric EvoCeram, Ceram X, and Premise), and microhybrid resin composites (Filtek Z250, Tetric Ceram, and Clearfil AP-X) with the materials after polishing or brushing. Forty specimens of each resin composite were polymerized for 40 seconds under a matrix strip in cylindrical molds. Each type of polymer was divided into four subgroups: unpolished, polished with abrasive disks (Sof-Lex), polished with silicone-impregnated polishing devices (Astropol), and brushed with a toothbrush (Oral B) and toothpaste (Colgate). The surface roughness of each specimen was determined using a contact stylus profilometer and by observation under a scanning electron microscope. No significant differences in surface roughness among the materials were found on unpolished surfaces. For the nanofill resin composites, there were no significant differences in surface roughness between the two polishing methods or among the unpolished surfaces. After brushing, the surfaces of all materials, except those made from Filtek Z350 and Filtek Supreme XT (dentin), had greater roughness than unpolished surfaces and surfaces polished with either abrasive disks or silicone devices. The scanning electron microscope studies revealed that the surface irregularities of the materials corresponded to the results obtained using the surface roughness tester. The use of nanofill resin composites made with nanoclusters demonstrated the smoothest surfaces after polishing and brushing.


Biomimetic one-pot route to acridine epoxides.
The first direct epoxidation of acridine on the edge positions is reported. The reaction proceeds under mild conditions using a biomimetic catalytic system based on a Mn(III) porphyrin. The successive oxyfunctionalization to mono-, di-, and tetraepoxy derivatives is accomplished using hydrogen peroxide as a green oxidant at room temperature. Computed optimized geometries showed only slight shifts to the base planarity upon dearomatization by epoxidation, which is an important feature for DNA intercalation and bioactivity. NMR studies and comparison with theoretical values allowed the assignment of the stereochemistry of the anti- and syn-diepoxy and -tetraepoxy derivatives as well as compounds resulting from epoxide ring opening, exemplified by epoxydiol. The diepoxide is formed in an anti:syn ratio of ∼4, and the attack by nucleophiles, exemplified by ethylaniline, occurs selectively and with full conversion, using a microwave process with acetonitrile reflux for 10 min. Finally, studies of the electrostatic potential allowed the mechanisms of the formation of 4-hydroxyacridine and the regioselective reaction of diepoxyacridine with nucleophiles to be rationalized.


(CN3H6)[FeIIFeIII(SO4)3(H2O)3]: A Framework Iron Sulfate with a Mixed S = 2 and S = 5/2 Honeycomb Lattice.
A new guanidinium-templated hydrated iron sulfate, [CN3H6][FeIIFeIII(SO4)3(H2O)3] (1), was prepared from strongly acidic aqueous solutions. Its crystal structure is comprised from FeIIIO6 and FeIIO3(H2O)3 octahedra linked by sulfate bridges forming a [FeIIFeII(SO4)3(H2O)3]- 3D framework with a layer-by-layer ordering of ferric and ferrous cations. The structural topology of the framework is related to the anhydrous rhombohedral mikasaite Fe2(SO4)3. The removal of part of the sulfate tetrahedra and the partial replacement of the Fe3+ cations in the [Fe3+2(SO4)3]0 framework by Fe2+ provide a negative charge and allow the incorporation of the protonated organic species in the voids. The compound 1 has been characterized by single-crystal X-ray diffraction, TG and DSC analyses, UV-vis-NIR spectroscopy, magnetic susceptibility, Mössbauer spectroscopy, IR and Raman spectroscopy, and density functional band-structure calculations. The magnetic behavior of 1 shows an interplay of FeII (S = 2) and FeIII (S = 5/2) sublattices that exhibit different types of antiferromagnetic couplings, one FeIII-FeIII (J1 ∼ 6.1 K) and two FeII-FeIII couplings (J2 ∼ 1 K, J3 ∼ 5.9 K) within corrugated honeycomb layers. These ferrimagnetic layers are coupled antiparallel to each other, resulting in an overall antiferromagnetic order below TN = 31 K.


Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan.
Isolated limb perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-alpha with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 microg kg(-1) TNF-alpha (n = 5), (2) 50 microg kg(-1) TNF-alpha plus 1 mg kg(-1) melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-alpha levels of 5.1 +/- 0.78 x 10(6) pg ml(-1) (+/- s.e.m). Systemic leakage of TNF-alpha from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-alpha levels was observed in groups 1 and 2 with a median peak level of 23 +/- 3 x 10(3) pg ml(-1) at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-alpha with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.