The contribution of geometry to the human connectome.
The human connectome is a topologically complex, spatially embedded network. While its topological properties have been richly characterized, the constraints imposed by its spatial embedding are poorly understood. By applying a novel resampling method to tractography data, we show that the brain's spatial embedding makes a major, but not definitive, contribution to the topology of the human connectome. We first identify where the brain's structural hubs would likely be located if geometry was the sole determinant of brain topology. Empirical networks show a widespread shift away from this geometric center toward more peripheral interconnected skeletons in each hemisphere, with discrete clusters around the anterior insula, and the anterior and posterior midline regions of the cortex. A relatively small number of strong inter-hemispheric connections assimilate these intra-hemispheric structures into a rich club, whose connections are locally more clustered but globally longer than predicted by geometry. We also quantify the extent to which the segregation, integration, and modularity of the human brain are passively inherited from its geometry. These analyses reveal novel insights into the influence of spatial geometry on the human connectome, highlighting specific topological features that likely confer functional advantages but carry an additional metabolic cost.


Folate and macrophage folate receptor-β in idiopathic pulmonary fibrosis disease: the potential therapeutic target?
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal disease with high mortality and poor prognosis. It is characterized by a gradual decline in lung function, and there are currently no effective therapeutic methods. Folate is a water-soluble B vitamin that plays an important role in one-carbon transfer reactions, nucleic acid biosynthesis and methylation reactions. Studies have shown that folate may participate in the pathogenesis of IPF through ways of DNA repair, methylation, and reactive oxygen species. Macrophage activation is an important early cellular event in IPF and the inflammatory response that they trigger is a significant feature of IPF. Folate receptor-β (FR-β) is a cell surface glycosylphosphatidylinositol-anchored glycoprotein that can mediate the unidirectional transport of folate into cells. And it has been found in previous studies that FR-β is usually overexpressed on activated macrophages, but the expression on resting macrophages was undetectable. Therefore, targeting FR-β may have potential value for the early diagnosis and therapy of IPF. Our goal is to highlight the biological role of folate and FR-β in IPF, and we hope to provide helpful insight for clinical treatment strategies.


Permeability and diffusion coefficient of oxygen in membranes for oxygen electrodes.
Oxygen diffusion coefficient and permeability in thin membranes of low-density polythene and laminated polytetrafluorethylene (PTFE) are measured over the temperature range of about 20 to 30 degrees C. The diffusion coefficient is estimated from the time response of a large area platinum electrode covered with the membrane material and exposed to a sudden change in PO2. outside the membrane. The electrode is operated at a very low polarising voltage so that consumption of oxygen at the cathode surface is made negligible. This method is considered to be more reliable than that based on operating the electrode at more normal polarising voltages at which the boundary condition for oxygen tension at the cathode surface is often ill-defined. Oxygen permeability is estimated from the flux of oxygen across an area of membrane separating a nitrogen gas stream from one containing oxygen, the oxygen being measured with a platinum/zirconium oxide reversible cell. Diffusion coefficient in the membranes is very temperature dependent, whereas oxygen solubility is only weakly so. The diffusion coefficient at 25 degrees C is 0.28 +/- 0.06 . 10(-6) and 1.0 +/- 0.2 . 10(-6) cm2 . sec-1 for PTFE and polythene respectively. The corresponding values for permeability are 0.80 +/- 0.08 . 10(-7) and 0.43 +/- 0.04 . 10(-7) ml O2 atm-1 . cm-1 . sec-1.


Molecular modeling, synthesis, and preliminary biological evaluation of glutathione-S-transferase inhibitors as potential therapeutic agents.
Changes in the GSH/GST system have been found to correlate with resistance to anticancer alkylating agents, presumably through accelerated detoxification of these drugs since some GSTs have been shown to catalyze the conjugation of GSH to specific antineoplastic agents. GSH-alkyl derivatives were designed by molecular modeling, synthesized, and tested as inhibitors of human GST-Pi.


Extraction procedures for use prior to HPLC nucleotide analysis using microparticle chemically bonded packings.
In preparing nucleotide extracts for HPLC analysis using microparticle, chemically bonded packings, tri-octyl-amine-freon solutions can be used for the extraction of the acid from the solution if the concentration of the amine is carefully controlled.


[The effect of root canal preparation with nickel-titanium rotary instruments in reducing post-operative pain].
To examine the effect of nickel-titanium rotary instruments in reducing post-operative pain. 95 molars with pulpal and/or periapical involvement were randomly assigned to two groups for root canal preparation. One group was treated with ProFile nickel-titanium rotary instruments; the other was treated by using stainless steel hand files-FlexoFile. The incidence and degree of post-operative pain after root canal preparation in the two groups were recorded. In ProFile group, the incidence of post-operative pain was 27.7%, while 62.5% of the teeth developed post-operative pain after hand preparation. The difference between two groups was statistically significant (P < 0.01). Root canal preparation on molars with stainless steel hand files resulted in relatively high incidence of post-operative pain. Mechanical preparation using ProFile nickel-titanium instruments generated less post-operative pain and discomfort.


Association Between the Autonomy of Peruvian Women and the Choice of the Place of Delivery: Analysis of a National Survey, 2019.
To determine the association between Peruvian women's autonomy and place of delivery. An analytical cross-sectional study of secondary data from the Demographic and Family Health Survey 2019 was carried out. The dependent variable was institutionalized childbirth, and the independent variable was women's autonomy. Likewise, the association between women's autonomy and institutionalized childbirth was evaluated using Poisson family generalized linear models with logarithmic link function, and crude (PR) and adjusted prevalence ratios (aPR) with their respective 95% confidence interval (CI) were estimated. The analysis included 15,334 women aged 15-49 years. It was found that a high proportion of women had a low level of autonomy (42.6%; 95% CI: 41.5-43.7), while 92.1% (95% CI: 91.3-92.9) had institutionalized childbirth. Moderate (PR: 1.10; 95% CI: 1.08-1.12) and high (PR: 1.13; 95% CI: 1.12-1.15) levels of women's autonomy were found to be associated with institutionalized childbirth, and the same association was found in the adjusted analysis. Being a woman with a higher level of autonomy was related to a higher prevalence of institutionalized childbirth. Therefore, as decision-making is a multifactorial characteristic, it is necessary to study in depth the determinants of non-institutionalized childbirth in women with less autonomy.


The morphological relationships between substance P immunoreactive processes and ventral horn neurons in the human and monkey spinal cord.
The distribution of substance P (SP)-containing neural processes in the ventral horn region of the human and monkey spinal cord was studied by staining for SP by the indirect antibody peroxidase-antiperoxidase technique and by light and electron microscopic examination of stained material. Immunoreactive fibers and terminals were found in all major cell columns of the ventral horn in the human and monkey spinal cord, with the immunoreactive profiles in close apposition to motoneurons. The immunoreactivity was contained in synaptic knoblike (bouton) structures, in which the label was associated with small agranular vesicles, dense-core vesicles, and mitochondria. The immunoreactive synaptic knobs formed synaptic junctions predominantly with dendrites. The labeled knobs were similar to "S" (agranular spheroid vesicles) and "G" (dense-core vesicles) type bulbs described previously in the monkey ventral horn. Their location, mainly on the neuron dendrites and soma supports the physiological evidence that SP-produced membrane depolarization is mediated primarily by a direct action of the neurochemical on the neuron rather than by a transynaptic mechanism.


Comparison of invasive blood pressure monitoring versus normal non-invasive blood pressure monitoring in ST-elevation myocardial infarction patients with percutaneous coronary intervention.
Hypotension post percutaneous coronary intervention (PCI) causes stent thrombosis and reduced coronary perfusion, which aggravate myocardial ischemia and lead to patient death. Therefore, the accuracy and timeliness of blood pressure monitoring (BPM) are crucial for the nursing of patients post PCI. However, it is still controversial whether invasive blood pressure monitoring (IBPM) or non-invasive blood pressure monitoring (NIBPM) should be used for patients post PCI, and the magnitude of their assistance for patients' recovery remains unclear. A randomized controlled trial was performed in this study. 126 ST-segment elevation myocardial infarction (STEMI) patients post PCI were recruited and randomly divided into two groups (NIBPM group n = 63; IBPM group n = 63). Clinical characteristics and physiological outcomes of participants received different BPM methods were collected and analyzed to compare the effects of these two methods on the nursing of PCI patients. Compared to NIBPM group, IBPM assisted to shorten the time of myocardial ischemia, promote coronary reperfusion, reduce the occurrence of cardiovascular disease and other complications, and ultimately reduce the mortality of patients post PCI. The application of IBPM contributed to reduce the occurrence of complications, shorten the time of vascular reperfusion, and guide treatment of clinicians in time.


68Ga-DOTANOC PET/CT With Lung Involvement in the Era of COVID-19 Pandemic.
Patient was a 55-year-old man with history of pancreas neuroendocrine tumor grade 2, Ki-67 index 10%. He was treated with surgical resection. 68Ga-DOTANOC PET/CT was performed as part of follow-up of known disease. The images showed opacities in both lungs' parenchyma with moderate uptake of radiotracer and mediastinal lymph nodes with high uptake suggestive of infection. Two weeks before a high-resolution CT was performed, these findings in the lungs were not present. The patient was asymptomatic and was referred to the emergency department for reverse transcriptase-polymerase chain reaction COVID-19 test, and the result was positive.


Cryoshock following cryoablation for hepatocellular carcinoma.
We present a case of profound shock and lactic acidemia occurring in the context of a cryoablative procedure for hepatocellular carcinoma. After out ruling more common possible etiologies, we diagnosed our patient as having a rare cause of shock, unique to these types of cryoablative procedures, known as cryoshock. Cryoablation can result in multiple complications one of which is 'cryoshock', a life-threatening syndrome of multiorgan failure and coagulopathy that carries a high mortality, up to 40%. While the mechanism of cryoshock has not been completely elucidated, it appears to be mediated by the release of cytokines TNF-alpha, IL-1, and IL-6. It is causally associated with complete thaw prior to refreezing and double freeze cycles, as well as volume of and duration of cryotherapy. Cryoreaction, which is a milder phenomenon including chills fever, tachycardia, tachypnea and temporary renal damage has been described after 1% of cryoablation sessions. Reports of the management of cryoshock are scarce and the mainstay of treatment is organ support. While cryoshock has been described in radiology and surgical literature it has not previously been described in anesthesiology literature. We highlight this as a potential serious complication which should be considered by all clinicians involved in these cases.


Functional reconstitution of TatB into the thylakoidal Tat translocase.
We have established an experimental system for the functional analysis of thylakoidal TatB, a component of the membrane-integral TatBC receptor complex of the thylakoidal Twin-arginine protein transport (Tat) machinery. For this purpose, the intrinsic TatB activity of isolated pea thylakoids was inhibited by affinity-purified antibodies and substituted by supplementing the assays with TatB protein either obtained by in vitro translation or purified after heterologous expression in E. coli. Tat transport activity of such reconstituted thylakoids, which was analysed with the authentic Tat substrate pOEC16, reached routinely 20-25% of the activity of mock-treated thylakoid vesicles analysed in parallel. In contrast, supplementation of the assays with the purified antigen comprising all but the N-terminal transmembrane helix of thylakoidal TatB did not result in Tat transport reconstitution which confirms that transport relies strictly on the activity of the TatB protein added and is not due to restoration of the intrinsic TatB activity by antibody release. Unexpectedly, even a mutated TatB protein (TatB,E10C) assumed to be incapable of assembling into the TatBC receptor complex showed low but considerable transport reconstitution underlining the sensitivity of the approach and its suitability for further functional analyses of protein variants. Finally, quantification of TatB demand suggests that TatA and TatB are required in approximately equimolar amounts to achieve Tat-dependent thylakoid transport.


Typing of 30 insertion/deletions in Danes using the first commercial indel kit--Mentype® DIPplex.
In this study, we tested the first commercial kit with insertion/deletion (indel) polymorphisms, the Mentype(®) DIPplex PCR Amplification Kit (DIPplex kit). A total of 30 biallelic autosomal indels and Amelogenin were amplified with the DIPplex kit. All loci were amplified in one PCR multiplex and all amplicon lengths were shorter than 160 bp. Full indel profiles were generated from as little as 100 pg of DNA. A total of 117 individuals from Danish paternity cases were successfully typed. No deviation from Hardy-Weinberg equilibrium was observed for any of the indels. The combined mean match probability was 3.3 × 10(-13), the mean paternity exclusion probability was 99.7% and the typical paternity indices for trios and duos were 2350 and 165, respectively. Furthermore, we typed five highly degraded DNA samples with the DIPplex kit, the AmpFlSTR(®) SGM Plus kit and the AmpFlSTR(®) SEfiler Plus kit. Full indel profiles were obtained with the DIPplex kit, whereas only partial profiles were obtained with the STR kits. In general, the DIPplex kit performed well and it would be a valuable assay for forensic genetic testing, especially in crime cases with partially degraded DNA or low amounts of template DNA. However, some difficulties with pull-ups were observed at DNA concentrations of 1000 pg. Rearrangement of the allele windows by changing the lengths of some of the PCR primers would greatly improve the assay, and more robustness towards higher amounts of DNA would allow the use of the DIPplex kit without prior quantification of the samples.


Allergenic Pollen Season Variations in the Past Two Decades Under Changing Climate in the United States.
Prevalence of allergic diseases has been increasing due to multiple factors, among which climate change has had the most impact. Climate factors increase production of pollen, which also exhibits increased allergenicity. Also, as a result of climate change, there has been a shift in flowering phenology and pollen initiation causing prolonged pollen exposure. Various numerical models have been developed to understand the effect of climate change on pollen emission and transport and the impact on allergic airway diseases.


"You must cut that long and stinking thing": uncovering the lived experiences of uncircumcised pokot women in North-Eastern Uganda.
Female circumcision remains a dominant practice among the Pokot of North-Eastern Uganda. This paper explores the lived experiences of uncircumcised Pokot women, as they continue to live in a community, where the practice is cherished. This qualitative study adopted an ethnographic research design. The study was based on thirty [30] serial interviews with 15 uncircumcised women in the Pokot local language between August and October 2021. Five [5] Key Informant Interviews were also conducted with key informants from Amudat District. A Focus Group Discussion with women, irrespective of their circumcision status, was organized as an entry point to identify the initial uncircumcised woman. Uncircumcised women were recruited using respondent-driven sampling while key informants were purposively selected. Data were analyzed thematically. Participants were allocated codes to ensure anonymity. Participants expressed understanding of female circumcision, and the procedure although they were not circumcised. Denial of participation in community and cultural functions, rejection by elders and relatives, difficulties in getting marriage partners, denial of conjugal rights and basic needs, refusal to give names to their children, and home desertion were the negative experiences reported by uncircumcised women. Sexual enjoyment during sexual intercourse, epitomized by the ease of reaching orgasms, fewer complications while giving birth as well as reduced risk of exposure to sexually transmitted diseases were mentioned by participants as their positive experiences. Uncircumcised Pokot women continue to experience unbearable challenges since female circumcision is perceived as the only rite of passage to womanhood. This calls for intensified awareness of the population on the challenges associated with female circumcision refusal while demonstrating the positive experiences mentioned by uncircumcised women, that can be exploited as the beacon of hope.


K+-dependent stimulation of dopamine synthesis in striatal synaptosomes is mediated by protein kinase C.
Dopamine synthesis rate was measured in striatal synaptosomes. Removal of Na+ increased synthesis rate; this was blocked in Ca2+-free medium and by addition of the Ca2+/calmodulin inhibitor N-6-aminohexyl-5-chloro-1-naphthalenesulfonamide (W7). The increase in dopamine synthesis rate caused by the addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was blocked by the protein kinase C inhibitor polymyxin B. K+-stimulated synthesis was unchanged in Ca2+-free medium or by addition of W7; it was blocked by polymyxin B. The effect of 50 mM K+ was additive with that of 8-Br cyclic AMP and of Na+ removal; the combined effect of 50 mM K+ and TPA was no greater than that of either alone. These results suggest that stimulation of dopamine synthesis in striatal synaptosomes by 50 mM K+ is mediated by protein kinase C.


Metal-tetracycline/H+ antiporter of Escherichia coli encoded by transposon Tn10. Roles of the aspartyl residues located in the putative transmembrane helices.
Three conserved aspartyl residues located in the putative transmembrane helices in the Tn10-encoded metal-tetracycline/H+ antiporter were replaced by Asn, Lys, or Glu with oligonucleotide-directed site-specific mutagenesis. Replacement of Asp84 or Asp15 by Asn or Lys caused a severe defect in tetracycline transport activity, however, the Glu84 and Glu15 mutants retained 150 and 40% of the wild type activity, respectively, indicating the critical role of the negative charge. The increase in the activity of the Glu84 mutant was due to an increase in the affinity for the substrate. H+/tetracycline coupling was intact in these mutants, including Asn and Lys mutants. On the other hand, all of the Asp285-substitution mutants showed a severe defect in tetracycline transport activity and a complete lack of tetracycline-coupled H+ transport. However, since in vivo tests showed the tetracycline resistance for the Glu285 mutant, a negative charge in position 285 plays some role in maintaining the possible down-hill and/or low affinity efflux of accumulated tetracycline from intact cells. Similar work was done for Asp365, and here the Asn and Glu mutants showed decreased but high activity, while the Lys mutant was only marginally active (5%), indicating that a negative charge is not so demanding in position 365, possibly because it is not in the membrane.


A data-driven evaluation of the size and content of expanded carrier screening panels.
The American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of noncarriers, one criterion requires a per-condition carrier rate greater than 1 in 100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel design criteria on at-risk couple detection warrants data-driven evaluation. Carrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and were evaluated for panels satisfying various criteria. Condition-specific clinical detection rates were estimated via simulation. Different interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11-81% fewer at-risk couples, and detect 36-79% fewer carriers than a 176-condition panel. If the carrier rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that the clinical detection rate remains >84% for conditions with carrier rates as low as 1 in 1000. The 1-in-100 criterion limits at-risk couple detection and should be reconsidered.


Assisted 3D printing of microneedle patches for minimally invasive glucose control in diabetes.
Recently, microneedle systems have become an attractive solution for drug delivery. Traditionally, microneedle systems were fabricated via template molding methods. In this study, we present a novel method for the fabrication of a microneedle patch system. We used extrusion-based 3D printing and post stretching to fabricate a microneedle patch system for minimally invasive and glucose-responsive insulin delivery for diabetes treatment. First, we investigated the printability of various bioinks composed of alginate with hydroxyapatite as an additive. After printing the substrate and a cylindrical array of the patch, we stretched the top surface of the cylindrical array to form needle-like tips. The prepared microneedle patch contained 6 × 6 microneedles, and only the microneedles performed glucose-responsive release of insulin. Each microneedle was conical in shape, with a base diameter of 601 μm, a tip diameter of 24 μm, and a height of 643 μm. The fabricated microneedles exhibited sufficient mechanical strength to penetrate the skin of mice and responsively released insulin according to the glucose levels both in glucose solution and in type 1 diabetic mice. When transdermal application was performed only once on the skin of mice, the microneedle patches regulated the blood glucose levels of diabetic mice in normoglycemic ranges for up to 40 h and alleviated the diabetic symptoms of the mice. Our study proposed a method for the fabrication of microneedle patch systems, which can be potentially applied for transdermal drug delivery.


Epileptic seizures in patients with anti-IgLON5 disease.
Anti-IgLON5 is a rare neurologic disease that can present with epileptic seizures. However, epileptic seizures have not been characterized and are underreported. We aimed to investigate the clinical characteristics and demographics of epileptic seizures in patients with anti-IgLON5 disease. We reported a case of anti-IgLON5 disease presenting with epileptic seizures and presented a comprehensive literature review on epileptic seizures in patients with the anti-IgLON5 disease. We searched the Medline, Pubmed, and Web of Science databases using the following search algorithm: "IgLON5" or "anti-IgLON5" or "IgLON5 antibody" limited to publications in English. We identified 183 cases from 66 publications. In addition to our case, nine (4.9%) patients with anti-IgLON5 disease had reported epileptic seizures, either focal or generalized. Of those, epileptic seizures were one of the main reasons for neurology consultation in six (3.2%). Patients with epileptic seizures affected both sexes similarly and usually developed in middle age. In addition to epileptic seizures, a majority of patients had sleep disorders and cognitive impairment. The frequency of epileptic seizures was reduced with the treatment of immunotherapy and antiseizure medication. Anti-IgLON5 disease can present with epileptic seizures, and our study expands the clinical spectrum of the anti-IgLON5 disease.


Familial centronuclear myopathy: a haploid DNA disease?
In the same family three boys (ages 8, 11, 14 years), suffering from a slowly progressive weakness of the flexors of the head and distal muscle groups of the extremities, were found to have a myopathy characterized by the presence of central nuclei in type I fibres. Their mother showed no histopathologic signs but a myopathic pattern on electromyography could be demonstrated. Cytophotometric examination of the anterior tibial muscle of these siblings revealed a reduction in DNA content by 50% in the central and subsarcolemmal nuclei (haploid DNA content) when compared with subsarcolemmal nuclei (diploid DNA content) of the same muscle of their mother. Nuclear DNA concentration in fibrocytes did not differ significantly between members of the family. Therefore, it is assumed that the nuclei of muscle fibres are selectively affected by the disease process which is indicated by a haploid DNA content.


Surgical management of extensive tracheal lesions.
Resection and end-to-end anastomosis has been effective in correcting localized tracheal obstruction. This procedure can be utilized in the definitive management of extensive tracheal lesions requiring the resection of at least eight tracheal rings. Important clinical considerations are the precise preoperative assessment of the lesion, careful planning of anesthetic management, choice of the appropriate incision, avoidance of circumferential dissection, and the construction of an anastomosis free of disruptive tension.


[The infected implant].
The periprosthetic infection is a permanent risk and a severe complication in joint arthroplasty. Raising numbers of cases, unsatisfactory results of treatment and high cost urge to sufficient prophylactic behaviour in primary surgery and research for new treatment strategies. In the future antibiotic coating of the implants and influence on biofilm could possibly be established. Disciplined early diagnostic measures and rational actions following the established concepts are able to create better results and reduce the extreme high costs.


Percutaneous tracheostomy after mechanical ventricular assist device implantation.
Several studies have shown that percutaneous dilational tracheostomy (PDT) is safe and cost-effective for patients recovering from surgery that requires a median sternotomy. We report our experience with PDT in patients receiving mechanical cardiac assistance. We reviewed the medical records of all patients who underwent ventricular assist device implantation at our institution between July 2000 and July 2003, and who subsequently required long-term ventilatory support during the same hospital admission. Data obtained from the records included demographic and biometric information, primary diagnosis, early (< or =30days) and late (>30days) complications, date and cause of death, type of anti-coagulation used at the time of tracheostomy, and various coagulation measures. Thirty-one consecutive patients (29 men, 2 women; mean age, 56 years) had PDT after ventricular assist device implantation. Four minor complications occurred among 3 of the patients (10%), including 3 early complications (2 peristomal oozing and 1 peristomal cellulitis) and 1 late complication (recurrent peristomal cellulitis), none of which affected long-term outcome. No major adverse events, long-term complications, or deaths resulted from the PDT procedure. PDT is feasible for patients with mechanical support devices who require long-term ventilatory support. Although some of these patients are coagulopathic, our results indicate that PDT is safe and effective in this challenging patient population.


The longevity of casein phosphopeptide-amorphous calcium phosphate fluoride varnish's preventative effects: Assessment of white spot lesion formation.
To test how long casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) fluoride varnish prevents enamel demineralization in vitro. Human molars and premolars were sectioned buccolingually and randomly assigned to two groups. Standardized pretreatment images of enamel surfaces were obtained using FluoreCam. The control group received no treatment, and the experimental group received an application of CPP-ACP fluoride varnish. Over simulated periods of 2, 4, 8, and 12 weeks, specimens were placed in a toothbrushing simulator, thermocycled, subjected to 9 days of pH cycling, and imaged with FluoreCam. Samples were sectioned and polished for polarized light microscope (PLM) evaluation. There were statistically significant time ( P < .001) and varnish ( P < .001) effects on area, intensity, and impact of enamel demineralization. The control group showed significant and progressive demineralization over the 12 weeks ( P < .001). The experimental group revealed no significant demineralization during the first 4 weeks ( P > .05) and significant ( P < .001) increases thereafter. Experimental demineralization after 12 weeks was comparable to 2-week demineralization in the controls, with significant between-group differences ( P < .001) in enamel demineralization at all time points. PLM of the control and experimental groups revealed lesion depths of 90 ± 34 μm and 37 ± 9 μm, respectively. Within the limitations of this in vitro study, CPP-ACP fluoride varnish prevents enamel demineralization for at least 4 weeks and limits demineralization up to 12 weeks.


The Government's plan for ensuring compassionate care in the NHS.
In this first of a two-part column, John Tingle discusses the recent speech given by Secretary of State for Health, Jeremy Hunt, at the King's Fund, on making health care more human-centered, not system-centered.


Ultra-sensitive graphene sensor for measuring high vacuum pressure.
We demonstrate here that several different graphene nanoribbon (GNR) samples can be separated from the GNR mixture synthesized by conventional methods. The sheet resistance of the purified GNR gradually decreased with decreasing pressure at 30 °C, whereas it increased at 100 °C. A hypothesis based on van der Waals attractive interactions between GNR sheets was introduced to explain this finding. This hypothesis verified by the shifted main peaks in vacuum X-ray diffraction spectra: 0.022 nm and 0.041 nm shifts were observed for reduced graphene oxide (RGO) and GNR, respectively. Theoretical calculations indicated that, for RGO, the shifted distance was similar to the calculated distance. The response of the GNR sensor to pressure changes occurred rapidly (in seconds). The normalized response time of each sample indicated that sensor using GNR reduced the tailing of the response time by shortening the diffusion path of gas molecules. The sensitivity of the GNR sensor was three times that of RGO in the given pressure range. Moreover, the sensitivity of GNR was much larger than those of the most popularly studied pressure sensors using Piezoresistivity, and the sensor could detect vacuum pressures of 8 × 10-7 Torr.


Negative urgency and alcohol-related problems: indirect links with alcohol expectancies and drinking motives.
Negative Urgency (NU), the tendency to act rashly during negative emotional states, is associated with alcohol misuse through various alcohol cognitions; however, these relationships are often examined in isolation and exclude certain alcohol cognitions. Objective: This study simultaneously modeled NU's association with alcohol-related problems through (a) beliefs about the likelihood of experiencing positive or negative effects from alcohol (i.e., expectancies), (b) desirability of alcohol's positive or negative effects (i.e., valuations), and (c) reasons for consuming alcohol (i.e., drinking motives). Methods: Participants (N = 565) completed measures of NU, expectancies, valuations, drinking motives, and alcohol problems online. Results: NU was indirectly associated with alcohol-related problems through coping motives, positive expectancies, and enhancement motives. Despite a positive association between NU and negative valuations, NU was not associated with alcohol-related problems through valuations. Conclusions: These results further researchers' understanding of how NU is associated with modifiable alcohol cognitions, with clear implications for informing treatment and future research.


Ultrafast interfacial solvation dynamics in specific protein DNA recognition.
An overwhelming number of structural and functional studies on specific protein-DNA complexes reveal the existence of water molecules at the interaction interface. What role does the interfacial water molecules play in determining the specificity of association is thus a critical question. Herein, we have explored the dynamical role of minor groove water molecules and DNA side chain flexibility in lambda repressor-operator DNA interaction using well-characterized DNA minor groove binder dye, Hoechst 33258. The most striking finding of our studies reveals that the solvation time scale corresponding to the minor groove water molecules (∼50 ps) and DNA side chain flexibility (∼10 ns) remain unaltered even in protein-DNA complex in comparison to unbound operator DNA. The temperature dependent study further reveals the slower exchange of minor grove water molecules with bulk water in DNA-protein complex in comparison to the unbound DNA. Detailed structural studies including circular dichroism (CD) and Förster resonance energy transfer (FRET) have also been performed to elucidate the interaction between protein and DNA.


Comparative incidence of early and late bloodstream and respiratory tract co-infection in patients admitted to ICU with COVID-19 pneumonia versus Influenza A or B pneumonia versus no viral pneumonia: wales multicentre ICU cohort study.
The aim is to characterise early and late respiratory and bloodstream co-infection in patients admitted to intensive care units (ICUs) with SARS-CoV-2-related acute hypoxemic respiratory failure (AHRF) needing respiratory support in seven ICUs within Wales, during the first wave of the COVID-19 pandemic. We compare the rate of positivity of different secondary pathogens and their antimicrobial sensitivity in three different patient groups: patients admitted to ICU with COVID-19 pneumonia, Influenza A or B pneumonia, and patients without viral pneumonia. Multicentre, retrospective, observational cohort study with rapid microbiology data from Public Health Wales, sharing of clinical and demographic data from seven participating ICUs. Seven Welsh ICUs participated between 10 March and 31 July 2020. Clinical and demographic data for COVID-19 disease were shared by each participating centres, and microbiology data were extracted from a data repository within Public Health Wales. Comparative data were taken from a cohort of patients without viral pneumonia admitted to ICU during the same period as the COVID-19 cohort (referred to as no viral pneumonia or 'no viral' group), and to a retrospective non-matched cohort of consecutive patients with Influenza A or B admitted to ICUs from 20 November 2017. The comparative data for Influenza pneumonia and no viral pneumonia were taken from one of the seven participating ICUs. A total of 299 consecutive patients admitted to ICUs with COVID-19 pneumonia were compared with 173 and 48 patients admitted with no viral pneumonia or Influenza A or B pneumonia, respectively. Primary outcome was to calculate comparative incidence of early and late co-infection in patients admitted to ICU with COVID-19, Influenza A or B pneumonia and no viral pneumonia. Secondary outcome was to calculate the individual group of early and late co-infection rate on a per-patient and per-sample basis, with their antimicrobial susceptibility and thirdly to ascertain any statistical correlation between clinical and demographic variables with rate of acquiring co-infection following ICU admission. A total of 299 adults (median age 57, M/F 2:1) were included in the COVID-19 ICU cohort. The incidence of respiratory and bloodstream co-infection was 40.5% and 15.1%, respectively. Staphylococcus aureus was the predominant bacterial pathogen within the first 48 h. Gram-negative organisms from Enterobacterales group were predominantly seen after 48 h in COVID-19 cohort. Comparative no viral pneumonia cohort had lower rates of respiratory tract infection and bloodstream infection. The influenza cohort had similar rates respiratory tract infection and bloodstream infection. Mortality in all three groups was similar, and no clinical or demographic variables were found to increase the rate of co-infection and ICU mortality. Higher incidence of bacterial co-infection was found in COVID-19 cohort as compared to the no viral pneumonia cohort admitted to ICUs for respiratory support.


Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter.
CNS white matter from higher vertebrates and cultured differentiated oligodendrocytes are nonpermissive substrates for neurite growth and fibroblast spreading. Membrane proteins of 35 kd and 250 kd with highly nonpermissive substrate properties could be extracted from CNS myelin fractions. Monoclonal antibodies were raised against these proteins: IN-1 and IN-2 bound both to the 35 kd and 250 kd inhibitors and to the surface to differentiated cultured oligodendrocytes. Adsorption of nonpermissive CNS myelin or nonpermissive oligodendrocytes with either antibody markedly improved their substrate properties. Optic nerve explants injected with IN-1 or IN-2 allowed axon ingrowth of cocultured sensory and sympathetic neurons. We conclude that the nonpermissive substrate properties of CNS white matter are due to these membrane proteins on the surface of differentiated oligodendrocytes and to their in vivo product, myelin.


Antigenic mapping reveals sites of vulnerability on α-HCoV spike protein.
Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective vaccine development. To depict the currently elusive antigenic signatures of α-HCoVs S proteins, we isolated a panel of antibodies against the HCoV-229E S protein and characterized their epitopes and neutralizing potential. We found that the N-terminal domain of HCoV-229E S protein is antigenically dominant wherein an antigenic supersite is present and appears conserved in HCoV-NL63, which holds potential to serve as a pan-α-HCoVs epitope. In the receptor binding domain, a neutralizing epitope is captured in the end distal to the receptor binding site, reminiscent of the locations of the SARS-CoV-2 RBD cryptic epitopes. We also identified a neutralizing antibody that recognizes the connector domain, thus representing the first S2-directed neutralizing antibody against α-HCoVs. The unraveled HCoVs S proteins antigenic similarities and variances among genera highlight the challenges faced by pan-HCoV vaccine design while supporting the feasibility of broadly effective vaccine development against a subset of HCoVs.


Separating the wheat from the chaff - Optimizing the diagnosis of enterovirus-associated meningitis.
Enteroviruses (EV) comprise the single most common cause of aseptic meningitis with variable geographical and temporal epidemiology. While EV-PCR in CSF is considered a gold standard for diagnosis, it is not-uncommon to use stool EV as a surrogate. Our aim was to assess the clinical significance of EV-PCR-positive CSF and stool in the investigation of patients with neurological symptoms. In this retrospective study from Sheba Medical centre, the largest tertiary hospital in Israel, we collected demographic, clinical and laboratory data of patients with EV-PCR-positive between 2016 and 2020. A comparison between various combinations of EV-PCR-positive CSF and stool was conducted. Data regarding EV strain-type and cycle threshold (Ct) were crossed with clinical symptoms and temporal kinetics. Between 2016-2020, 448 CSF samples with positive EV-PCR were recorded from unique patients, the vast majority of which were diagnosed with meningitis (98%, 443/448). Unlike the diverse strain types of EV background activity, meningitis-related EV showed a clear epidemic pattern. In comparison with the EV CSF+/Stool+ group, the EV CSF-/Stool+ group had frequently more alternative pathogens detected and a higher stool Ct-value. Clinically, EV CSF-/Stool+ patients were less febrile and more lethargic and convulsive. The comparison of the EV CSF+/Stool+ and CSF-/Stool+ groups suggests that putative diagnosis of EV meningitis is prudent in the febrile, non-lethargic non-convulsive patients with an EV-PCR-positive stool. Otherwise, the detection of stool EV only, in a non-epidemic setup, especially with a high Ct-value, may be incidental and mandate a continuous diagnostic effort for an alternative culprit.


Spin-labeling studies of rat liver NADPH-cytochrome p450 reductase: conformation and function relationship.
ESR spin-labeling studies designed to yield information regarding the relationship between function and conformation of rat liver NADPH-cytochrome P450 reductase (EC 188.8.131.52) were carried out. The purified enzyme was spin labeled by a nitroxide derivative of p-chloromercuribenzoate. Two conditions for spin labeling were employed: (i) the presence of NADP+, yielding an active site-protected spin-labeled reductase, and (ii) the absence of NADP+, yielding completely spin-labeled reductase. Reductase in which the active site was protected by binding NADP+ and then spin-labeled retains most of its enzymatic activity; on the other hand, completely spin-labeled reductase is devoid of any enzymatic activity. Completely spin-labeled reductase yields a two-component resolved ESR spectrum that reflects two classes of spin-labeled binding sites, a strongly immobilized (S) and a weakly immobilized (W) site. The ratio of W/S provides a valuable parameter for studying the relationship between function and conformation. Structural perturbants, such as urea, KCl, and pH, were employed to determine their effects on the activity of the enzyme and their relationship to changes in the conformational state of the reductase. It was further observed that the enzymatically active spin-labeled derivative generated superoxide radical in the presence of NADPH and cytochrome c, which in turn reduced completely the attached spin-label.


Sex Differences in the Developmental Trajectories of Autism Spectrum Disorder.
Females and males are disproportionately diagnosed with autism, a sex difference that has historically represented this neurodevelopmental condition. The current review examines lifespan developmental trajectories of autism based on sex to elucidate behavioral phenotypic differences that may contribute to differential rates of diagnosis. We review sex differences in diagnostic criteria: social communication and restricted interests/repetitive behaviors (RRBs). Results suggest RRBs are more indicative of a diagnosis in males, whereas social differences are more indicative of a diagnosis in females. Factors contributing to a later diagnosis in females include social strengths (camouflaging) and diagnostic overshadowing. Sex differences in diagnostic criteria may contribute to differential rates of identification in males and females. Sex differences are most pronounced when assessing naturalistic social communication instead of reliance on standardized measure. Numerous future directions are identified including increasing samples of sub-threshold autistic females and evaluating longitudinal sex differences.


Topography of the yeast ATP synthase F0 sector.
The interaction between the hydrophilic C-terminal part of subunit 4 (subunit b) and OSCP, which are two components of the connecting stalk of the yeast ATP synthase, was shown after reconstitution of the two over-expressed proteins and by the two-hybrid method. The organization of a part of the F0 sector was studied by the use of mutants containing cysteine residues in a loop connecting the two N-terminal postulated membrane-spanning segments. Labelling of the mutated subunits 4 by a maleimide fluorescent probe revealed that the sulfhydryl groups were modified upon incubation of intact mitochondria. In addition, non-permeant maleimide reagents labeled subunit 4D54C, thus showing a location of this residue in the intermembrane space. Cross-linking experiments revealed the proximity of subunits 4 and f. In addition, a disulfide bridge between subunit 4D54C and subunit 6 was evidenced, thus demonstrating near-neighbor relationships of the two subunits and a location of the N-terminal part of the mitochondrially-encoded subunit 6 in the intermembrane space.


Accidental actinomycin D overdosage in man, a case report.
Although actinomycin D is a relatively old cytotoxic agent, relatively little is known about its toxicity in man in comparison with some of the newer cytotoxic agents that have been extensively investigated. We wish to describe a case where an overdose of actinomycin D was inadvertently administered.


Arsenic and fluoride removal by electrocoagulation process: A general review.
The environmental sector has expressed a growing interest in using electrocoagulation (EC) to treat groundwater/wastewater for drinking/recycling purposes. In the EC process, the electro-dissolution of sacrificial metallic anodes through direct application of current/cell potential dissolves the metals, which precipitate as oxides and hydroxides depending on the electrolyte pH. These particles have large surface areas and can remove pollutants by coagulation. The EC process has been considered an alternative technology due to its versatility, efficiency, low cost, and environmental compatibility. Unfortunately, the lack of knowledge about scaling-up this process has limited its implementation at the industrial scale. The aim of this study is to provide a review of the EC process used for removing arsenic and fluoride from groundwater and wastewater. Approximately 80 published studies were reviewed for this paper. The fundamentals of the EC process and importance of its operating conditions, i.e., electrode material, current density, supporting electrolyte, and pH, are reported in this paper. Additionally, overview of floc characterization and energy consumption are also presented. Finally, this paper also discusses the future perspectives.


Sequence of the cDNA encoding Ras GTPase-activating protein from rat.
We cloned and sequenced a 3296-bp cDNA encoding the rat Ras GTPase-activating protein (GAP). Comparison of the nucleotide (nt) and deduced amino acid (aa) sequences to those of previously described GAP cDNAs revealed greater than 90% identity. Homology is highest between rat and mouse GAP both at the nt (96% identity) and deduced aa levels (98% identity).


Development and validation of a differential pulse polarographic method for quinolinic acid determination in human plasma and urine after solid-phase extraction: a chemometric approach.
A chemometric approach was applied for determining quinolinic acid in human plasma by differential pulse polarography after solid phase extraction. A fractional factorial design was used to examine the significant experimental variables for the peak height maximization. A Doehlert design, which allowed a sequential response surface methodology to be performed, was applied to the variables scan rate and drop size. The results indicated that the scan rate had the greatest effect on the response peak height. The linear range was extended from 8.52 x 10(-8) to 1.34 x 10(-5) M and the limit of detection was 2.9 x 10(-8) M. The validation process consisted of a pre-validation study followed by the main validation in the plasma matrix. The robustness and the intermediate precision were evaluated by means of experimental design. A 3(4)//9 screening symmetric matrix and a central composite design were used to optimize the solid phase extraction procedure of the analyte from human plasma using anion exchange cartridges. The goal was to select the best retention, wash and elution solvents and their volumes in order to maximize the extraction efficiency using as the response the polarographic peak height. An extraction efficiency of 90% was found. The method was also applied to the determination of quinolinic acid in urine and the mean concentration in human plasma and urine, was found to be 3.7 x 10(-7) and 4.9 x 10(-5) M respectively.


Multiple clonal chromosome aberrations in two thymomas.
Cytogenetic investigations of two thymomas of different histopathology revealed unrelated clonal karyotypic changes: 44,XY,+X,inv(2)(p25q13),del(6)(q15),-8,-16,-17 in a cortical thymoma, and 48-49,XX,+del(X)(q24),+i(5p),+?del(7)(q22),der(11)t(1;11)(q23;q25),t(11; ?)(p15;?),-18,+r in a mixed-type thymoma. These are the first thymic tumors of epithelial origin that have been investigated with banding technique.


Perspectives on clinician-delivered firearm safety counseling during routine care: Results of a national survey.
Only 7.5% of United States (U.S.) adults report ever having spoken with a clinician about firearm safety. One reason that clinicians may infrequently counsel patients about firearm safety is that they are unsure whether patients are open to these discussions. The aim of this study was to assess public opinion about whether clinicians should provide firearm safety counseling for patients in specific clinical contexts. We conducted a cross-sectional analysis of online survey data collected in 2019 from a nationally representative sample of U.S. adults residing in households with firearms (n = 4030, response 65%). Participants were asked "As part of routine care, should physicians and/or other health care professionals talk with their patients about firearms and firearm safety if their patient or their patient's family member (is at risk of suicide; has mental health or behavioral problems; is abusing or addicted to alcohol or drugs; is a victim of domestic violence; has Alzheimer's disease or another dementia; is going through a hard time)?" Across the six contexts, 76-89% of adults reported that clinicians should "sometimes" or "always" discuss firearm safety with patients. These findings demonstrate that a large majority of U.S. adults who live in households with firearms believe that clinicians should discuss firearm safety when patients or their family members are experiencing specific clinical scenarios. Clinicians' and healthcare systems' concerns that patients might object to discussing firearm safety in these contexts should not impede efforts to integrate such interventions into routine care.


Femoral and Tibial Bony Risk Factors for Anterior Cruciate Ligament Injuries Are Present in More Than 50% of Healthy Individuals.
Anterior cruciate ligament (ACL) injuries are multifactorial events that may be influenced by morphometric parameters. Associations between primary ACL injuries or graft ruptures and both femoral and tibial bony risk factors have been well described in the literature. To determine values of femoral and tibial bony morphology that have been associated with ACL injuries in a reference population. Further, to define interindividual variations according to participant demographics and to identify the proportion of participants presenting at least 1 morphological ACL injury risk factor. Cross-sectional study; Level of evidence, 3. Computed tomography scans of 382 healthy participants were examined. The following bony ACL risk factors were analyzed: notch width index (NWI), lateral femoral condylar index (LFCI), medial posterior plateau tibial angle (MPPTA), and lateral posterior plateau tibial angle (LPPTA). The proportion of this healthy population presenting with at least 1 pathological ACL injury risk factor was determined. A multivariable logistic regression model was constructed to determine the influence of demographic characteristics. According to published thresholds for ACL bony risk factors, 12% of the examined knees exhibited an intercondylar notch width <18.9 mm, 25% had NWI <0.292, 62% exhibited LFCI <0.67, 54% had MPPTA <83.6°, and 15% had LPPTA <81.6°. Only 14.4% of participants exhibited no ACL bony risk factors, whereas 84.5% had between 2 and 4 bony risk factors and 1.1% had all bony risk factors. The multivariate analysis demonstrated that only the intercondylar notch width (P < .0001) was an independent predictor according to both sex and ethnicity; the LFCI (P = .012) and MMPTA (P = .02) were independent predictors according to ethnicity. The precise definition of bony anatomic risk factors for ACL injury remains unclear. Based on published thresholds, 15% to 62% of this reference population would have been considered as being at risk. Large cohort analyses are required to confirm the validity of previously described morphological risk factors and to define which participants may be at risk of primary ACL injury and reinjury after surgical reconstruction.


Myopathic changes in diaphragm of rats fed pyridostigmine bromide subchronically.
To determine if alterations in muscle morphology occur after subchronic oral administration of pyridostigmine bromide, rats were fed 90 mg/kg continuously in meal and examined at 1, 2, 4, 7, and 15 days. Within the first day, cholinesterase activity was reduced by 87% and remained inhibited by 74-91% for the entire course of the feeding. Light microscopy demonstrated that by the first day approximately 1 in 100 myofibers was shrunken and contained centralized nuclei. Electron microscopic examination showed that while presynaptic areas of neuromuscular junctions were relatively unaffected by this dose, postsynaptic areas invariably showed maximal changes. Ultrastructural alterations included disruption of myofilaments, mitochondrial changes consistent with accumulation of calcium, and nuclear alterations. These effects appeared not to be cumulative and were greatly diminished by 15 days even under constant drug administration and inhibition of cholinesterase activity. We conclude that subchronic feeding of pyridostigmine bromide induces primarily myopathic rather than neurogenic changes in the diaphragm and that some mechanism of accommodation may be activated that minimizes continued muscle injury.


Management of mandibular angle fractures using a 1.7 mm 3-dimensional strut plate.
We report our experience with the use of 1.7 mm 3-dimentional (3D) strut plate for the management of mandibular angle fractures. This prospective study enrolled 15 patients in whom mandibular angle fractures were treated with 1.7 mm 3D plate using trans-buccal trochar. Patients were evaluated at 72 h, 2 weeks, 6 weeks and 12 weeks for fracture stability, occlusion, soft-tissue swelling, infection and post-operative inferior alveolar nerve damage. Other complications like wound dehiscence, non-union, mal-union and hardware failure were also assessed. In the immediate post-operative period, fracture instability was seen in 1 (6.7%) patient which resolved by 2 weeks. Mild occlusal discrepancy was also noted in 1 (6.7%) patient. Wound dehiscence was seen in 5 (33.3%) patients and all resolved by local measures. 1 (6.7%) patient developed post-operative nerve paraesthesia. Immediate post-operative radiographic evaluation demonstrated optimal reduction in all cases with no inferior border gaping. No case of infection, hardware failure, non-union and mal-union was noted. Within the limitations of the study, 1.7 mm 3D strut plate was found to be effective for management of non-communited mandibular angle fractures.


The role of thrombocytosis in prognostic evaluation of epithelial ovarian tumors.
Thrombocytosis has been reported in a variety of solid tumors, including certain gynecologic cancers such as endometrial, vulvar, and cervical cancers. The present study aims to determine the incidence of thrombocytosis in women with epithelial ovarian tumors and to evaluate its association with clinical and pathologic prognostic factors. Between January 2001 and December 2006, 292 patients were diagnosed with epithelial ovarian tumors, and they underwent primary surgical treatment and subsequent platinum-based chemotherapy at the Gynecologic Oncology Department of the study center. The medical records of these patients were evaluated retrospectively. Of the 292 women with epithelial ovarian tumors undergoing primary surgical exploration, 124 (42.5%) had thrombocytosis, indicating platelet counts >400 x 10(9)/l. Patients with thrombocytosis were found to have statistically higher levels of preoperative CA-125 levels, more advanced stage disease, higher grade tumors, and shorter periods of survival. Thrombocytosis is a significant negative prognostic factor for survival in patients with epithelial ovarian tumors. Thrombocytosis is frequently detected in preoperative evaluation of women diagnosed with epithelial ovarian tumors. The data obtained by the previous and present studies suggest that thrombocytosis is associated with factors reflecting a more aggressive tumor biology, and predicting poor survival in women with epithelial ovarian tumors. However, these data are limited by the retrospective nature of the studies and do not confirm a casual relationship between thrombocytosis and tumor behavior. Molecular studies investigating the expression of platelet secretory factors are required to clarify the differences among data provided by the literature.


Transfection of human hepatocyte growth factor gene inhibits advancing pulmonary arterial hypertension induced by shunt flow in a rabbit model.
We investigated gene transfer with human hepatocyte growth factor (HGF) to suppress pulmonary arterial hypertension (PAH) produced by an arteriovenous shunt in a rabbit model. The rabbit model of advanced PAH was used to show that HGF targets pulmonary arteriolar endothelial cells and inhibits disease progression. In the PAH rabbit model transfected with the HGF gene, hemodynamic abnormalities and right ventricular hypertrophy were prevented, as confirmed by invasive measurements and electrocardiographic examinations. In addition to augmented expression of HGF, an increased number of pulmonary arterioles were detected by immunohistochemical analysis. Western Blot and real-time reverse transcriptase-polymerase chain reaction indicated increased protein and mRNA levels of HGF and endothelial nitricoxide synthase (eNOS) in lungs after HGF transfection. Notably, exogenous HGF reduced lung expression of endothelin-1 (ET-1), which was critically involved in PAH-related pathologic changes. Our results suggested that HGF transfection suppresses PAH induced by shunt flow through enhanced expression of HGF with subsequent regulation of the concentrations of eNOS and ET-1 secreted by endothelial cells thereby promoting angiogenesis in injured lung tissue.


Trends-process analytical technology in solid oral dosage manufacturing.
Quality is the lifeline for all pharmaceuticals. Process analytical technology (PAT), introduced by FDA in 2004, providing significant opportunities for improving pharmaceutical development, manufacturing, and quality assurance. Therefore, in this review various PAT tools were introduced for solid oral dosage manufacture quality monitor and control. Throughout this review, we would like to provide more information to both researchers and manufacturers in order to improve the drug quality.


Dibutyl phthalate disrupts energy metabolism and morphology in the gills and induces hepatotoxicity in zebrafish.
This study investigated the acute effects of dibutyl phthalate (DBP) exposure on energy metabolism and gill histology in zebrafish (Danio rerio). The in vitro incubation of gill tissue with 10 μM DBP for 60 min altered tissue energy supply, as shown by decreased lactate content and lactate dehydrogenase (LDH) activity. Higher concentrations of DBP (100 μM and 1 mM) increased lactate content and LDH activity; however, they blocked glucose uptake, depleted the glycogen content in cellular stores, and induced injury to the gills, as measured by LDH release to the extracellular medium. In addition, in vivo exposure of fish to 1 pM DBP for 12 h induced liver damage by increasing alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) activities. Gill histology indicated hyperemia, lamellar fusion, lamellar telangiectasis, and necrosis. Data indicate that acute exposure of zebrafish gills to the higher DBP concentrations studied induces anaerobic cellular activity and high lactate production, causing gill damage, diminishing cell viability, and incurring liver dysfunction.


Machine learning strengthened prediction of tracheal, bronchus, and lung cancer deaths due to air pollution.
This work pointed out the use of machine learning tools to predict the effect of CO, O3, CH4, and CO2 on TBL (tracheal, bronchus, and lung cancer) deaths from 1990 to 2019. In this study, data from 203 countries/locations were used. We used evaluation metrics like accuracy, area under curve (AUC), recall, precision, and Matthews correlation coefficient (MCC) to determine the prediction efficiency of the models. The models that yielded accuracy between 89 and 90 were selected in this study. The essential features in the prediction process were extracted, and it was found that CO influenced the prediction process. Extra trees classifier, random forest classifier, gradient boosting classifier, and light gradient boosting machine were selected from 14 other classifiers based on the accuracy metric. The best-performing models, according to our benchmark standards, are the extra trees classifier (90.83%), random forest classifier (89.17%), gradient boosting classifier (89.17%), and light gradient boosting machine (89.17). We conclude that machine learning models can be used in predicting mortality, i.e., the number of deaths, and could assist us in predicting the role of air pollutants on TBL deaths globally.


Construction of Yeast One-Hybrid Library of Alternaria oxytropis and Screening of Transcription Factors Regulating swnK Gene Expression.
The indolizidine alkaloid-swainsonine (SW) is the main toxic component of locoweeds and the main cause of locoweed poisoning in grazing animals. The endophytic fungi, Alternaria Section Undifilum spp., are responsible for the biosynthesis of SW in locoweeds. The swnK gene is a multifunctional complex enzyme encoding gene in fungal SW biosynthesis, and its encoding product plays a key role in the multistep catalytic synthesis of SW by fungi using pipecolic acid as a precursor. However, the transcriptional regulation mechanism of the swnK gene is still unclear. To identify the transcriptional regulators involved in the swnK gene in endophytic fungi of locoweeds, we first analyzed the upstream non-coding region of the swnK gene in the A. oxytropis UA003 strain and predicted its high transcriptional activity region combined with dual-luciferase reporter assay. Then, a yeast one-hybrid library of A. oxytropis UA003 strain was constructed, and the transcriptional regulatory factors that may bind to the high-transcriptional activity region of the upstream non-coding region of the swnK gene were screened by this system. The results showed that the high transcriptional activity region was located at -656 bp and -392 bp of the upstream regulatory region of the swnK gene. A total of nine candidate transcriptional regulator molecules, including a C2H2 type transcription factor, seven annotated proteins, and an unannotated protein, were screened out through the Y1H system, which were bound to the upstream high transcriptional activity region of the swnK gene. This study provides new insight into the transcriptional regulation of the swnK gene and lays the foundation for further exploration of the regulatory mechanisms of SW biosynthesis in fungal endophytic locoweeds.


Cloning and characterization of a novel lipase from Vibrio harveyi strain AP6.
A lipolytic enzyme designated Vst, was cloned from Vibrio harveyi strain AP6. The vst gene was 1650 bp and was predicted to encode a 549 amino acid precursor with a molecular mass of about 61 kDa. The predicted polypeptide shared about 30% sequence identity with Bacillus esterases. Sequence alignment of Vst and related esterases revealed the presence of an active site serine located in the middle of the GESAG motif, at positions 212-216. This motif resembled the GXSXG consensus motif characteristic of lipolytic enzymes. Vst was expressed as a carboxy-terminal 6 x His tagged recombinant enzyme from E. coli TOP10 cells. SDS-PAGE and Western blot analysis using anti-His antibodies confirmed that the size of the mature protein was about 61 kDa. Substrate specificity of Vst was investigated using p -nitrophenyl (p NP) esters with varying carbon chain lengths, from C2 to C18. Vst showed the highest activity with the long chain p -nitrophenyl ester p NPC12 but was able to hydrolyze longer chain esters (p NPC14-p NPC16) as well as short and medium chain esters (p NPC4 and p NPC8).


Quantitative double-staining methods for tryptophyl and cysteinyl residues and protein in model films.
The reliability of three new staining methods developed by the authors were examined with polyacrylamide gel films containing concanavalin A and ovalbumin. The methods were a 2-nitrophenylsulphenyl chloride technique for staining tryptophyl and cysteinyl residues together, a nitrophenylsulphenyl-2-mercaptoethanol method for tryptophyl residues only, and the combination of both these techniques with Coomassie Brilliant Blue for staining total protein. The relative contents of tryptophyl and cysteinyl residues of concanavalin A and ovalbumin in the films, calculated from absorbance values at 370 and 650 nm of double-stained films, were in good agreement with the theoretical values calculated from their amino acid compositions. Thus, these quantitative double-staining methods are reliable and should be useful for histochemical investigations of changes in the amount and composition of tissue proteins.


The role of selenium-dependent and selenium-independent glutathione peroxidases in the formation of prostaglandin F2 alpha.
In recent years, growing evidence suggests that glutathione peroxidases (GSH-Pxs), both selenium-dependent GSH-Px (Se-GSH-Px) and selenium-independent GSH-Px (non-Se-GSH-Px) play an important role in the biosynthesis of prostaglandins and leukotrienes and in the regulation of key enzymes associated with the arachidonic acid cascade. The precise nature of their involvement in eicosanoid metabolism, however, is not yet completely understood. In the study reported here, we have systematically determined the catalytic efficiencies of Se-GSH-Px and non-Se-GSH-Px toward prostaglandin (PG) G2 (PGG2) and PGH2. Se-GSH-Px exhibited high catalytic activity for the reduction of PGG2 as indicated by Km and Vmax values of 12 microM and 78 mumol/min/mg, respectively, whereas PGH2 was found to be a poor substrate, an indication that Se-GSH-Px reduces the hydroperoxide moiety but not the endoperoxide moiety of PGG2. The kinetic constants of Se-GSH-Px toward PGG2 were comparable to those determined for such classical substrates as H2O2 and cumene hydroperoxide. In contrast to Se-GSH-Px, non-Se-GSH-Px associated with cationic isozyme II of glutathione S-transferases (GSTs) from sheep lung cytosol was very active in the conversion of PGH2 to PGF2 alpha with a Vmax of 960 nmol/min/mg and a Km of 77 microM. This study shows that PGF2 alpha formation by non-Se-GSH-Px occurred in a GSH-dependent reduction of either PGG2 or PGH2. When PGG2 was used as the substrate for non-Se-GSH-Px, a novel intermediate compound appeared and was later identified by several methods of structural analysis as 15-hydroperoxy PGF2 alpha. Thus, the reductive cleavage of the endoperoxide occurs faster than the 15-hydroperoxide reduction allowing 15-hydroperoxy PGF2 alpha to accumulate briefly. A study of GSTs from several different tissues and species indicated that the transformation of PG endoperoxides to PGF2 alpha is catalyzed specifically by GST isozymes, which contain Ya size subunits. This specificity of GST isozymes in PG biosynthesis, coupled with their tissue-specific expression, may be a mechanism by which the body modulates the type of PGs produced in these tissues. Also, these results suggest a possible interaction of Se-GSH-Px and non-Se-GSH-Px in the biosynthesis of PGF2 alpha.


2D-DIGE in Proteomics.
The two-dimensional difference gel electrophoresis method is a valuable approach for proteomics. The method, using cyanine fluorescent dyes, allows the co-migration of multiple protein samples in the same gel and their simultaneous detection, thus reducing experimental and analytical time. 2D-DIGE, compared to traditional post-staining 2D-PAGE protocols (e.g., colloidal Coomassie or silver nitrate), provides faster and more reliable gel matching, limiting the impact of gel to gel variation, and allows also a good dynamic range for quantitative comparisons. By the use of internal standards, it is possible to normalize for experimental variations in spot intensities and gel patterns. Here we describe the experimental steps we follow in our routine 2D-DIGE procedure that we then apply to multiple biological questions.


Cholinergic supersensitivity of the iris sphincter in Adie's tonic pupil.
In patients with unilateral Adie's syndrome, we compared the relative supersensitivity of the tonic pupil to methacholine hydrochloride (Mecholyl 2.5%) and pilocarpine 0.125%. We tested a large series of patients and photographed the pupils before and 30 minutes after the eyedrops. In a group of 36 patients, Mecholyl was positive in 64% of the tests; and in a group of 20 patients, pilocarpine 0.125% was positive in 80% of the tests. Eight patients who failed to show supersensitivity with Mecholyl were tested with pilocarpine and five of the eight were shown to be supersensitive. We concluded that pilocarpine, in this concentration is not only an adequate substitute for Mecholyl 2.5%, but is a more sensitive testing substance in unilateral cases, simply because it has a slightly stronger miotic action.


Acute brucella sacroiliitis: clinical features.
Although back pain is very common, the differential diagnosis may sometimes be very difficult. Both inflammation and infections of spinal or sacroiliac joints are examples of such causes. We report three cases of brucella sacroiliitis resembling acute low back pain or lumbar disc herniation. All patients had had a recent infection and were referred complaining of acute back pain with a suspicion of lumbar disc herniation. The complaints of all patients reduced dramatically after proper medication. Radiographs of all patients and bone scans of two patients revealed sacroiliitis. One of the patients was positive for HLA-B27; in the other two patients HLA-B27 could not be determined.


Amoxicillin pulsatile - MiddleBrook: APC 111, APC-111, PULSYS-enhanced amoxicillin.
MiddleBrook Pharmaceuticals (formerly Advancis Pharmaceutical) is developing an improved version of amoxicillin using its pulsatile oral drug delivery technology, called PULSYS. Amoxicillin PULSYS is intended to provide a lower treatment dose, once-daily alternative to currently approved amoxicillin and penicillin regimens for the treatment of adolescents/adults with pharyngitis and/or tonsillitis. If amoxicillin PULSYS is approved, it will be the first and only once-daily amoxicillin therapy approved for use in the US. Regulatory submissions for the treatment of pharyngitis/tonsillitis have been made in the US. Amoxicillin PULSYS is in clinical development for the treatment of pharyngitis and/or tonsillitis due to group A streptococcal infections in adolescents/adults as a tablet formulation. MiddleBrook was conducting clinical development of a sprinkle formulation for children. However, this has been put on hold for financial reasons. MiddleBrook is seeking regulatory approval for this product as a 505(b)(2) product, which is one that is not considered to be a completely new product, but is also not a generic product. It is a product with some differences from a previously approved product and clinical data to support such differences are required; however, the basic safety and efficacy studies may have been conducted by other organisations. In June 2007, Advancis Pharmaceutical was renamed as MiddleBrook Pharmaceuticals, Inc. MiddleBrook and Par Pharmaceuticals entered a co-promotion agreement for this product in June 2004. Par was to fund future development in exchange for co-exclusive marketing rights and exclusive rights to sell amoxicillin PULSYS. MiddleBrook retained responsibility for the manufacturing programme and also retained all patents and brand names and was responsible for their enforcement. However, this collaboration was subsequently terminated in August 2005 by Par Pharmaceutical. MiddleBrook received the US $4.75 million R&D reimbursement payment due in the third quarter of 2005 and expects no further payments under the collaboration. Under certain circumstances, the termination clauses of the agreement may entitle Par to receive a share of net profits up to 50% of its total US $23 million investment in the development of certain amoxicillin PULSYS products, should a product covered by the agreement be successfully commercialised. Following the end of the first quarter of 2005, MiddleBrook entered into agreements with Clonmel Healthcare Ltd (STADA Group), which will provide MiddleBrook with commercial supply of its amoxicillin PULSYS products being evaluated in phase III trials. MiddleBrook has closed US $24 million in private placement of common equity; funds will be used to support the regulatory approval process for the once-daily amoxicillin pulsatile product. The company conducted phase III trials of this once-daily pulsatile amoxicillin product for the treatment of pharyngitis/tonsillitis due to group A streptococcal infections (commonly referred to as strep throat). Two trials of a 775 mg tablet formulation were conducted in adolescent/adult populations. In December 2006, the company entered into a definitive private placement agreement, raising US $18 million in gross proceeds. It intends to use the proceeds to prepare for the potential commercial launch of amoxicillin PULSYS and to continue the development of other products. The first of the adolescent/adult phase III trials was initiated in October 2004 in the US. This double-blind, non-inferiority, pivotal trial enrolled 510 such patients who received amoxicillin PULSYS 775 mg administered in tablet form once daily for 7 days or the US FDA standard comparator regimen, penicillin 250 mg administered four times daily for 10 days. However, in June 2005, the company reported that amoxicillin PULSYS failed to achieve the primary endpoint of this trial (i.e. bacterial eradication). The company initiated the second adolescent/adult phase III trial in November 2005. This two-arm, double-blind, double-dummy, non-inferiority trial enrolled a total of 620 patients from the US and Canada. Patients received amoxicillin PULSYS (775 mg tablet once daily for 10 days) or the standard penicillin regimen previously mentioned. Top-line results presented in August 2006 showed that the desired microbiological and clinical endpoints were achieved in this trial. In addition, the trial showed that amoxicillin PULSYS achieved 85% bacterial eradication in the per-protocol population, in accordance with the FDA's guidance for approval as a first-line therapy for pharyngitis. MiddleBrook has completed a phase I dose finding trial of its paediatric 'sprinkle' formulation of amoxicillin PULSYS in healthy volunteers. The company commenced a two-arm, investigator-blinded, non-inferiority, US-based, phase III trial in Janary 2005 to evaluate a 'sprinkle' formulation of amoxicillin PULSYS among paediatric patients with acute pharyngitis/tonsillitis caused by group A streptococcal infections. The drug was administered in multiparticulate granules, designed to be sprinkled over food, in two dosages: 475 mg once daily in patients aged 6 months to 4 years, and 775 mg once daily for children aged 5-12 years. Patients were given either 7 days' treatment with amoxicillin PULSYS or penicillin VK four times daily for 10 days. The primary endpoint of the paediatric trial was the same as the adult one. However, in July 2005, the company reported that the product failed to achieve its desired microbiological and clinical endpoints (primary and secondary) in this trial. MiddleBrook was to review the full data and evaluate what steps, if any, could be taken to improve future outcomes.


Nanoscale quantum sensing with Nitrogen-Vacancy centers in nanodiamonds - A magnetic resonance perspective.
Nanodiamonds containing fluorescent Nitrogen-Vacancy (NV) centers are the smallest single particles, of which a magnetic resonance spectrum can be recorded at room temperature using optically-detected magnetic resonance (ODMR). By recording spectral shift or changes in relaxation rates, various physical and chemical quantities can be measured such as the magnetic field, orientation, temperature, radical concentration, pH or even NMR. This turns NV-nanodiamonds into nanoscale quantum sensors, which can be read out by a sensitive fluorescence microscope equipped with an additional magnetic resonance upgrade. In this review, we introduce the field of ODMR spectroscopy of NV-nanodiamonds and how it can be used to sense different quantities. Thereby we highlight both, the pioneering contributions and the latest results (covered until 2021) with a focus on biological applications.


[Erdheim-Chester disease: a rare histiocytosis with outstanding response to cobimetinib.]
Erdheim-Chester Disease (ECD) is a rare form of histiocytosis, characterized by xanthogranulomatous infiltration of multiple organs by lipid-laden histiocytes. It is considered a myeloid inflammatory clonal disorder that mainly affects men with a mean age of 55 years. We present the case of a 65-year-old man who consulted our Endocrinology Unit because of polyuria and polydipsia of 4 months of evolution, diagnosing central diabetes insipidus associated with pituitary infiltration. Physical examination showed skin lesions he has had for several years, that were papules-nodules in the anterior chest and xantelasma-like in the face and neck, with biopsy compatible with non-Langerhans histiocytosis. The genetic study of the skin biopsy showed the presence of a mutation in MAP2K1, confirming the ECD. The patient started treatment with interferon alfa, but the response was incomplete and associated with severe intolerance, so given the findings of the genetic study, we decided to indicate treatment with cobimetinib, a potent and selective inhibitor of MEK. After 8 months of treatment, skin lesions have disappeared, as has the pituitary infiltration, with a remarkable improvement in his quality of life. We present a 65-year-old patient with a rare form of histiocytosis (ECD) who in turn presented an atypical form of ECD and, where the genetic study allowed us to confirm the diagnosis and use targeted therapy with cobimetinib with outstanding results.


Behavioral economics: merging psychology and economics for lifestyle interventions.
The field of behavioral economics combines psychology and economics to investigate how individuals actually behave as opposed to how they would behave if they were being perfectly rational (as in the sense of maximizing their utility). Although initial applications focused on consumer behavior, such as explaining why people failed to save adequately for retirement, the field has moved increasingly into the area of explaining health behaviors as well as the design of lifestyle interventions, such as weight loss and smoking-cessation programs. This article provides an overview of several important behavioral economics concepts of relevance to public health and health behavior change.


Gas chromatographic-mass spectrometric determination of ethyl carbamate in alcoholic beverages.
A sensitive and specific method based on gas chromatography-mass spectrometry for the quantitative determination of ethyl carbamate in table wines, fortified wines (such as ports and sherries), distilled spirits, brandies and liqueurs has been developed. Three characteristic ions from ethyl carbamate [m/z 89 (molecular ion), 74 and 62] were monitored in the selected-ion monitoring (SIM) mode. The lowest detection limit (based on the response on the m/z 62 ion) was estimated to be 0.5 ng/g (ppb). Additional confirmation techniques, including high-resolution SIM, and methane or isobutane chemical ionization are described.


Nervonic Acid Attenuates Accumulation of Very Long-Chain Fatty Acids and is a Potential Therapy for Adrenoleukodystrophy.
Adrenoleukodystrophy (ALD) is an X-linked inherited peroxisomal disorder due to mutations in the ALD protein and characterized by accumulation of very long-chain fatty acids (VLCFA), specifically hexacosanoic acid (C26:0). This can trigger other pathological processes such as mitochondrial dysfunction, oxidative stress, and inflammation, which if involves the brain tissues can result in a lethal form of the disease called childhood cerebral ALD. With the recent addition of ALD to the Recommended Uniform Screening Panel, there is an increase in the number of individuals who are identified with ALD. However, currently, there is no approved treatment for pre-symptomatic individuals that can arrest or delay symptom development. Here, we report our observations investigating nervonic acid, a monounsaturated fatty acid as a potential therapy for ALD. Using ALD patient-derived fibroblasts, we examined whether nervonic acid can reverse VLCFA accumulation similar to erucic acid, the active ingredient in Lorenzo's oil, a dietary intervention believed to alter disease course. We have shown that nervonic acid can reverse total lipid C26:0 accumulation in a concentration-dependent manner in ALD cell lines. Further, we show that nervonic acid can protect ALD fibroblasts from oxidative insults, presumably by increasing intracellular ATP production. Thus, nervonic acid can be a potential therapeutic for individuals with ALD, which can alter cellular biochemistry and improve its function.


Drugging the microbiome: targeting small microbiome molecules.
The human microbiome represents a large and diverse collection of microbes that plays an integral role in human physiology and pathophysiology through interactions with the host and within the microbial community. While early work exploring links between microbiome signatures and diseases states has been associative, emerging evidence demonstrates the metabolic products of the human microbiome have more proximal causal effects on disease phenotypes. The therapeutic implications of this shift are profound as manipulation of the microbiome by the administration of live biotherapeutics, ongoing, can now be pursued alongside research efforts toward describing inhibitors of key microbiome enzymes involved in the biosynthesis of metabolites implicated in various disease states and processing of host-derived metabolites. With growing interest in 'drugging the microbiome', we review few notable microbial metabolites for which traditional drug-development campaigns have yielded compounds with therapeutic promise.


Visual mental imagery in psychopathology--implications for the maintenance and treatment of depression.
Negative mental images are a common feature in a range of mental disorders as well as in healthy subjects. Intrusive negative mental images have only recently become a focus of attention in clinical research on depression. Research so far indicates that they can be an important factor regarding the onset and chronicity of affective disorders. This article is the first to provide an extensive overview of the current state of research in the field of visual mental images in depression. It aims to investigate disorder-specific characteristics, as well as the role of imagery as a maintaining factor. A detailed definition and description of empirical results about mental images in depressive disorders is followed by a presentation and analysis of treatment studies using imagery techniques in depressed samples. Additionally, methodological issues like small sample sizes and the lack of control groups are pointed out and implications for future research are discussed. Case vignettes are included in the appendix to exemplify the importance of negative mental images in patients suffering from depression.


Correction to: A 2-Cys peroxiredoxin gene from Tamarix hispida improved salt stress tolerance in plants.
An amendment to this paper has been published and can be accessed via the original article.


Quantification of eccrine sweat glands with acetylcholine sweat-spot test and anatomical redistribution of sweating after T2-T3 thoracoscopic sympathicolysis.
In this study, patients treated by thoracoscopic sympathicolysis for palmar hyperhidrosis were evaluated to determine the number and response of sweat glands to intradermal acetylcholine stimulus. A total of 30 patients were included in the study. Group A consisted of 10 patients with palmar hyperhidrosis who underwent thoracoscopic sympathicolysis in October 2005, and group B consisted of 20 patients who underwent surgery during the years 1999, 2000, and 2001. The study procedure involved applying iodine alcohol to the palm and then intradermally injecting 0.1 ml 1% acetylcholine. This activated the sweat glands, which were then photographed and counted. The study procedure was performed prospectively over different periods in group A and retrospectively in group B. In group A, the mean number of glands activated 1, 3, 6, and 12 months after surgery were 41, 174.20, 522.8, and 747.2, respectively; this gradual increase was statistically significant over the first 6 months (p = 0.004) but not between months 6 and 12 (p = 0.255). The trend towards an increasing number of active glands occurred in both groups, with a mean of 1369.8 active glands in group B compared to 747.2 (p = 0.095) in group A after 12 months. It is well-known that Cannon's law of denervation (1939) is not applicable to the sweat glands, that is, there is no hyperactivation following intradermal acetylcholine stimulation. However, some response, which increased over the first 6 months following surgery, was observed in our study. Nevertheless, this activation is subsequently self-limiting, resulting in no gland atrophy, and reinnervation occurs without patient awareness.


Impact of climate change on vector- and rodent-borne infectious diseases.
Endemic and imported vector- and rodent-borne infectious agents can be linked to high morbidity and mortality. Therefore, vector- and rodent-borne human diseases and the effects of climate change are important public health issues. For this review, the relevant literature was identified and evaluated according to the thematic aspects and supplemented with an analysis of surveillance data for Germany. Factors such as increasing temperatures, changing precipitation patterns, and human behaviour may influence the epidemiology of vector- and rodent-borne infectious diseases in Germany. The effects of climatic changes on the spread of vector- and rodent-borne infectious diseases need to be further studied in detail and considered in the context of climate adaptation measures.


The baby, the bathwater and the bath itself: a response to Tyrer et al.'s review of the successes and failures of dangerous and severe personality disorder.
A recent paper by Tyrer et al. in this journal has reviewed the dangerous and severe personality disorder (DSPD) initiative in the assessment and management of severe personality disorder associated with high risk. This previous paper summarized the authors' perceptions of the successes and failures of the DSPD pilot. In the present paper we identify some inaccuracies in the previous review and provide a critique of the conclusions reached.


Membrane penetration of nitric oxide and its donor S-nitroso-N-acetylpenicillamine: a spin-label electron paramagnetic resonance spectroscopic study.
S-nitroso-N-acetylpenicillamine (SNAP) is a pharmacological agent with diverse biological effects that are mainly attributable to its favorable characteristics as a nitric oxide (NO)-evolving agent. It is found that SNAP incorporates readily into dimyristoyl phosphatidylcholine (DMPC) bilayer membranes; and an approximate penetration profile was obtained from the depth dependence of the perturbation that it exerts on spin-labeled lipid chains. The profile of SNAP locates it deep in the hydrophobic core of both fluid- and gel-phase membranes. The spin relaxation enhancement of spin-labeled phospholipids with nitroxide group located at different depths in DMPC membranes was determined for nitric oxide (NO) and molecular oxygen (O(2)), at close to atomic spatial resolution. The relaxation enhancement, which is proportional to the corresponding vertical membrane profile of the concentration-diffusion product, was measured in the gel and fluid phases of the lipid bilayer. No significant membrane penetration was observed in the gel phase for the two water-dissolved gases. In the fluid phase, the transmembrane profiles of NO and O(2) are similar and could be well described by a sigmoidal function with a maximum in the center of the bilayer, but that of NO is less steep and is shifted toward the center of the membrane, relative to that of O(2). These differences can be attributed mainly to the difference in hydrophobicity between the two gases and the presence of the donor in the NO experiments. The biological implications of the above results are discussed.


Genomic organization, DNA sequence, and expression of chicken embryonic histone genes.
We have isolated and characterized in detail 15 lambda Charon 4A recombinant bacteriophage containing histone genes from a chicken genomic library. Restriction enzyme-mapping analysis and Southern hybridization to sequenced, homologous histone probes indicate that these genes are not tandemly reiterated within the chicken genome; they usually reside in clusters even though there is no unique array of genes that appears to constitute a typical cluster. Chicken H4 and H1 genes were identified within the genomic recombinants and subsequently sequenced. Extensive regions of homology exist in the 5'- and 3'-flanking regions of the chicken H4 gene when compared to H4 genes from other organisms. In addition to the well documented histone-specific domains, two previously unreported regions of homology lie 5' to this gene: an octanucleotide and a pentanucleotide sequence lying 59 and 116 nucleotides upstream from the H4 gene CAP site, respectively. The H1 gene sequence predicts that the H1 polypeptide is 217 amino acids in length. The 5'-flanking domain of this gene contains, in addition to the transcriptional initiation site and the ATA box, two unusual sequences: one is a nonamer which resides 29 nucleotides upstream from the "ATA" box and is conserved in both the chicken and sea urchin H1 genes, while the other is a GC-rich repetitive sequence element. The majority of the chicken histone genes among the 15 unique lambda recombinant clones are expressed almost exclusively during in ovo development (i.e. from at least 4 days postfertilization up to hatching, about 20-21 days postfertilization) and appear not to be associated with any particular tissue type.


Central auditory processing. IV. Ear dominance--spatial and temporal complexity.
Ear dominance for dichotically presented tones was measured in 63 righthanded subjects when the frequency difference (delta f) was small compared to the center frequency (fc) and again when it was large. Although two-thirds of the population exhibited a left-ear dominance in both conditions, a shift toward right-ear dominance occurred when the delta f was increased. An additional study, employing the alternating tone illusion described by Deutsch, revealed the same general effect, i.e., a shift toward right-ear dominance with increasing values of delta f/fc. The results of these experiments, coupled with a review of previously published data of other dichotic experiments, indicate that as the ratio of delta f/fc increases, the subjective complexity of the sound image increases, and there is a progressive emergence of a "right-ear advantage" (or ear dominance). A tentative explanation relates these results to the effects of anatomical asymmetries of primary and auditory association cortex and the efferent temporal lobe enhancement mechanism described by R. Efron, P.H. Crandall, B. Koss, P.L. Divenyi, and E.W. Yund (Brain and Language, 1983, 19, 254-263.


[Genetic analysis of the polyauxotrophy of the early mitotic progeny of Saccharomyces cerevisiae zygotes. III. The behavior of the chromosome-III markers in polyauxotrophic clones and their mitotic and meiotic segregants].
Cloning and segregation analysis of polyauxotrophic (PA) progeny, as well as the study of diploid segregants, revealed an unusual state of the diploid genome in these strains. Analysis of linkage markers of chromosome III in all crosses may be expected to illuminate relationships between the homologous chromosomes. All PA strains were assigned to two major classes. In the class of PA strains with recombinant chromosome III, the effect of approachment of third linkage markers was noted. In other strains, transposition of genetic marker metA1 to chromosome III and its linkage to leu2 were discovered. The present study has demonstrated that the unusual state of the diploid genome of PA strains induces multiple nonspecific alterations in chromosome relationship and structure. It is likely that these alterations are the consequence of disturbance in mitotic apparatus of cell.


Prefrontal solution to the bias-variance tradeoff during reinforcement learning.
Evidence that the brain combines different value learning strategies to minimize prediction error is accumulating. However, the tradeoff between bias and variance error, which imposes different constraints on each learning strategy's performance, poses a challenge for value learning. While this tradeoff specifies the requirements for optimal learning, little has been known about how the brain deals with this issue. Here, we hypothesize that the brain adaptively resolves the bias-variance tradeoff during reinforcement learning. Our theory suggests that the solution necessitates baseline correction for prediction error, which offsets the adverse effects of irreducible error on value learning. We show behavioral evidence of adaptive control using a Markov decision task with context changes. The prediction error baseline seemingly signals context changes to improve adaptability. Critically, we identify multiplexed representations of prediction error baseline within the ventrolateral and ventromedial prefrontal cortex, key brain regions known to guide model-based and model-free reinforcement learning.


Do fibre containing enteral diets have advantages over existing low residue diets?
This study investigated the influence of fibre on the pattern of absorption of protein and carbohydrate following administration of polymeric enteral diet and also the effect of added fibre on frequency of bowel action, stool weight and gastrointestinal side effects during enteral nutrition. No difference was seen in frequency of bowel action, stool weight or gastrointestinal side effects in five patients fed with either a fibre free polymeric diet or with the same diet augmented with 24 g fibre/24 h. Addition of fibre did not significantly alter breath hydrogen excretion. In an oral tolerance test on six normal subjects, the post prandial rises in blood glucose and levels of 17 amino acids were similar on ingestion of a fibre containing or fibre free test meal.


A neural network algorithm for semi-supervised node label learning from unbalanced data.
Given a weighted graph and a partial node labeling, the graph classification problem consists in predicting the labels of all the nodes. In several application domains, from gene to social network analysis, the labeling is unbalanced: for instance positive labels may be much less than negatives. In this paper we present COSNet (COst Sensitive neural Network), a neural algorithm for predicting node labels in graphs with unbalanced labels. COSNet is based on a 2-parameter family of Hopfield networks, and consists of two main steps: (1) the network parameters are learned through a cost-sensitive optimization procedure; (2) a suitable Hopfield network restricted to the unlabeled nodes is considered and simulated. The reached equilibrium point induces the classification of the unlabeled nodes. The restriction of the dynamics leads to a significant reduction in time complexity and allows the algorithm to nicely scale with large networks. An experimental analysis on real-world unbalanced data, in the context of the genome-wide prediction of gene functions, shows the effectiveness of the proposed approach.