Effect of pain neuroscience education and transcutaneous electrical nerve stimulation on trigeminal postherpetic neuralgia. A case report.
Postherpetic neuralgia (PHN) is a complex neuropathic painful condition in which pain is a direct consequence of the response to peripheral nerve damage experienced during herpes zoster attack. PHN is the most common chronic complication of herpes zoster and it causes considerable suffering, affecting the physical functioning and psychological well-being of patients. To describe the effect of a conservative treatment using pain neuroscience education (PNE) and transcutaneous electrical nerve stimulation (TENS) in a patient with trigeminal PHN. A 67-year-old woman sought care for pain, dysfunction, and sensory loss in the left jaw. The assessment included: 1) pain, using the numerical pain rating scale (NPRS), pressure pain threshold (PPT), Douleur Neuropathique 4 (DN4), McGill Pain Questionnaire (MPQ), Graded Chronic Pain Scale (GCPS), and classic body charts of the cranial region; 2) somatosensory function, by means of mechanical detection threshold (MDT) and pressure pain threshold (PPT); 3) jaw function, using the Jaw Functional Limitation Scale-20 (JFLS-20); and 4) psychosocial features, by means of the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorders Questionnaire-7 (GAD-7). Treatment consisted of 12 sessions of PNE and TENS. After treatment, a clinically significant improvement in NPRS, DN4, MDT, GCPS, and PHQ-9 was observed. In this case report, a treatment based on the combination of PNE and TENS seemed to have contributed to improving pain, sensory abnormalities, and jaw function. Psychosocial factors also showed a trend to improve after the treatment.


Esophagogastric anastomoses: the value of fibrin glue in preventing leakage.
Disruption of an esophagogastric anastomosis can result in a high mortality despite aggressive treatment. The efficacy of fibrin "glue" to seal esophagogastric anastomoses was evaluated as a means of preventing this complication. A left thoracotomy was performed in 25 adult mongrel dogs. After esophagogastric resection, a standardized esophagogastrostomy was performed and eight interrupted sutures were used to completely close the posterior wall. The anterior wall was approximated with only three sutures, leaving four large holes between sutures. The dogs were then randomized into the control group (n = 14; no attempt to seal the leaks) or into the fibrin glue-treated group (n = 11). An average of 3.3 ml of glue was applied to the anterior wall of the anastomosis in the treated group. In the control group, 13 of 14 dogs (92.9%) died of anastomotic leak a median of 3 days after operation. In the fibrin glue-treated group, only four of 11 dogs (36.4%) died of anastomotic leaks (p less than 0.01). Dogs that survived were put to death at 14 days. Postmortem examination in all dogs revealed no deleterious effects or complications related to the glue. Postmortem examination of the one surviving control dog and the seven fibrin glue-treated dogs that did not die of sepsis revealed a healed anastomosis without abscess formation. We conclude that fibrin glue is effective in lessening the incidence of esophagogastric anastomotic leaks as employed in this experimental model.


Genetic variation in insulin-like growth factors and brain tumor risk.
Many studies support a role for insulin-like growth factors (IGFs) in the regulation of tumor cell biology. We hypothesized that single-nucleotide polymorphisms (SNPs) in IGF genes are risk factors for glioma and meningioma. To test the hypothesis, we examined associations of brain tumor risk with nine variants in five IGF genes in a hospital-based case-control study. The study was conducted at hospitals in Boston, Phoenix, and Pittsburgh between 1994 and 1998. Eligible cases were individuals (18 years or older) newly diagnosed with glioma or meningioma. Controls were selected among patients who were admitted to the same hospitals for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race, and distance from residence. The present analysis was restricted to non-Hispanic whites. DNA was extracted from blood samples collected from 354 glioma cases, 133 meningioma cases, and 495 control individuals. We evaluated nine SNPs in five IGF genes (IGF1, IGF1R, IGF2, IGF2R, and IGFBP3). The majority of the analyzed IGF SNPs did not display statistically significant associations with glioma or meningioma. For glioma, one IGF1R SNP (rs2272037) indicated a possible association. No indications of association were seen for glioblastoma, but for low-grade gliomas, the odds ratio under a dominant model was 0.56 (95% confidence interval [CI], 0.35-0.90) for IGF1 rs6220, 2.98 (95% CI, 1.65-5.38) for IGF1R rs2272037, and 1.60 (95% CI, 0.90-2.83) for IGF1R rs2016347. Overall, our results do not provide strong evidence of associations of brain tumor risk with IGF polymorphic variants but identify several associations for glioma that warrant further examination in other, larger studies.


Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity.
Recent studies have revealed gender differences in cold perception, and pointed to a possible direct action of testosterone (TST) on the cold-activated TRPM8 (Transient Receptor Potential Melastatin Member 8) channel. However, the mechanisms by which TST influences TRPM8-mediated sensory functions remain elusive. Here, we show that TST inhibits TRPM8-mediated mild-cold perception through the noncanonical engagement of the Androgen Receptor (AR). Castration of both male rats and mice increases sensitivity to mild cold, and this effect depends on the presence of intact TRPM8 and AR. TST in nanomolar concentrations suppresses whole-cell TRPM8-mediated currents and single-channel activity in native dorsal root ganglion (DRG) neurons and HEK293 cells co-expressing recombinant TRPM8 and AR, but not TRPM8 alone. AR cloned from rat DRGs shows no difference from standard AR. However, biochemical assays and confocal imaging reveal the presence of AR on the cell surface and its interaction with TRPM8 in response to TST, leading to an inhibition of channel activity.


Structure of 3-hydroxy-17-oxoestra-1,3,5(10)-trien-11 beta-yl acetate.
C20H24O4, Mr = 328.41, orthorhombic, P2(1)2(1)2(1), a = 11.688 (3), b = 15.377 (5), c = 9.466 (2) A, V = 1701 (1) A3, Z = 4, Dx = 1.282 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.823 cm-1, F(000) = 704, T = 298 K, R = 0.063 for 1921 reflections with F greater than 2 sigma (F). The structure was determined to observe the effect of the 11 beta-acetate substituent on the conformation of the molecule. The 3-hydroxy is hydrogen bonded to O19 at 2.86 A. The B ring has a 7 alpha, 8 beta-half chair conformation, the most commonly observed B ring conformation in estrogen analogues.


A case study of the mechanism of alcohol-mediated Morita Baylis-Hillman reactions. The importance of experimental observations.
The mechanism of the Morita Baylis-Hillman reaction has been heavily studied in the literature, and a long series of computational studies have defined complete theoretical energy profiles in these reactions. We employ here a combination of mechanistic probes, including the observation of intermediates, the independent generation and partitioning of intermediates, thermodynamic and kinetic measurements on the main reaction and side reactions, isotopic incorporation from solvent, and kinetic isotope effects, to define the mechanism and an experimental mechanistic free-energy profile for a prototypical Morita Baylis-Hillman reaction in methanol. The results are then used to critically evaluate the ability of computations to predict the mechanism. The most notable prediction of the many computational studies, that of a proton-shuttle pathway, is refuted in favor of a simple but computationally intractable acid-base mechanism. Computational predictions vary vastly, and it is not clear that any significant accurate information that was not already apparent from experiment could have been garnered from computations. With care, entropy calculations are only a minor contributor to the larger computational error, while literature entropy-correction processes lead to absurd free-energy predictions. The computations aid in interpreting observations but fail utterly as a replacement for experiment.


Modulation of inflammation by slit protein in vivo in experimental crescentic glomerulonephritis.
A basic conservation of cell migration guidance mechanisms in the nervous and immune systems was proposed when Slit, known for its role in axon guidance, was found to inhibit chemokine-induced leukocyte chemotaxis in vitro. These studies examined the role of Slit2 in modulating inflammation in vivo. In a rat model of glomerulonephritis, endogenous glomerular Slit2 expression fell after disease induction, and its inhibition during the early disease period accelerated inflammation. Ex vivo glomerular leukocytes showed decreased chemokine and chemoattractant-induced chemotaxis in response to Slit2, suggesting an anti-inflammatory role for glomerular Slit2. In contrast to the effect of inhibition, glomerulonephritis was ameliorated by systemic Slit2 administration. Slit2 treatment improved disease histologically and also improved renal function when given early in the disease course. Leukocytes harvested from rats receiving Slit2 showed decreased monocyte chemoattractant protein-1 (MCP)-1-mediated migration, consistent with a peripheral Slit2 effect. In keeping with this functional alteration, Slit2-mediated inhibition of RAW264.7 cell chemotaxis was associated with decreased levels of active cdc42 and Rac1, implicating GTPases in leukocyte Slit2 signaling. These findings suggest a role for endogenous Slit2 in the inhibition of chemoattractant-mediated signals, demonstrate a potentially important anti-inflammatory effect for Slit2 in vivo, and provide further evidence for conserved mechanisms guiding the process of migration in distinct cell types.


Effect of occupational exposure to vapors, gases, dusts, and fumes on COPD mortality risk among Swedish construction workers: a longitudinal cohort study.
The aim of the present study was to elucidate whether occupational exposure to vapors, gases, dusts, and fumes increases the mortality risk of COPD, especially among never smokers. The study population was a cohort of 354,718 male construction workers; of these, 196,329 were exposed to vapors, gases, dusts, and fumes, and 117,964 were unexposed. Exposure to inorganic dust, wood dust, vapors, fumes, gases, and irritants was based on a job-exposure matrix with a focus on exposure in the mid-1970s. The cohort was followed from 1971 to 2011. Relative risks (RRs) were obtained using Poisson regression models adjusting for age, BMI, and smoking habits. There were 1,085 deaths from COPD among the exposed workers, including 49 never smokers. Workers with any occupational exposure to vapors, gases, fumes, and dust showed an increased mortality due to COPD (RR, 1.32; 95% CI, 1.18-1.47). When comparing different exposure groups, there was a significantly increased mortality due to COPD among those exposed to fumes (RR, 1.20; 95% CI, 1.07-1.36) and inorganic dust (RR, 1.19; 95% CI ,1.07-1.33). Among never smokers, there was high mortality due to COPD among workers with any occupational airborne exposure (RR, 2.11; 95% CI, 1.17-3.83). The fraction of COPD attributable to occupational exposure was 0.24 among all workers and 0.53 among never-smoking workers. Occupational exposure to airborne pollution increases the mortality risk for COPD, especially among never smokers.


Role of human beta-defensin-2 during tumor necrosis factor-alpha/NF-kappaB-mediated innate antiviral response against human respiratory syncytial virus.
Human respiratory syncytial virus (RSV) constitutes a highly pathogenic virus that infects lung epithelial cells to cause a wide spectrum of respiratory diseases. Our recent studies have revealed the existence of an interferon-alpha/beta-independent, innate antiviral response against RSV that was dependent on activation of NF-kappaB. We demonstrated that NF-kappaB inducing pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) confers potent antiviral function against RSV in an NF-kappaB-dependent fashion, independent of interferon-alpha/beta. During our efforts to study this pathway, we identified HBD2 (human beta-defensin-2), a soluble secreted cationic protein as an antiviral factor induced during NF-kappaB-dependent innate antiviral activity in human lung epithelial cells. Our results demonstrated that HBD2 is induced by TNF and RSV in an NF-kappaB-dependent manner. Induction of HBD2 in infected cells was mediated by the paracrine/autocrine action of TNF produced upon RSV infection. HBD2 plays a critical role during host defense, because purified HBD2 drastically inhibited RSV infection. We also show that the antiviral mechanism of HBD2 involves blocking of viral cellular entry possibly because of destabilization/disintegration of the viral envelope. The important role of HBD2 in the innate response was also evident from loss of antiviral activity of TNF upon HBD2 silencing by short interfering RNA. The in vivo physiological relevance of HBD2 in host defense was apparent from induction of murine beta-defensin-4 (murine counterpart of HBD2) in lung tissues of RSV-infected mice. Thus, HBD2 functions as an antiviral molecule during NF-kappaB-dependent innate antiviral immunity mediated by the autocrine/paracrine action of TNF.


A random set view of texture classification.
Texture classification of an image or subimage is an important problem in texture analysis. Many procedures have been proposed. A global framework for texture classification based on random closed set theory is proposed in this paper. In this approach, a binary texture is considered as an outcome of a random closed set. Some distributional descriptors of this stochastic model are used as texture features in order to classify the binary texture, in particular spherical and linear contact distributions and K-functions. If a grayscale texture has to be classified, then the original texture is reduced to a multivariate random closed set where each component (a different random set) corresponds with those pixels verifying a local property. Again, some functional descriptors of the multivariate random closed set defined from the texture can be used as texture features to describe and classify the grayscale texture. Marginal and cross spherical and linear contact distributions and K-functions have been used. Experimental validation is provided by using Brodatz's database and another standard texture database.


Inhibition of phospholipase D by clathrin assembly protein 3 (AP3).
In the accompanying paper (Chung, J.-K., Sekiya, F., Kang, H.-S., Lee, C., Han, J.-S., Kim, S. R., Bae, Y. S., Morris, A. J., and Rhee, S. G. (1997) J. Biol. Chem. 272, 15980-15985), synaptojanin is identified as a protein that inhibits phospholipase D (PLD) activity stimulated by ADP-ribosylation factor and phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2). Here, the purification from rat brain cytosol of another PLD-inhibitory protein that is immunologically distinct from synaptojanin is described, and this protein is identified as clathrin assembly protein 3 (AP3) by peptide sequencing and immunoblot analysis. AP3 binds both inositol hexakisphosphate and preassembled clathrin cages with high affinity. However, neither inositol hexakisphosphate binding nor clathrin cage binding affected the ability of AP3 to inhibit PLD. AP3 also binds to PI(4,5)P2 with low affinity. But the PI(4,5)P2 binding was not responsible for PLD inhibition, because the potency and efficacy of AP3 as an inhibitor of PLD were similar in the absence and presence of PI(4,5)P2. A bacterially expressed fusion protein, glutathione S-transferase-AP3 (GST-AP3), also inhibited PLD with a potency equal to that of brain AP3. The inhibitory effect of AP3 appeared to be the result of direct interaction between AP3 and PLD because PLD bound GST-AP3 in an in vitro binding assay. Using GST fusion proteins containing various AP3 sequences, we found that the sequence extending from residues Pro-290 to Lys-320 of AP3 is critical for both inhibition of and binding to PLD. The fact that AP3 is a synapse-specific protein indicates that the AP3-dependent inhibition of PLD might play a regulatory role that is restricted to the rapid cycling of synaptic vesicles.


Bacterial Lipid II Analogs: Novel In Vitro Substrates for Mammalian Oligosaccharyl Diphosphodolichol Diphosphatase (DLODP) Activities.
Mammalian protein N-glycosylation requires the transfer of an oligosaccharide containing 2 residues of N-acetylglucosamine, 9 residues of mannose and 3 residues of glucose (Glc3Man9 GlcNAc2) from Glc3Man9GlcNAc2-diphospho (PP)-dolichol (DLO) onto proteins in the endoplasmic reticulum (ER). Under some pathophysiological conditions, DLO biosynthesis is perturbed, and truncated DLO is hydrolyzed to yield oligosaccharyl phosphates (OSP) via unidentified mechanisms. DLO diphosphatase activity (DLODP) was described in vitro, but its characterization is hampered by a lack of convenient non-radioactive substrates. Our objective was to develop a fluorescence-based assay for DLO hydrolysis. Using a vancomycin-based solid-phase extraction procedure coupled with thin layer chromatography (TLC) and mass spectrometry, we demonstrate that mouse liver membrane extracts hydrolyze fluorescent bacterial lipid II (LII: GlcNAc-MurNAc(dansyl-pentapeptide)-PP-undecaprenol) to yield GlcNAc-MurNAc(dansyl-pentapeptide)-P (GM5P). GM5P production by solubilized liver microsomal proteins shows similar biochemical characteristics to those reported for human hepatocellular carcinoma HepG2 cell DLODP activity. To conclude, we show, for the first time, hydrolysis of lipid II by a eukaryotic enzyme. As LII and DLO are hydrolyzed by the same, or closely related, enzymes, fluorescent lipid II analogs are convenient non-radioactive substrates for investigating DLODP and DLODP-like activities.


High-Dimensional Clustering of 4000 Irritable Bowel Syndrome Patients Reveals Seven Distinct Disease Subsets.
Irritable bowel syndrome (IBS) is a pain disorder classified by bowel habits, disregarding other factors that may influence the clinical course. The aim of this study was to determine if IBS patients can be clustered based on clinical, dietary, lifestyle, and psychosocial factors. Between 2013 and 2020, the Mayo Clinic Biobank surveyed and received 40,291 responses to a questionnaire incorporating Rome III criteria. Factors associated with IBS were determined and latent class analysis, a model-based clustering, was performed on IBS cases. We identified 4021 IBS patients (mean 64 years; 75% women) and 12,063 controls. Using 26 variables separating cases from controls, the optimal clustering revealed 7 latent clusters. These were characterized by perceived health impairment (moderate or severe), psychoneurological factors, and bowel dysfunction (diarrhea or constipation predominance). Health impairment clusters demonstrated more pain, with the severe cluster also having more psychiatric comorbidities. The next 3 clusters had unique enrichment of psychiatric, neurological, or both comorbidities. The bowel dysfunction clusters demonstrated less abdominal pain, with diarrhea cluster most likely to report pain improvement with defecation. The constipation cluster had the highest exercise score and consumption of fruits, vegetables, and alcohol. The distribution of clusters remained similar when Rome IV criteria were applied. Physiologic tests were available on a limited subset (6%), and there were no significant differences between clusters. In this cohort of older IBS patients, 7 distinct clusters were identified demonstrating varying degrees of gastrointestinal symptoms, comorbidities, dietary, and lifestyle factors. Further research is required to assess whether these unique clusters could be used to direct clinical trials and individualize patient management.


Spatial Associations of Key Lepidopteran Pests With Defoliation, NDVI, and Plant Height in Soybean.
In soybean, Glycine max (L.) Merrill, production, losses to, and control costs for insect pests can be significant limiting factors. Although the heterogeneity of pests has typically been ignored in traditional field management practices, technological advancements have allowed for site-specific pest management systems to be developed for the precise control of pests within a field. In this study, we chose to determine how the in-field distributions of the larvae of three major lepidopteran pests [velvetbean caterpillar Anticarsia gemmatalis (Hübner) (Lepidoptera: Erebidae), soybean looper Chrysodeixis includens (Walker) (Lepidoptera: Noctuidae), and green cloverworm Hypena scabra (Lepidoptera: Erebidae) (Fabricius)] were spatially associated with defoliation, Normalized Difference Vegetation Index (NDVI), and plant height in soybean. Spatial analysis by distance indices (SADIE) of data from two South Carolina soybean fields in 2017 and 2018 revealed a limited number of spatial aggregations for insect datasets. However, 14% and 6% of paired plant-insect datasets were significantly associated or dissociated, respectively. NDVI was found to be more associated with pest distributions than soybean plant heights and defoliation estimates, and the majority of all plant-insect associations and dissociations occurred in the first 4 wk of sampling (late July-early August). If changes are to be implemented regarding how a pest is managed, critical factors explaining the spatial distribution of pests must be identified. Results from this study advocate for the relationship between early-season distributions of pests and important plant variables such as NDVI to be further investigated to better determine the strength of the correlations across years and sites.


Role of myosin VI in the differentiation of cochlear hair cells.
The mouse mutant Snell's waltzer (sv) has an intragenic deletion of the Myo6 gene, which encodes the unconventional myosin molecule myosin VI (K. B. Avraham et al., 1995, Nat. Genet. 11, 369-375). Snell's waltzer mutants exhibit behavioural abnormalities suggestive of an inner ear defect, including lack of responsiveness to sound, hyperactivity, head tossing, and circling. We have investigated the effects of a lack of myosin VI on the development of the sensory hair cells of the cochlea in these mutants. In normal mice, the hair cells sprout microvilli on their upper surface, and some of these grow to form a crescent or V-shaped array of modified microvilli, the stereocilia. In the mutants, early stages of stereocilia development appear to proceed normally because at birth many stereocilia bundles have a normal appearance, but in places there are signs of disorganisation of the bundles. Over the next few days, the stereocilia become progressively more disorganised and fuse together. Practically all hair cells show fused stereocilia by 3 days after birth, and there is extensive stereocilia fusion by 7 days. By 20 days, giant stereocilia are observed on top of the hair cells. At 1 and 3 days after birth, hair cells of mutants and controls take up the membrane dye FM1-43, suggesting that endocytosis occurs in mutant hair cells. One possible model for the fusion is that myosin VI may be involved in anchoring the apical hair cell membrane to the underlying actin-rich cuticular plate, and in the absence of normal myosin VI this apical membrane will tend to pull up between stereocilia, leading to fusion.


Ethyl acrylate risk assessment with a hybrid computational fluid dynamics and physiologically based nasal dosimetry model.
Cytotoxicity in the nasal epithelium is frequently observed in rodents exposed to volatile organic acids and esters by inhalation. An interspecies, hybrid computational fluid dynamics and physiologically based pharmacokinetic (CFD-PBPK) dosimetry model for inhaled ethyl acrylate (EA) is available for estimating internal dose measures for EA, its metabolite acrylic acid (AA), and EA-mediated reductions in tissue glutathione (GSH). Nasal tissue concentrations of AA were previously used as the dose metric for a chronic Reference Concentration (RfC) calculation with this compound. However, EA was more toxic than expected, based on calculated tissue AA concentrations. Unlike AA, EA causes depletion of tissue GSH. We have developed an RfC for EA using tissue GSH depletion in the olfactory epithelium as the primary measure of nasal tissue dose. The hybrid CFD-PBPK model was refined to improve the accuracy of simulations for GSH in rat olfactory tissues. This refined model was used to determine the concentration for continuous human exposures to EA predicted to reduce nasal GSH levels to the same extent as seen in rats exposed to EA at the no-observed-effect level (NOEL). Importantly, AA concentrations in the human nasal olfactory epithelium at the proposed chronic RfC were predicted to be lower than the AA concentrations estimated in the rat at the NOEL. Thus, a chronic RfC based on maintaining GSH in the human nasal olfactory epithelium at levels equivalent to the rat NOEL would also provide an adequate margin of safety with respect to AA concentrations in nasal tissues.


Laser supraarytenoidectomy for laryngomalacia with apnea.
Laryngomalacia, the most common congenital abnormality of the larynx, is a mild self-limiting disorder in the vast majority of cases. Severely obstructive cases do occur. In the past, these have required treatment with a tracheotomy. At St. Christopher's Hospital for Children, laryngomalacia was diagnosed in one-hundred and fifty-three infants during the three-year period from 1986 through 1988. Patients who had unusually severe symptoms, such as apneic spells, impaired ability to eat and severe choking episodes, were evaluated with four channel nasal thermister pneumocardiograms (sleep studies). Four infants with severe laryngomalacia had sleep studies which demonstrated obstructive apnea. In these infants, the carbon dioxide laser was used to vaporize excess floppy supraarytenoid tissue, a supraarytenoidectomy.


Fine structure physical map locations of alterations that affect cell fusion in herpes simplex virus type 1.
Fine structure physical map locations were determined for syncytial mutants (MP, syn-20, syn-102, syn-103, and syn-105) of Herpes Simplex Virus type 1 (HSV-1). All except MP were derived from the KOS strain. MP contains multiple mutations, including one that leads to the loss of accumulation of glycoprotein gC (Ruyechan et al., J. Virol. 29, 677-697, 1979). Overlapping DNA subclones within the prototypic map coordinates 0.707 to 0.810 were constructed from a library of KOS fragments. These were used along with intact mutant DNA to rescue the syn marker. Mutations in all of the mutants were rescued by KOS DNA sequences between 0.732 and 0.745. This cell-dependent syn mutation is the only lesion in the KOS-derived mutants. A second syn mutation in MP was mapped at coordinates 0.745 to 0.753. This lesion produces less fusion and is also cell-type dependent for the fusion phenotype. Cell-type independent fusion requires the presence of both mutations. The locus determining glycoprotein C (gC) production in strain MP was also mapped, using indirect immunofluorescence, to coordinates 0.745 to 0.753. Nucleotide sequences for ICP-27, an immediate early or alpha protein of unknown function, are within these coordinates. Since gC production and the syn phenotype are separable by recombination, they must be caused by independent mutations.


Predictors of Water Lead Levels in Drinking Water of Homes With Domestic Wells in 3 Illinois Counties.
Millions of US homes receive water from private wells, which are not required to be tested for lead (Pb). An approach to prioritizing high-risk homes for water lead level (WLL) testing may help focus outreach and screening efforts, while reducing the testing of homes at low risk. To (1) characterize distribution of WLLs and corrosivity in tap water of homes with private residential wells, and (2) develop and evaluate a screening strategy for predicting Pb detection within a home. Cross-sectional. Three Illinois counties: Kane (northern), Peoria (central), and Jackson (southern). 151 private well users from 3 Illinois counties. Water samples were analyzed for WLL and corrosivity. (1) WLL and corrosivity, and (2) the sensitivity, specificity, and predictive value of a strategy for prioritizing homes for WLL testing. Pb was detected (>0.76 ppb) in tap water of 48.3% homes, and 3.3% exceeded 15 ppb, the US Environmental Protection Agency action level for community water systems. Compared with homes built in/after 1987 with relatively low corrosivity, older homes with more corrosive water were far more likely to contain measurable Pb (odds ratio = 11.07; 95% confidence interval, 3.47-35.31). The strategy for screening homes with private wells for WLL had a sensitivity of 88%, specificity of 42%, positive predictive value of 58%, and negative predictive value of 80%. Pb in residential well water is widespread. The screening strategy for prioritizing homes with private wells for WLL testing is greater than 85% sensitive.


Production of all-male non-transgenic zebrafish by conditional primordial germ cell ablation.
Many fish species exhibit remarkable sexual dimorphism, with males possessing numerous advantageous traits for commercial production by aquaculture such as faster growth rate, more efficient food energy utilization for muscle development, and better breeding performance. Several studies have shown that a decrease in the number of primordial germ cells (PGCs) during early development leads predominantly to male progeny. In this study, we developed a method to obtain all-male zebrafish (Danio rerio) by targeted PGC ablation using the nitroreductase/metronidazole (NTR/Mtz) system. Embryos generated by female heterozygous Tg(nanos3:nfsB-mCherry-nanos3 3'UTR) and male wild-types (WTs) were treated with vehicle or Mtz. Compared to vehicle-treated controls, 5.0 and 10.0 mM Mtz treatment for 24 h significantly reduced the number of PGCs and yielded an exclusively male phenotype in adulthood. The gonads of offspring treated with 5.0 mM Mtz exhibited relatively normal morphology and histological characteristics. Furthermore, these males were able to chase females, spawn, and produce viable offspring, while about 20.0% of males treated with 10.0 mM Mtz were unable to produce viable offspring. The 5.0 mM Mtz treatment protocol may thus be suitable for large-scale production of fertile male offspring. Moreover, about half of these males were WT as evidenced by the absence of nfsB gene expression. It may thus be possible to breed an all-male WT fish population by Mtz-mediated PGC ablation.


Exploring the relationship between cryptocurrencies and hedge funds during COVID-19 crisis.
In this paper, we investigated the relationship between cryptocurrency market and hedge funds in two different ways. First, we focus on the dependence between Cryptocurrency hedge funds and conventional hedge funds strategies using VAR and VECM models, while analyzing the impact of COVID-19 on the hedge funds' values. Secondly, we choose between ARDL and ARDL-ECM models to study the effects of cryptocurrency price changes on Crypto- Currency hedge funds' values during COVID-19 crisis. Our empirical findings demonstrate that there is substantial interactions between Crypto-Currency and conventional hedge funds. The COVID-19 pandemic has significant negative impact on the performance of the following hedge funds: Event Driven, Relative Value and Distressed Debt fund strategies, this has reflected in a significant drop in their values during this critical period. However, we demonstrate that COVID-19 pandemic did not affect the relationship between crypto-currency hedge funds and both bitcoin and Ethereum. These findings hold profound implications for hedge funds managers, cryptocurrency market main players and policy makers. Our study is crucial in forecasting the performance of these markets especially during global pandemics.


Validating International Classification of Disease 10th Revision algorithms for identifying influenza and respiratory syncytial virus hospitalizations.
Routinely collected health administrative data can be used to efficiently assess disease burden in large populations, but it is important to evaluate the validity of these data. The objective of this study was to develop and validate International Classification of Disease 10th revision (ICD -10) algorithms that identify laboratory-confirmed influenza or laboratory-confirmed respiratory syncytial virus (RSV) hospitalizations using population-based health administrative data from Ontario, Canada. Influenza and RSV laboratory data from the 2014-15, 2015-16, 2016-17 and 2017-18 respiratory virus seasons were obtained from the Ontario Laboratories Information System (OLIS) and were linked to hospital discharge abstract data to generate influenza and RSV reference cohorts. These reference cohorts were used to assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ICD-10 algorithms. To minimize misclassification in future studies, we prioritized specificity and PPV in selecting top-performing algorithms. 83,638 and 61,117 hospitalized patients were included in the influenza and RSV reference cohorts, respectively. The best influenza algorithm had a sensitivity of 73% (95% CI 72% to 74%), specificity of 99% (95% CI 99% to 99%), PPV of 94% (95% CI 94% to 95%), and NPV of 94% (95% CI 94% to 95%). The best RSV algorithm had a sensitivity of 69% (95% CI 68% to 70%), specificity of 99% (95% CI 99% to 99%), PPV of 91% (95% CI 90% to 91%) and NPV of 97% (95% CI 97% to 97%). We identified two highly specific algorithms that best ascertain patients hospitalized with influenza or RSV. These algorithms may be applied to hospitalized patients if data on laboratory tests are not available, and will thereby improve the power of future epidemiologic studies of influenza, RSV, and potentially other severe acute respiratory infections.


Fluconazole in the treatment of hepatosplenic candidiasis.
Hepatosplenic candidiasis has increased in frequency among immunocompromised hosts. Risk factors include hematologic malignancy, intensive chemotherapy, prolonged neutropenia, and treatment with broad-spectrum antibiotics. Patients most commonly present with abdominal pain, persistent fevers despite antibiotic therapy, and an elevated alkaline phosphatase level that is out of proportion to other hepatic enzyme levels. Gastrointestinal mucosal damage secondary to intensive chemotherapy may allow colonization with Candida species and subsequent seeding of the portal vein. Treatment has consisted of prolonged courses of amphotericin B, with mortality rates approaching 50%. We report a case of hepatosplenic candidiasis in a patient with acute myelogenous leukemia who had clinical and radiographic improvement during fluconazole therapy. Fluconazole may be an efficacious and less toxic alternative to amphotericin B.


Chondrosarcomas of the phalanges of the hand.
This study aims to evaluate the diagnosis and treatment approaches of the rarely seen chondrosarcomas of the phalanges of the hand. Fifty-two patients (27 males, 25 females; mean age 41.2 years; range 12 to 70 years) with chondroid lesions localized in hand phalanges who were performed surgical treatment between December 2012 and September 2016 were retrospectively reviewed. The study included 62 phalangeal chondroid lesions. Patients' mean follow-up duration was 60.6 months (range 13 to 165 months). Incisional biopsy was performed for the diagnosis. One patient with bilateral and multiple involvement was performed tru-cut biopsy. Phalangeal chondrosarcoma was diagnosed in five patients (9.6%). Of the chondroid lesions, 37 were localized in proximal phalanges (59.6%), 16 in midphalanges (25.8%), and nine in distal phalanges (14.6%). Chondrosarcoma was detected in 15 phalanges of five patients. Of the two patients with Ollier disease, localization was detected in nine phalanges (four proximal, two mid, three distal phalanges) of one patient and in three phalanges (one proximal, two midphalanges) of the other patient. None of the patients had distant metastasis on diagnosis. Ray amputation was performed in two patients under general anesthesia and amputation was performed in one patient. One patient did not give consent for operation. The other patient with Ollier disease gave consent for amputation of only one finger. No local recurrence was seen. The hand localization of chondrosarcomas is rare with scarce information in the literature. Their metastasis potential is low but local recurrence rates are high after insufficient surgery. Amputation or ray amputation is the applicable treatment.


Do environmental temperatures and altitudes affect physical outputs of elite football athletes in match conditions? A systematic review of the 'real world' studies.
Players involved in the various football codes compete throughout the calendar year around the world. Therefore, environmental stressors such as temperature and altitude should be considered in preparation for, and during, matches. We aimed to systematically review the observational and quasi-experimental studies that have been specifically designed to quantify the effects of temperature (hot or cold) high altitude on in-match physical performance indicators. A search of electronic databases (Web of Science, Scopus, SPORTDiscus, PubMed/MEDLINE) was conducted, with 19,424 papers identified as relevant. Following sifting in relation to the eligibility criteria, 12 papers were deemed directly relevant. The reviewed studies scored 6-9 (on a 0-9 scale) for quality assessment using a previously used scale. The major outcome variables relevant to the current review were total distance (m), high-speed running (m) and high-speed runs (count) measured during matches. Standardized effect sizes (ES) were heterogeneous across studies for total distance (ES: -0.96 to -0.14) and high-speed running (ES: -0.69 to 0.12) for >1000 m vs sea-level, time spent at the given altitude being a putative factor for this heterogeneity. Heat had mainly detrimental effects on performance, but ES were, again, heterogeneous across studies (ES: -1.25 to 0.26), dependent on temperature. Given the small number of studies that involved mostly male athletes, and large heterogeneity across studies, more research needs be conducted on physical performance in these environmental conditions, with attention paid to standardizing outcomes and broadening the approaches of studies to guide future decision-making in professional sporting environments.


Stroke: causes and clinical features.
Stroke is a clinically defined syndrome of acute, focal neurological deficit attributed to vascular injury (infarction, haemorrhage) of the central nervous system. Stroke is the second leading cause of death and disability worldwide. Stroke is not a single disease but can be caused by a wide range of risk factors, disease processes and mechanisms. Hypertension is the most important modifiable risk factor for stroke, although its contribution differs for different subtypes. Most (85%) strokes are ischaemic, predominantly caused by small vessel arteriolosclerosis, cardioembolism and large artery athero-thromboembolism. Ischaemic strokes in younger patients can result from a different spectrum of causes such as extracranial dissection. Approximately 15% of strokes worldwide are the result of intracerebral haemorrhage, which can be deep (basal ganglia, brainstem), cerebellar or lobar. Deep haemorrhages usually result from deep perforator (hypertensive) arteriopathy (arteriolosclerosis), while lobar haemorrhages are mainly caused by cerebral amyloid angiopathy or arteriolosclerosis. A minority (about 20%) of intracerebral haemorrhages are caused by macrovascular lesions (vascular malformations, aneurysms, cavernomas), venous sinus thrombosis or rarer causes; these are particularly important in young patients (<50 years). Knowledge of vascular and cerebral anatomy is important in localizing strokes and understanding their mechanisms. This guides rational acute management, investigation, and secondary prevention.


Childhood adversity and parent perceptions of child resilience.
Adverse childhood experiences (ACEs) negatively impact health throughout the life course. For children exposed to ACEs, resilience may be particularly important. However, the literature regarding resilience, particularly the self-regulation aspect of resilience, is not often described in children with ACEs. Additionally, family and community factors that might help promote resilience in childhood may be further elucidated. We aimed to describe the relationship between ACEs and parent-perceived resilience in children and examine the child, family, and community-level factors associated with child resilience. Using the US-based, 2011-2012 National Survey of Children's Health, we examined adverse childhood experiences (NSCH-ACEs) as the main exposure. Affirmative answers to adverse experiences generated a total parent-reported NSCH-ACE score. Bivariate and multivariable logistic regression models were constructed for parent-perceived child resilience and its association with ACEs, controlling for child, family, and neighborhood-level factors. Among 62,200 US children 6-17 years old, 47% had 0 ACEs, 26% had 1 ACE, 19% had 2-3 ACEs, and 8% had 4 or more ACEs. Child resilience was associated with ACEs in a dose-dependent relationship: as ACEs increased, the probability of resilience decreased. This relationship persisted after controlling for child, family, and community factors. Specific community factors, such as neighborhood safety (p < .001), neighborhood amenities (e.g., libraries, parks) (p < .01) and mentorship (p < .05), were associated with significantly higher adjusted probabilities of resilience, when compared to peers without these specific community factors. While ACEs are common and may be difficult to prevent, there may be opportunities for health care providers, child welfare professionals, and policymakers to strengthen children and families by supporting community-based activities, programs, and policies that promote resilience in vulnerable children and communities in which they live.


Clinical evaluation of cats with lower urinary tract disease.
In a prospective study, 141 cats with hematuria, dysuria, urethral obstruction, or combinations of these signs were evaluated by contemporary diagnostic methods and compared with 26 clinically normal cats (controls). Specific diagnosis was established in 45% (64/141) of cats affected with lower urinary tract disease (LUTD). Crystalline matrix plug-induced urethral obstruction was diagnosed in 21% (30/141) of affected cats, uroliths were identified in 21% (30/141) of affected cats, uroliths with concomitant bacterial urinary tract infection (UTI) were identified in less than 2% (2/141) of affected cats, and bacterial UTI alone was identified in less than 2% (2/141) of cats with LUTD. Viruses, mycoplasmas, and ureaplasmas were not isolated from urine samples collected from affected or control cats. Bovine herpesvirus 4 (BHV-4)-neutralizing antibodies were not detected in any serum sample obtained from cats with LUTD or from control cats. In contrast, BHV-4 antibodies were detected by an indirect immunofluorescent antibody (IFA) test in sera obtained from 31% (44/141) of cats with LUTD and 23% (6/26) of control cats. The prevalence of positive BHV-4 IFA test results in affected cats was not significantly different from that observed in control cats. Significant association was not apparent between positive BHV-4 IFA test results and clinical diagnosis, abnormal laboratory findings, or cat age. However, the number of male cats with BHV-4 IFA titer was significantly (P less than 0.02, chi 2 test) greater than that of female cats. Detection of BHV-4 antibodies in approximately 30% of affected and control cats indicates prior virus exposure. Further investigations are warranted to clarify the specific role of BHV-4 in cats with naturally acquired LUTD.


CRISPR-based Activation of Endogenous Neurotrophic Genes in Adipose Stem Cell Sheets to Stimulate Peripheral Nerve Regeneration.
Background: Peripheral nerve regeneration requires coordinated functions of neurotrophic factors and neuronal cells. CRISPR activation (CRISPRa) is a powerful tool that exploits inactive Cas9 (dCas9), single guide RNA (sgRNA) and transcription activator for gene activation, but has yet to be harnessed for tissue regeneration. Methods: We developed a hybrid baculovirus (BV) vector to harbor and deliver the CRISPRa system for multiplexed activation of 3 neurotrophic factor genes (BDNF, GDNF and NGF). The hybrid BV was used to transduce rat adipose-derived stem cells (ASC) and functionalize the ASC sheets. We further implanted the ASC sheets into sciatic nerve injury sites in rats. Results: Transduction of rat ASC with the hybrid BV vector enabled robust, simultaneous and prolonged activation of the 3 neurotrophic factors for at least 21 days. The CRISPRa-engineered ASC sheets were able to promote Schwann cell (SC) migration, neuron proliferation and neurite outgrowth in vitro. The CRISPRa-engineered ASC sheets further enhanced in vivo functional recovery, nerve reinnervation, axon regeneration and remyelination. Conclusion: These data collectively implicated the potentials of the hybrid BV-delivered CRISPRa system for multiplexed activation of endogenous neurotrophic factor genes in ASC sheets to promote peripheral nerve regeneration.


Enhancing Medical Image Denoising with Innovative Teacher-Student Model-Based Approaches for Precision Diagnostics.
The realm of medical imaging is a critical frontier in precision diagnostics, where the clarity of the image is paramount. Despite advancements in imaging technology, noise remains a pervasive challenge that can obscure crucial details and impede accurate diagnoses. Addressing this, we introduce a novel teacher-student network model that leverages the potency of our bespoke NoiseContextNet Block to discern and mitigate noise with unprecedented precision. This innovation is coupled with an iterative pruning technique aimed at refining the model for heightened computational efficiency without compromising the fidelity of denoising. We substantiate the superiority and effectiveness of our approach through a comprehensive suite of experiments, showcasing significant qualitative enhancements across a multitude of medical imaging modalities. The visual results from a vast array of tests firmly establish our method's dominance in producing clearer, more reliable images for diagnostic purposes, thereby setting a new benchmark in medical image denoising.


Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals.
Transcriptomics, proteomics and metabolomics are genomics technologies with great potential in toxicological sciences. Toxicogenomics involves the integration of conventional toxicological examinations with gene, protein or metabolite expression profiles. An overview together with selected examples of the possibilities of genomics in toxicology is given. The expectations raised by toxicogenomics are earlier and more sensitive detection of toxicity. Furthermore, toxicogenomics will provide a better understanding of the mechanism of toxicity and may facilitate the prediction of toxicity of unknown compounds. Mechanism-based markers of toxicity can be discovered and improved interspecies and in vitro-in vivo extrapolations will drive model developments in toxicology. Toxicological assessment of chemical mixtures will benefit from the new molecular biological tools. In our laboratory, toxicogenomics is predominantly applied for elucidation of mechanisms of action and discovery of novel pathway-supported mechanism-based markers of liver toxicity. In addition, we aim to integrate transcriptome, proteome and metabolome data, supported by bioinformatics to develop a systems biology approach for toxicology. Transcriptomics and proteomics studies on bromobenzene-mediated hepatotoxicity in the rat are discussed. Finally, an example is shown in which gene expression profiling together with conventional biochemistry led to the discovery of novel markers for the hepatic effects of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole.


Growth control in cultured 3T3 fibroblasts. V. Purification of an Mr 13,000 polypeptide responsible for growth inhibitory activity.
A growth regulatory factor, which reversibly inhibits DNA synthesis and proliferation of fibroblasts, has been isolated from medium conditioned by exposure to density-inhibited mouse 3T3 cells. This factor, termed FGR-s (13K), yielded a single polypeptide (Mr 13,000) when analyzed by SDS PAGE under both reducing and nonreducing conditions. The dose-response curve of growth inhibition by FGR-s (13K) showed that 50% inhibition of 3T3 cell proliferation was achieved at a concentration of approximately 3 ng/ml, corresponding to approximately 0.23 nM. The activity of FGR-s (13K) was depleted by passing the material over an affinity column containing the monoclonal antibody 2A4; this monoclonal antibody had been previously characterized to bind to the Mr 13,000 polypeptide. These results indicate that we have purified a growth regulatory factor that acts to inhibit the proliferation of cells in an autocrine pathway.


Angiotensinogen gene polymorphism predicts hypertension, and iridological constitutional classification enhances the risk for hypertension in Koreans.
This study investigated the relationship between iridological constitution and angiotensinogen (AGN) gene polymorphism in hypertensives. In addition to angiotensin converting enzyme gene, AGN genotype is also one of the most well studied genetic markers of hypertension. Furthermore, iridology, one of complementary and alternative medicine, is the diagnosis of the medical conditions through noting irregularities of the pigmentation in the iris. Iridological constitution has a strong familial aggregation and is implicated in heredity. Therefore, the study classified 87 hypertensive patients with familial history of cerebral infarction and controls (n = 88) according to Iris constitution, and determined AGN genotype. As a result, the AGN/TT genotype was associated with hypertension (chi2 = 13.413, p < .05). The frequency of T allele was 0.92 in patients and 0.76 in controls (chi2 = 13.159, p < .05). In addition, iridological constitutional classification increased the relative risk for hypertension in the subjects with AGN/T allele. These results suggest that AGN polymorphism predicts hypertension, and iridological constitutional classification enhances the risk for hypertension associated with AGN/T in a Korean population.


Recent Updates on the Antimicrobial Compounds from Marine-Derived Penicillium fungi.
In this review, 72 compounds isolated from marine-derived Penicillium fungi and their antimicrobial activities are reviewed from 2020 to 2023. According to their structures, these compounds can be divided into terpenoids, polyketides, alkaloids and other structural compounds, among which terpenoids and polyketides are relatively large in number. Some compounds have powerful inhibitory effects against different pathogenic bacteria and fungi. This review aims to provide more useful information and enlightenment for further efficient utilization of Penicillium spp. and their secondary metabolites.


Monodomain theory: experimental verification.
The Néel thermal-activation theory of remanence in monodomain grains has been verified quantitatively in experiments on four ferrite micropowders and two natural rocks. Magnetization and demagnetization curves of thermal, isothermal, viscous, and anhysteretic remanences can all be predicted with reasonable accuracy when the Neél theory is generalized to include effects of grain interaction. Results with the natural materials indicate that interacting, single-domain grains or regions are the carriers of the magnetically hard natural remanence of some paleomagnetic rocks.


Treatment of exacerbations of COPD.
Chronic obstructive pulmonary disease (COPD) affects approximately 14 million Americans. Treatment of COPD includes bronchodilators, corticosteroids and antibiotics. The most common bacterial isolates during exacerbations of COPD are Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis.


Extension of the PNA world by functionalized PNA monomers eligible candidates for inverse Diels Alder Click Chemistry.
Progress in genome research led to new perspectives in diagnostic applications and to new promising therapies. On account of their specificity and sensitivity, nucleic acids (DNA/RNA) increasingly are in the focus of the scientific interest. While nucleic acids were a target of therapeutic interventions up to now, they could serve as excellent tools in the future, being highly sequence-specific in molecular diagnostics. Examples for imaging modalities are the representation of metabolic processes (Molecular Imaging) and customized therapeutic approaches ("Targeted Therapy"). In the individualized medicine nucleic acids could play a key role; this requires new properties of the nucleic acids, such as stability. Due to evolutionary reasons natural nucleic acids are substrates for nucleases and therefore suitable only to a limited extent as a drug. To use DNA as an excellent drug, modifications are required leading e.g. to a peptide nucleic acid (PNA). Here we show that an easy substitution of nucleobases by functional molecules with different reactivity like the Reppe anhydride and pentenoic acid derivatives is feasible. These derivatives allow an independent multi-ligation of functionalized compounds, e.g. pharmacologically active ones together with imaging components, leading to local concentrations sufficient for therapy and diagnostics at the same time. The high chemical stability and ease of synthesis could enhance nucleic chemistry applications and qualify PNA as a favourite for delivery. This system is not restricted to medicament material, but appropriate for the development of new and highly efficient drugs for a sustainable pharmacy.


First High-Resolution Crystal Structures of the Glucocorticoid Receptor Ligand-Binding Domain-Peroxisome Proliferator-Activated γ Coactivator 1-α Complex with Endogenous and Synthetic Glucocorticoids.
Both synthetic and endogenous glucocorticoids are important pharmaceutic drugs known to bind to the ligand-binding domain (LBD) of glucocorticoid receptor (GR), a member of the nuclear receptor (NR) superfamily. Ligand binding induces conformational changes within GR, resulting in subsequent DNA binding and differential coregulator recruitment, ultimately activating or repressing target gene expression. One of the most crucial coregulators is peroxisome proliferator-activated γ coactivator 1-α (PGC1α), which acts to regulate energy metabolism by directly interacting with GR to modulate gene expression. However, the mechanisms through which PGC1α senses GR conformation to drive transcription are not completely known. Here, an ancestral variant of the GR (AncGR2) LBD was used as a tool to produce stable protein for biochemical and structural studies. PGC1α is found to interact more tightly and form a more stable complex with AncGR2 LBD than nuclear receptor coactivator 2. We report the first high-resolution X-ray crystal structures of AncGR2 LBD in complex with PGC1α and dexamethasone (DEX) or hydrocortisone (HCY). Structural analyses reveal how distinct steroid drugs bind to GR with different affinities by unique hydrogen bonds and hydrophobic interactions. Important charge clamps are formed between the activation function 2 and PGC1α to mediate their specific interactions. These interactions lead to a high level of protection from hydrogen-deuterium exchange at the coregulator interaction site and strong intramolecular allosteric communication to ligand binding site. This is the first structure detailing the GR-PGC1α interaction providing a foundation for future design of specific therapeutic agents targeting these critical metabolic regulators. SIGNIFICANCE STATEMENT: High-resolution structures of AncGR2 LBD bound to DEX and HCY in complex with PGC1α reveal the molecular mechanism of PGC1α binding to AncGR2 LBD as well as the distinct affinities between DEX and HCY binding. Identifying the structural mechanisms that drive drug affinity is of pharmacologic interest to the glucocorticoid receptor field as an avenue to guide future drug design targeting GR-PGC1α signaling, which plays a crucial role in controlling hepatic glucose output.


Multilevel summation method for electrostatic force evaluation.
The multilevel summation method (MSM) offers an efficient algorithm utilizing convolution for evaluating long-range forces arising in molecular dynamics simulations. Shifting the balance of computation and communication, MSM provides key advantages over the ubiquitous particle–mesh Ewald (PME) method, offering better scaling on parallel computers and permitting more modeling flexibility, with support for periodic systems as does PME but also for semiperiodic and nonperiodic systems. The version of MSM available in the simulation program NAMD is described, and its performance and accuracy are compared with the PME method. The accuracy feasible for MSM in practical applications reproduces PME results for water property calculations of density, diffusion constant, dielectric constant, surface tension, radial distribution function, and distance-dependent Kirkwood factor, even though the numerical accuracy of PME is higher than that of MSM. Excellent agreement between MSM and PME is found also for interface potentials of air–water and membrane–water interfaces, where long-range Coulombic interactions are crucial. Applications demonstrate also the suitability of MSM for systems with semiperiodic and nonperiodic boundaries. For this purpose, simulations have been performed with periodic boundaries along directions parallel to a membrane surface but not along the surface normal, yielding membrane pore formation induced by an imbalance of charge across the membrane. Using a similar semiperiodic boundary condition, ion conduction through a graphene nanopore driven by an ion gradient has been simulated. Furthermore, proteins have been simulated inside a single spherical water droplet. Finally, parallel scalability results show the ability of MSM to outperform PME when scaling a system of modest size (less than 100 K atoms) to over a thousand processors, demonstrating the suitability of MSM for large-scale parallel simulation.


Decolorization of reactive dye Remazol Brilliant Blue R by zirconium oxychloride as a novel coagulant: optimization through response surface methodology.
The aim of the present study was to investigate the performance of a novel coagulant, i.e. ZrOCl2, for the removal of anthraquinone-based reactive dye from aqueous solution. An ideal experimental setup was designed based on central composite design using response surface methodology to determine the individual and interactive effects of different operational variables (i.e. pH, coagulant dose and dye concentration) on treatment performance in terms of dye and chemical oxygen demand (COD) removal efficiencies. Total 92.58% dye and 85.33% COD removal were experimentally attained at optimized conditions at low coagulant dose, i.e. 156.67 mg/L for the dye concentration of 105.67 mg/L at pH 2. To validate the working pH of the metal coagulant, the static charge of ZrOCl2 was measured using Eh value. The performance of the coagulant was validated with experimental and predicted values in the selected data set, and R2 values for both responses were found to be 0.99 and 0.95 respectively, which shows the reliability of the experimental design. Further, the toxicity of the coagulant was assessed and no such toxicity was found even up to the concentration of 500 mg/L, proclaiming the disposal of sludge may not exhibit any threat to humans. Experimental results suggested that the ZrOCl2 could be used as an eco-friendly coagulant for dye wastewater treatment.


Gingerol suppresses sepsis-induced acute kidney injury by modulating methylsulfonylmethane and dimethylamine production.
Acute kidney injury (AKI) and metabolic dysfunction are critical complications in sepsis syndrome; however, their pathophysiological mechanisms remain poorly understood. Therefore, we evaluated whether the pharmacological properties of 6-gingerol (6G) and 10-gingerol (10G) could modulate AKI and metabolic disruption in a rat model of sepsis (faecal peritonitis). Animals from the sham and AKI groups were intraperitoneally injected with 6G or 10G (25 mg/kg). Septic AKI decreased creatinine clearance and renal antioxidant activity, but enhanced oxidative stress and the renal mRNA levels of tumour necrosis factor-α, interleukin-1β, and transforming growth factor-β. Both phenol compounds repaired kidney function through antioxidant activity related to decreased oxidative/nitrosative stress and proinflammatory cytokines. Metabolomics analysis indicated different metabolic profiles for the sham surgery group, caecal ligation and puncture model alone group, and sepsis groups treated with gingerols. 1H nuclear magnetic resonance analysis detected important increases in urinary creatine, allantoin, and dimethylglycine levels in septic rats. However, dimethylamine and methylsulfonylmethane metabolites were more frequently detected in septic animals treated with 6G or 10G, and were associated with increased survival of septic animals. Gingerols attenuated septic AKI by decreasing renal disturbances, oxidative stress, and inflammatory response through a mechanism possibly correlated with increased production of dimethylamine and methylsulfonylmethane.


What Biopsychosocial Factors are Associated With Work Ability in Conservatively Managed Patients with Cervical Radiculopathy? A Cross-Sectional Analysis.
No previous studies have investigated what biopsychosocial factors are associated with self-reported work ability in conservatively managed patients with cervical radiculopathy. To develop a theoretical model of factors and potential processes associated with variation in work ability based on a thorough assessment of biopsychosocial variables in conservatively managed patients with cervical radiculopathy. Cross-sectional observational study. Tertiary neurosurgery clinic. A total of 144 conservatively managed patients with cervical pain and radiculopathy participated in the study. From 64 biopsychosocial candidate variables, significant (P < .05) bivariate correlators with Work Ability Index (WAI) were entered as independent variables in a categorical regression. Elastic net regularization maintained the most parsimonious set of independent variables significantly associated with variation in WAI as the dependent variable. Process analysis of significant independent variable associations with WAI was performed. WAI. From 42 bivariate correlates of WAI, multivariate regression displayed a total of seven variables that were significantly (F [25,98] = 5.74, P < .05) associated with 65.8% of the variation in WAI. The Neck Disability Index (NDI) and Fear-Avoidance Beliefs Questionnaire Work subscale (FABQ-W) were significant individual factors within the final regression model. Process analysis displayed FABQ-W having a significant specific indirect association with the direct association between NDI and WAI, with the model associated with 77% of the variability in WAI (F [2,84] = 141.17, P < .001). Of 64 candidate biopsychosocial factors, NDI and FABQ-W were the most significant multivariate correlates with work ability. FABQ-W has a significant indirect association with baseline NDI scores and perceived work ability. This warrants future research trialing work-related fear avoidance interventions in conservatively managed patients with cervical radiculopathy. III.


Conditioned Medium of Human Menstrual Blood-Derived Endometrial Stem Cells Protects Against MPP+-Induced Cytotoxicity in vitro.
Mesenchymal stem cells (MSCs) showed the potential to treat Parkinson's disease (PD). However, it is unknown whether the conditioned medium of human menstrual blood-derived endometrial stem cells (MenSCs-CM) has the function to alleviate syndromes of PD. In this study, human neuroblastoma SH-SY5Y cells were exposed to neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) for inducing a range of response characteristics of PD. After culturing this cell model with 24 h/48 h collected MenSCs-CM for different days, cell viability, pro-inflammation cytokines, mitochondrial membrane potential (ΔΨm), oxidative stress, and cell apoptosis were detected. Finally, protein assay was performed to detect 12 kinds of neurotrophic factors inside MenSCs-CM. Our results showed that MPP+ caused SH-SY5Y cell viability reduction as an increasing dose and time dependent manner. MPP+ treatment resulted in inflammation, mitochondrial dysfunction, reactive oxygen species (ROS) production accumulation, and apoptosis of SH-SY5Y at its IC50 concentration. Forty-eight hours-collected MenSCs-CM and culturing with the MPP+-treated SH-SY5Y for 2 days are the optimized condition to increase cell viability. Besides, MenSCs-CM was efficacious against MPP+ induced inflammation, ΔΨm loss, ROS generation, and it could significantly decrease cells numbers in late apoptosis stage. What's more, protein assay showed that MenSCs-CM contained various neuroprotective factors. Our study provided the first evidence that MenSCs-CM has a protective effect on MPP+-induced cytotoxicity in various aspects, and firstly showed that MenSCs can release at least 12 kinds of neurotrophic factors to medium, which may contribute to the protective function of MenSCs-CM to treat PD. This research enlightening that MenSCs-CM is beneficial in the therapy for PD and probably also for other neurodegenerative diseases.


[Clinical and experimental studies of rheum on preventing progression of chronic renal failure].
Rheum, a well known herb unique in its cathartic effect is now introduced to prevent progression of uremia. A clinical prospective trial was conducted to evaluate its effect in comparison with the Captopril. 30 cases with initial Scr level of 344.8 +/- 114.0 mumol/L were allocated randomly to 3 groups. Rheum E treated group, Captopril treated group and Rheum E + Captopril group. The long term (6-22 mos) follow-up results showed that the progression rate of renal failure, calculated by regression analysis of 1/Scr vs time, was found to be retarded after treatment, being more marked in both Rheum E and Rheum E + Captopril group. Uremic symptoms improved after the treatment with serum albumin level increased. To explore the mechanism of therapeutic effects of Rheum on CRF, a series of experimental studies were performed. Rheum can suppress the proliferation of glomerular mesangial cells in culture. In 5/6 nephrectomized rats, the O2 consumption of remnant kidney was obviously decreased by feeding the animal Rheum E and the hypermetabolic state was ameliorated as well. A group of 5/6 nephrectomized rats were fed with Rheum E for 28 wks. It was found that the level of azotemia of this treated group was lessened remarkably as compared with the controls. The serum albumin and transferrin contents of the treated animals were much higher than the controls while the blood cholesterol and triglycerides decreased unexpectedly. In conclusion, both the in vivo and in vitro studies have proved the effectiveness of Rheum in preventing the progression of CRF.


Universal method for constructing N-port non-blocking optical router based on 2 × 2 optical switch for photonic networks-on-chip.
We propose a universal method for constructing N-port non-blocking optical router for photonic networks-on-chip, in which all microring (MR) optical switches or Mach-Zehnder (M-Z) optical switches behave as 2 × 2 optical switches. The optical router constructed by the proposed method has minimum optical switches, in which the number of the optical switches is reduced about 50% compared to the reported optical routers based on MR optical switches and more than 30% compared to the reported optical routers based on M-Z optical switches, and therefore is more compact in footprint and more power-efficient. We also present a strict mathematical proof of the non-blocking routing of the proposed N-port optical router.


On the formation of narrowly polydispersed PMMA by surface initiated polymerization (SIP) from AIBN-coated/intercalated clay nanoparticle platelets.
Various free radical surface initiated polymerization (SIP) conditions were investigated on clay nanoparticles coated with monocationic 2,2'-azobisisobutyronitrile (AIBN) type free radical initiators. Interesting differences in the mechanism of polymer nanocomposite product formation and the role of nanoparticle surface bound AIBN initiators were observed on three types of poly(methyl methacrylate) (PMMA) polymerization conditions: bulk, suspension, and solution. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) measurements confirmed the attachment of the initiator on the clay particles without decomposition of the azo group. XRD and transmission electron microscopy (TEM) showed that a well-dispersed structure was accomplished only by bulk and solution SIP. The suspension SIP product consisted of a partially exfoliated structure as shown by XRD and clay particle aggregate formation as shown by TEM. In general, the molecular weights (MWs) of the surface bound polymers were found to be lower than those of the free polymer. Using the same clay loading and initiator concentrations, we observed that relatively higher MW polymers were obtained from suspension and bulk polymerizations in contrast to solution method. However, the most interesting observation is that the surface bound polymers (on all three conditions) showed much narrower polydispersity compared to that of a typical AIBN type free radical polymerization.


A Novel in vitro Model Delineating Hair Cell Regeneration and Neural Reinnervation in Adult Mouse Cochlea.
The study of an adult mammalian auditory system, such as regeneration, has been hampered by the lack of an in vitro system in which hypotheses can be tested efficiently. This is primarily due to the fact that the adult inner ear is encased in the toughest bone of the body, whereas its removal leads to the death of the sensory epithelium in culture. We hypothesized that we could take advantage of the integral cochlear structure to maintain the overall inner ear architecture and improve sensory epithelium survival in culture. We showed that by culturing adult mouse cochlea with the (surrounding) bone intact, the supporting cells (SCs) survived and almost all hair cells (HCs) degenerated. To evaluate the utility of the explant culture system, we demonstrated that the overexpression of Atoh1, an HC fate-determining factor, is sufficient to induce transdifferentiation of adult SCs to HC-like cells (HCLCs). Transdifferentiation-derived HCLCs resemble developmentally young HCs and are able to attract adult ganglion neurites. Furthermore, using a damage model, we showed that degenerated adult ganglions respond to regenerated HCLCs by directional neurite outgrowth that leads to HCLC-neuron contacts, strongly supporting the intrinsic properties of the HCLCs in establishing HCLC-neuron connections. The adult whole cochlear explant culture is suitable for diverse studies of the adult inner ear including regeneration, HC-neuron pathways, and inner ear drug screening.


Hyponatremia may reflect severe inflammation in children with febrile urinary tract infection.
Hyponatremia is the most common electrolyte abnormality in clinical practice, but little is known about the association between febrile urinary tract infection (UTI) and hyponatremia or its significance to clinical outcomes. Data from 140 children with febrile UTI between 2000 and 2010 were retrospectively analyzed. Laboratory examinations [white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum sodium concentration], renal ultrasonography, (99m)Technetium-dimercaptosuccinic acid (DMSA) scintigraphy, and voiding cystourethrogram were performed. Culture growing >50,000 colonies of one single bacterial species on a urine sample obtained by catheter or >100,000 colonies on two clean-catch samples was required to establish diagnosis of UTI. In children with renal cortical defects diagnosed after DMSA scintigraphy (group 1), duration of fever was significantly longer (P = 0.038) and WBC (P = 0.047) and CRP (P < 0.0001) levels significantly higher than in those without renal cortical defects (group 2). However, serum sodium levels were significantly lower in group 1 than group 2 (135.9 ± 2.4 vs 137.4 ± 2.7 mEq/L, P = 0.007). Hyponatremia (serum sodium ≤ 135 mEq/L) was also more frequent in group 1 than in group 2 (74.1 % vs 45.3 %, P = 0.012). Serum sodium concentration was negatively correlated with WBC count (r = -0.156, P = 0.011) and CRP levels (r = -0.160, P= 0.028). Our study indicates that hyponatremia may be a substantial inflammatory marker and is significantly and independently associated with the degree of inflammation in children with febrile UTI.


Significant Enhancement of Antimicrobial Activity in Oxygen-Deficient Zinc Oxide Nanowires.
The fabrication of antimicrobial surfaces that exhibit enhanced activity toward a large variety of microbial species is one of the major challenges of our time. In fact, the negative effects associated with both bacterial and fungal infections are enormous, especially considering that many microbial species are developing resistance to known antibiotics. In this work, we show how a combination of a specific surface morphology and surface chemistry can create a surface that exhibits nearly 100% antimicrobial activity toward both Gram-negative and Gram-positive bacteria and fungal cells. Arrays of vertically aligned, oxygen-deficient zinc oxide (ZnO) nanowires grown on a substrate exhibit enhanced antimicrobial activity compared with surfaces containing either less defective nanowires or highly oxygen-deficient flat films. This synergistic effect between physical activity (morphology) and chemical activity (surface composition) has been shown to be responsible for the outstanding antimicrobial activity of our surfaces, especially toward notoriously resilient bacterial or fungal species. These findings provide a series of design rules for tuning the activities of antibacterial and antifungal nanomaterials. These rules constitute an excellent platform for the development of next-generation antimicrobial surfaces.


Maternal influences on oral and faecal microbiota maturation in neonatal calves in beef and dairy production systems.
The dam is considered an important source of microbes for the calf; consequently, the development of calf microbiota may vary with farming system due to differences between the contact the calf has with the dam. The objective of this study was to characterise the early changes in the composition of oral and faecal microbiota in beef and dairy calves (N = 10) using high-throughput sequencing of the 16S rRNA gene. The microbiota of calves was compared to selected anatomical niches on their dams which were likely to contribute to the vertical transfer of microbes. A total of 14,125 amplicon sequence variants (ASVs) were identified and taxonomically assigned. The oral microbiota of calves and their dams were composed of more similar microbes after the first 4 weeks of life than immediately after calving. The faecal microbiota of four-week old calves was composed of microbes which were more similar to those found in the oral microbiota of calves and adult cows than the faecal microbiota of adult cows. Specific ASVs were identified in the oral microbiota of four-week old calves that were also present in cow niches at calving, whereas very few ASVs were present in the calf faecal microbiota at four-weeks of age were present in any adult cow niche at calving. These results were observed in both beef and dairy calves. We did not observe any marked differences in the maturation of the oral and faecal microbiota between beef or dairy calves, despite dairy calves having very limited contact with their dam. This suggests the development of gastrointestinal microbiota in calves may not be affected by continued vertical transmission of microbes from the dam. Although the calf faecal microbiota changed over the first four-weeks of life, it was composed of microbes which were phylogenetically closer to those in the oral microbiota of calves and adult cows than the faeces of adult cows. There was little evidence of persistent microbial seeding of the calf faeces from anatomical niches on the cow at calving in either beef or dairy animals.


Kikuchi-Fujimoto disease with lateral neck localisation: a case report.
The case is described of a Kikuchi-Fujimoto disease, in a 22-year-old female, onset of which was characterised by rapidly evolving lateral neck lymphadenopathy. Since clinico-radiological findings suggested a lymphoproliferative disease, it was mandatory, in order to establish the diagnosis and programme a suitable treatment protocol, to collect a lymph node biopsy specimen. The histological pattern was characteristic of Kikuchi-Fujimoto disease necrotizing lymphadenitis. Bearing in mind the difficulties encountered in the diagnosis of Kikuchi-Fujimoto disease, due not only to lack of a characteristic clinical pattern but also to the generic and aspecific findings emerging from radiological evaluation, the Authors stress the important role of histological examination in establishing the nature of the disease. In their opinion, onset of a rapidly evolving lateral neck lymphadenopathy, in a young patient, in the absence of well-defined disorders possibly responsible for the condition, and in order to establish a correct diagnostic approach, should induce the ENT specialist to take into consideration the possible presence of Kikuchi-Fujimoto disease, even if this is to be considered a rare finding.


Experiences of hospitalization for suicide ideation and suicide attempt in gender diverse adults.
This study sought to investigate general perceptions of suicide-related hospital-based care that Transgender/Gender Diverse (TGD) adults have experienced as well as correlates of their perceived usefulness of this care. Data were collected via a cross-sectional online survey of N = 3718 self-identified TGD individuals. Single-item self-report measures of all constructs of interest were used. A total of n = 1056 participants indicated hospitalization for either a past suicide attempt (SA) or suicidal ideation (SI). Irrespective of being hospitalized for SI or SA, perceived usefulness of hospital-based care was low with 50% or more of participants rating their care as some degree of unhelpful. Older age, general trust in mental healthcare providers, and voluntary admission were related to higher perceived helpfulness of care for both SI and SA admissions. Higher pride in TGD identity was positively related to perceived helpfulness of care but only for admissions related to SAs. Improving perceived usefulness of hospital-based care may be important for improving subsequent suicide-related help-seeking. Increasing training and provision of care that improves trust with mental healthcare providers and potentially reduces need for involuntary admission may help improve hospital-based, suicide-related care in TGD adults.


Interactions of NO with hemoglobin: from microbes to man.
Hemoglobins are found in organisms from every major phylum and subserve life-sustaining respiratory functions across a broad continuum. Sustainable aerobic respiration in mammals and birds relies on the regulated delivery of oxygen (O2) and nitric oxide (NO) bioactivity by hemoglobin, through reversible binding of NO and O2 to hemes as well as S-nitrosylation of cysteine thiols (SNO synthase activity). In contrast, bacterial and yeast flavohemoglobins function in vivo as denitrosylases (O2 nitroxylases), and some multimeric, invertebrate hemoglobins function as deoxygenases (Cys-dependent NO dioxygenases), which efficiently consume rather than deliver NO and O2, respectively. Analogous mechanisms may operate in plants. Bacteria and fungi deficient in flavohemoglobin show compromised virulence in animals that results from impaired resistance to NO, whereas animals and humans deficient in S-nitrosylated Hb exhibit altered vasoactivity. NO-related functions of hemoglobins center on reactions with ferric (FeIII) heme iron, which is exploited in enzymatic reactions that address organismal requirements for delivery or detoxification of NO and O2. Delivery versus detoxification of NO/O2 is largely achieved through structural changes and amino acid rearrangements within the heme pockets, thereby influencing the propensity for heme/cysteine thiol redox coupling. Additionally, the behavior exhibited by hemoglobin in vivo may be profoundly dependent both on the abundance of NO and O2 and on the allosteric effects of heterotropic ligands. Here we review well-documented examples of redox interactions between NO and hemoglobin, with an emphasis on biochemical mechanisms and physiological significance.


A new dynamic Bayesian network (DBN) approach for identifying gene regulatory networks from time course microarray data.
Signaling pathways are dynamic events that take place over a given period of time. In order to identify these pathways, expression data over time are required. Dynamic Bayesian network (DBN) is an important approach for predicting the gene regulatory networks from time course expression data. However, two fundamental problems greatly reduce the effectiveness of current DBN methods. The first problem is the relatively low accuracy of prediction, and the second is the excessive computational time. In this paper, we present a DBN-based approach with increased accuracy and reduced computational time compared with existing DBN methods. Unlike previous methods, our approach limits potential regulators to those genes with either earlier or simultaneous expression changes (up- or down-regulation) in relation to their target genes. This allows us to limit the number of potential regulators and consequently reduce the search space. Furthermore, we use the time difference between the initial change in the expression of a given regulator gene and its potential target gene to estimate the transcriptional time lag between these two genes. This method of time lag estimation increases the accuracy of predicting gene regulatory networks. Our approach is evaluated using time-series expression data measured during the yeast cell cycle. The results demonstrate that this approach can predict regulatory networks with significantly improved accuracy and reduced computational time compared with existing DBN approaches.


Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts.
Acute myeloid leukemia (AML) is the most common type of acute leukemia, affecting older individuals at a median age of 67 years. Resistance to intensive induction chemotherapy is the major cause of death in elderly AML; hence, novel treatment strategies are warranted. CD33-directed antibody-drug conjugates (gemtuzumab ozogamicin) have been shown to improve overall survival, validating CD33 as a target for antibody-based therapy of AML. Here, we report the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody using AML cell lines and primary AML blasts as targets. BI 836858-opsonized AML cells significantly induced both autologous and allogeneic natural killer (NK)-cell degranulation and NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In vitro treatment of AML blasts with decitabine (DAC) or 5-azacytidine, 2 hypomethylating agents that show efficacy in older patients, did not compromise BI 836858-induced NK-cell-mediated ADCC. Evaluation of BI 836858-mediated ADCC in serial marrow AML aspirates in patients who received a 10-day course of DAC (pre-DAC, days 4, 11, and 28 post-DAC) revealed significantly higher ADCC in samples at day 28 post-DAC when compared with pre-DAC treatment. Analysis of ligands to activating receptors (NKG2D) showed significantly increased NKG2D ligand [NKG2DL] expression in day 28 post-DAC samples compared with pre-DAC samples; when NKG2DL receptor was blocked using antibodies, BI 836858-mediated ADCC was significantly decreased, suggesting that DAC enhances AML blast susceptibility to BI 836858 by upregulating NKG2DL. These data provide a rationale for combination therapy of Fc-engineered antibodies such as BI 836858 with azanucleosides in elderly patients with AML.


Maternal valvular heart disease in pregnancy.
Valvular heart disease is common in pregnancy. Maternal physiology changes significantly during gestation with substantial increases in cardiac output and blood volume; this can cause unmasking or worsening of cardiac disease. Acquired valvular lesions most frequently arise from rheumatic fever, especially in patients who have emigrated from developing nations. Congenital lesions are also encountered. The most common conditions seen, mitral stenosis and regurgitation and aortic stenosis and regurgitation, each require a specific evaluation and management and are associated with their own set of possible complications. Patients with prosthetic valves require anticoagulation, and maternal and fetal risks and benefits must be carefully weighed. Patients with heart disease should be meticulously managed preconceptionally up to the postpartum period by maternal-fetal medicine specialists, obstetricians, cardiologists, and anesthesiologists using a multi-disciplinary approach to their cardiac conditions. Obstetricians & Gynecologists and Family Physicians. After the completing the CME activity, physicians should be better able to examine the epidemiology of valvular heart disease in pregnancy, categorize key physiologic parameters that change in the cardiovascular system during pregnancy, classify the pathophysiology of valvular lesions, and evaluate the general principles of maternal and fetal management for cardiac disease.


Efficacy of 4 percent chlorhexidine gluconate skin cleanser in the treatment of acne vulgaris.
We conducted three controlled, comparative studies to assess the effectiveness of a 4 percent chlorhexidine gluconate skin cleanser (Hibiclens) for the treatment of acne lesions in patients with acne vulgaris. In all studies, the chlorhexidine gluconate formulation achieved statistically significant reduction of the papules plus pustules count, which is generally accepted as the principal criterion of efficacy.


Annotated Draft Genome Assemblies for the Northern Bobwhite (Colinus virginianus) and the Scaled Quail (Callipepla squamata) Reveal Disparate Estimates of Modern Genome Diversity and Historic Effective Population Size.
Northern bobwhite (Colinus virginianus; hereafter bobwhite) and scaled quail (Callipepla squamata) populations have suffered precipitous declines across most of their US ranges. Illumina-based first- (v1.0) and second- (v2.0) generation draft genome assemblies for the scaled quail and the bobwhite produced N50 scaffold sizes of 1.035 and 2.042 Mb, thereby producing a 45-fold improvement in contiguity over the existing bobwhite assembly, and ≥90% of the assembled genomes were captured within 1313 and 8990 scaffolds, respectively. The scaled quail assembly (v1.0 = 1.045 Gb) was ∼20% smaller than the bobwhite (v2.0 = 1.254 Gb), which was supported by kmer-based estimates of genome size. Nevertheless, estimates of GC content (41.72%; 42.66%), genome-wide repetitive content (10.40%; 10.43%), and MAKER-predicted protein coding genes (17,131; 17,165) were similar for the scaled quail (v1.0) and bobwhite (v2.0) assemblies, respectively. BUSCO analyses utilizing 3023 single-copy orthologs revealed a high level of assembly completeness for the scaled quail (v1.0; 84.8%) and the bobwhite (v2.0; 82.5%), as verified by comparison with well-established avian genomes. We also detected 273 putative segmental duplications in the scaled quail genome (v1.0), and 711 in the bobwhite genome (v2.0), including some that were shared among both species. Autosomal variant prediction revealed ∼2.48 and 4.17 heterozygous variants per kilobase within the scaled quail (v1.0) and bobwhite (v2.0) genomes, respectively, and estimates of historic effective population size were uniformly higher for the bobwhite across all time points in a coalescent model. However, large-scale declines were predicted for both species beginning ∼15-20 KYA.


Association Between Leptin, Cognition, and Structural Brain Measures Among "Early" Middle-Aged Adults: Results from the Framingham Heart Study Third Generation Cohort.
There is growing interest in the pathophysiological processes of preclinical Alzheimer's disease (AD), including the potential role of leptin. Human studies have shown that both low and high levels of leptin can be associated with worse neurocognitive outcomes, suggesting this relationship may be moderated by another risk factor. We examined the association between plasma leptin levels and both neuropsychological test performance and structural neuroimaging and assessed whether body mass index (BMI) is an effect modifier of these associations. Our study sample consisted of 2,223 adults from the Framingham Heart Study Third Generation Cohort (average age = 40 years, 53% women). Among the entire sample, there was no association between leptin and any of the neuropsychological domain measures or any of the MRI brain volume measures, after adjustment for BMI, APOE4, and other clinical factors. However, we did observe that BMI category was an effect modifier for the association between leptin and verbal memory (p for interaction = 0.03), where higher levels of leptin were associated with better performance among normal weight participants (BMI 18.5-24.9) kg/m2 (beta = 0.12, p = 0.02). No association was observed between leptin level and verbal memory test performance among participants who were overweight or obese. These findings suggest that the association between leptin and cognitive function is moderated by BMI category. Prospective examination of individuals transitioning from middle age to older adulthood will help to clarify the contribution of leptin to AD and other neurodegenerative conditions.


The binding of a 2-chloroethylamine derivative of oxotremorine (BM 123) to muscarinic receptors in the rat cerebral cortex.
The interaction of a mustard analogue of oxotremorine, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), with muscarinic receptors in the rat cerebral cortex was investigated using 3H-ligand-binding methods. When cortical homogenates were preincubated with BM 123 (1.0 mM), washed extensively, and then assayed for the binding of the specific muscarinic antagonist, [3H](-)-N-methylscopolamine, a decrease in binding capacity was noted without an accompanying change in affinity. The rate at which BM 123 alkylated muscarinic receptors was sensitive to temperature, with little or no receptor alkylation occurring at 0 degree. Thus, it was possible to estimate the affinity of BM 123 and its transformation products for muscarinic receptors by measuring their ability to competitively inhibit 3H-ligand binding to cortical homogenates at 0 degree. When measured by competitive inhibition of [3H]oxotremorine-M and [3H](-)-N-methylscopolamine binding, the concentrations of the aziridinium ion of BM 123 required to displace 50% of specific 3H-ligand binding were 3.5 nM and 4.5 microM, respectively. In contrast, the parent 2-chloroethylamine and its alcoholic hydrolysis product were much less active. The kinetics of the alkylation of muscarinic receptors by BM 123 were consistent with a model in which the aziridinium ion rapidly forms reversible complexes with superhigh high and low affinity sites which slowly convert to covalent complexes. The rate of alkylation of the superhigh affinity site was slowest whereas the converse was true for the low affinity site. It was possible to alkylate the high and low affinity sites selectively with BM 123 by taking advantage of kinetic differences in the rates of alkylation of these two sites. Atropine, oxotremorine, and oxotremorine-M antagonized the rate of alkylation of muscarinic receptors in a manner that was consistent with competitive inhibition.


Coproduction of thermostable amylase and beta-galactosidase enzymes by Geobacillus stearothermophilus SAB-40: aplication of Plackett-Burman design to evaluate culture requirements affecting enzyme production.
A locally isolated thermophile, Geobacillus sp. SAB-40, producing thermostable extracellular amylase constitutively and an induced intracellular beta-galactosidase was characterized and identified based on 16S rRNA sequencing. A phylogenetic analysis then revealed its closeness to Geobacillus stearothermophilus. To evaluate the effect of the culture conditions on the coproduction of both enzymes by G. stearothermophilus SAB-40, a Plackett-Burman fractional factorial design was applied to determine the impact of twenty variables. Among the tested variables, CaCl2, the incubation time, MgSO4.7H2O, and tryptone were found to be the most significant for encouraging amylase production. Lactose was found to promote beta-galactosidase production, whereas starch had a significantly negative effect on lactase production. Based on a statistical analysis, a preoptimized medium attained the maximum production of amylase and beta-galactosidase at 23.29 U/ml/min and 12,958 U/mg biomass, respectively, which was 3- and 2-fold higher than the yield of amylase and lactase obtained with the basal medium, respectively.


[Executive dysfunctions in female patients with borderline personality disorder with regard to impulsiveness and depression].
Because of the presence of pronounced impulsiveness and affective dysregulation in subjects with Borderline Personality Disorder (BPD) executive dysfunctions have been suspected. Previous studies in this area revealed inconsistent results. However, most of these studies did not control for comorbidity (e. g. impulsiveness, depression) and current medication of participants. The aim of this study was, therefore, to investigate executive (dys)functions in patients with BPD and healthy controls controlling for impulsivity. Furthermore, a second control group with depression was included to test the specificity of the results. 24 unmedicated, female BPD patients as well as 24 healthy controls were matched for age, sex, and intelligence. Additionally, 22 female subjects with a life-time diagnosis of depression were included. All subjects completed a neuropsychological test battery assessing executive functions. No significant differences in executive functioning were found between the three groups. BPD patients showed, however, a decreased ability to delay a gratification compared with controls. These results implicate that BPD patients have deficits in motivational areas while other executive functions are not or only marginally involved.


Sequential Multiple-Target Sensor: In3+, Fe2+, and Fe3+ Discrimination by an Anthracene-Based Probe.
Indium is a nonphysiological toxic metal widely used in industry. While misunderstood, its toxicity is proposed to be linked to a perturbation of Fe3+ homeostasis through the binding of In3+ ions to essential iron metalloproteins such as transferrins. Therefore, the monitoring of In3+ and Fe3+ in biological environments is of prime interest for both basic research and diagnosis. Here we report the design of a salen-type anthracene-based probe able to selectively sense and discriminate In3+ and Fe2+/3+ ions by fluoro-colorimetry.


Mediated Social Touch with Mobile Devices: A Review of Designs and Evaluations.
Mediated social touch has been widely studied for remote affective communication in the field of human-computer interaction. We conducted this literature review to comprehensively understand the state of the art of the designs and evaluations of mediated social touch for mobile devices. We selected 52 articles based on related keywords from four main digital libraries, i.e., ACM, IEEE, Springer, and Scopus. We summarized from these articles how mediated social touch signal is designed, prototyped, and evaluated, and what the main research findings are. Based on the analysis, we identified opportunities for later work.


Relaxin increases insulin-like growth factors (IGFs) and IGF-binding proteins of the pig uterus in vivo.
Relaxin promotes growth of reproductive tissues, including the uterus. Although we have evidence of a role for insulin-like growth factor I (IGF-I) in mediating relaxin-induced growth of porcine granulosa cells in vitro, the mechanism of action by which relaxin enhances uterine growth has not been identified. To investigate a role for the uterine insulin-like growth factor (IGF) system in relaxin-induced uterine growth, we monitored the effects of relaxin on porcine IGFs and IGF-binding proteins (IGFBPs) in vivo. The trophic effects of relaxin on the uterus were elicited by administering relaxin or saline to prepubertal gilts every 6 h for 54 h. Three hours after the last injection, uterine flushes, uteri, follicular fluid, and ovaries were collected. Estradiol was measured in plasma and follicular fluid to confirm the prepubertal status of each animal. Significantly higher concentrations of uterine lumen IGF-I (P < 0.05) and IGF-II (P < 0.01) were observed in animals treated with relaxin. However, relaxin administration did not affect uterine IGF-I and -II gene expression, as determined by a ribonuclease protection assay and Northern analysis, respectively. In uterine flushes, relaxin treatment increased an IGFBP doublet (33 and 34.5 kDa) and IGFBP-3. The uterine IGFBP doublet was identified as IGFBP-2 by immunoprecipitation. Plasma or follicular fluid IGFs and IGFBPs were unaffected by relaxin administration. In addition, relaxin did not influence IGF-I binding to its uterine receptor. This is the first study to demonstrate regulation of the pig uterine IGF system by relaxin. In conclusion, the data point to IGF-I, IGF-II, IGFBP-2, and IGFBP-3 as putative mediators of relaxin-induced uterine growth in the pig.