Requirements for Arabidopsis ATARP2 and ATARP3 during epidermal development.
Plant cells employ the actin cytoskeleton to stably position organelles, as tracks for long distance transport, and to reorganize the cytoplasm in response to developmental and environmental cues. While diverse classes of actin binding proteins have been implicated in growth control, the mechanisms of cytoskeletal reorganization and the cellular functions of specific actin filament arrays are unclear. Arabidopsis trichome morphogenesis includes distinct requirements for the microtubule and actin filament cytoskeletons. It also is a genetically tractable process that is providing new knowledge about cytoskeleton function in plants. The "distorted group" of mutants defines a class of at least eight genes that are required during the actin-dependent phase of trichome growth. Using map-based cloning and a candidate gene approach, we identified mutations in ARP3 (ATARP3) and ARP2 (ATARP2) genes as the cause of the distorted1 (dis1) and wurm (wrm) phenotypes, respectively. ARP2 and ARP3 are components of the evolutionarily conserved ARP2/3 complex that nucleates actin filament polymerization [3]. Mutations in DIS1 and WRM caused severe trichome growth defects but had relatively mild effects on shoot development. DIS1 rescued the phenotype of Deltaarp3 when overexpressed in S. cerevisiae. Developing dis1 trichomes had defects in cytoplasmic actin bundle organization and reduced relative amounts of cytoplasmic actin filaments in developing branches.


Maternal diabetes induces changes in the umbilical cord gene expression.
Since maternal diabetes may affect fetal development and the umbilical cord provides an extension of the fetal vasculature, we decided to investigate cords' biological responses to maternal diabetic milieu. Using microarray analysis, we determined the gene expression profiles in the umbilical cords of six neonates born to type 1 diabetic mothers and in six control cords. Umbilical cord tissue was collected immediately after elective cesarean section. Expression data were confirmed by real-time polymerase chain reaction (11 genes). Additionally, the same umbilical cords were analyzed histologically. Two hundred eighty six genes were differentially expressed in the umbilical cords from diabetic pregnancies compared to the controls (fold change ±1.5 and P < 0.01). Maternal diabetes had a major effect on the expression of genes involved in vascular development (Bone morphogenetic protein 4, Delta-like 1, and Notch homolog 4), vessel wall integrity (Collagen type VIII alpha 1, Myocyte enhancer factor 2C, and Matrix metalloproteinase 2), and vascular function (Natriuretic peptide precursor B, Endothelin 1, Endothelin receptor B, Cyclooxygenase 1, and Phosphodiesterase 5A). Maternal diabetes was associated with thicker umbilical vein intima-media layers and larger umbilical vein and artery intima-media areas compared to the controls. Maternal diabetic environment seems to alter umbilical cord expression of genes involved in the regulation of vascular development and function with simultaneous umbilical vessel muscle layer thickening. These alterations suggest vascular phenotypic modifications, which in turn may lead to long-term vascular consequences in various tissues in infants of diabetic mothers.


Localization of neuron-specific enolase (NSE) mRNA in human brain.
In situ hybridization with biotinylated DNA and RNA probes derived from the 3' untranslated region of human neuron-specific or gamma gamma-enolase (NSE) permits histochemical detection of NSE mRNA in autopsy samples of human brain. In both aged controls and Alzheimer's disease (AD) patients, NSE probe hybridized with variable intensity to nerve cells in visual cortex and cerebellum, but not to glial or liver cells. These results provide evidence that NSE mRNA is expressed in neurons in human brain tissue, pattern of NSE mRNA expression in unaffected brain regions in AD is qualitatively normal, and NSE mRNA expression may vary widely among different classes of neurons.


The DNA sugar backbone 2' deoxyribose determines toll-like receptor 9 activation.
CpG motifs within phosphorothioate (PS)-modified DNA drive Toll-like receptor 9 (TLR9) activation, but the rules governing recognition of natural phosphodiester (PD) DNA are less understood. Here, we showed that the sugar backbone determined DNA recognition by TLR9. Homopolymeric, base-free PD 2' deoxyribose acted as a basal TLR9 agonist as it bound to and activated TLR9. This effect was enhanced by DNA bases, even short of CpG motifs. In contrast, PS-modified 2' deoxyribose homopolymers acted as TLR9 and TLR7 antagonists. They displayed high affinity to both TLRs and did not activate on their own, but they competitively inhibited ligand-TLR interaction and activation. Although addition of random DNA bases to the PS 2' deoxyribose backbone did not alter these effects, CpG motifs transformed TLR9-inhibitory to robust TLR9-stimulatory activity. Our results identified the PD 2' deoxyribose backbone as an important determinant of TLR9 activation by natural DNA, restrict CpG-motif dependency of TLR9 activation to synthetic PS-modified ligands, and define PS-modified 2' deoxyribose as a prime effector of TLR9 and TLR7 inhibition.


Histone messenger RNA synthesis and accumulation during early development in the echiuroid worm, Urechis caupo.
RNA isolated from Urechis caupo mature oocytes and embryos was analyzed for the presence of histone messenger RNAs (mRNAs) by in vitro translation and by filter blot hybridization to determine the contribution of maternal and newly transcribed histone mRNAs to the pattern of histone synthesis during early development. Histone mRNAs were not detected in mature oocyte RNA which suggests that relatively few if any maternal histone mRNAs are sequestered in the mature oocytes. Histone mRNAs were detected in cleavage-stage RNA and increased in amount from midcleavage through late gastrula stages. The in vitro translation analysis also demonstrated that the amount of H1 histone mRNA in late cleavage- and early blastula-stage embryos exceeds that of the individual core histone mRNAs. The disproportionate accumulation of individual histone mRNAs correlates with the noncoordinate synthesis of H1 and core histones which occurs during early embryogenesis.


A material (PUPA) presenting both the properties of polyurethanes and the capacity of adsorbing a high quantity of heparin.
Polyurethanes are widely used for biomedical applications, but there is still a constant search for improved blood-compatible materials. We studied a material (PUPA) obtained by the interconnection between a poly(amido-amine), N2LL, capable of forming stable complexes with heparin and a commercial polyurethane, Pellethane 2363-80AE, using hexamethylenediisocyanate as the crosslinking agent. The amount of absorbed heparin (evaluated by biological tests) was generally much higher than that found on the poly(amido-amine) surface-grafted polyurethane.


Definition of compartment-based radical surgery in uterine cancer: radical hysterectomy in cervical cancer as 'total mesometrial resection (TMMR)' by M Höckel translated to robotic surgery (rTMMR).
Radical hysterectomy has been developed as a standard treatment in Stage I and II cervical cancers with and without adjuvant therapy. However, there have been several attempts to standardize the technique of radical hysterectomy required for different tumor extension with variable success. Total mesometrial resection as ontogenetic compartment-based oncologic surgery - developed by open surgery - can be standardized identically for all patients with locally defined tumors. It appears to be promising for patients in terms of radicalness as well as complication rates. Robotic surgery may additionally reduce morbidity compared to open surgery. We describe robotically assisted total mesometrial resection (rTMMR) step by step in cervical cancer and present feasibility data from 26 patients. Patients (n = 26) with the diagnosis of cervical cancer were included. Patients were treated by robotic total mesometrial resection (rTMMR) and pelvic or pelvic/periaortic robotic therapeutic lymphadenectomy (rtLNE) for FIGO stage IA-IIB cervical cancer. No transition to open surgery was necessary. No intraoperative complications were noted. The postoperative complication rate was 23%. Within follow-up time (mean: 18 months) we noted one distant but no locoregional recurrence of cervical cancer. There were no deaths from cervical cancer during the observation period. We conclude that rTMMR and rtLNE is a feasible and safe technique for the treatment of compartment-defined cervical cancer.


Calcium-alginate beads as a formulation for the application of entomopathogenic nematodes to control rootworms.
Entomopathogenic nematodes (EPN) have great potential as biological control agents against root-feeding insects. They have a rapid and long-lasting mode of action, minimal adverse effects on the environment and can be readily mass-produced. However, they have a relatively short shelf-life and are susceptible to desiccation and UV light. These shortcomings may be overcome by encapsulating EPN in Ca2+-alginate hydrogels, which have been shown to provide a humid and UV protective shelter. Yet, current Ca2+-alginate formulations do not keep EPN vigorous and infectious for a prolonged period of time and do not allow for their controlled release upon application. Here, we introduce solid Ca2+-alginate beads which we supplemented with glycerol to better retain the EPN during storage and to ensure a steady release when applied in soil. Glycerol-induced metabolic arrest in EPN (Heterorhabditis bacteriophora) resulting in quiescence and total retainment of EPN when added to beads made with 0.5% sodium alginate and 2% CaCl2·2H2O solutions. More than 4,000 EPN could be embedded in a single 4-5-mm diameter bead, and quiescence could be broken by adding water, after which the EPN readily emerged from the beads. In a field trial, the EPN beads were as effective in reducing root damage by the western corn rootworm (WCR, Diabrotica virgifera virgifera) as EPN that were applied in water. Although further improvements are desirable, we conclude that Ca2+-alginate beads can provide an effective and practical way to apply EPN for the control of WCR larvae. The online version contains supplementary material available at 10.1007/s10340-021-01349-4.


Western Blotting and Co-immunoprecipitation of Endogenous STIM/ORAI and Protein Partners.
The characterization of protein-protein interactions through methods such as co-immunoprecipitation, followed by Western blot analysis, is a crucial step in the understanding of protein functions and the biology of the cell. Since the discovery of ORAI and STIM proteins as component of store-operated channel (SOC), overexpressing systems have been used to demonstrate how ORAI and STIM can associate with physiological and pathological conditions. Here we describe a protocol allowing endogenous studies.


Acute cardiovascular effects of inhaled ambient particulate matter: Chemical composition-related oxidative stress, endothelin-1, blood pressure, and ST-segment changes in Wistar rats.
Short-term increases in particulate matter (PM) are associated with heightened morbidity and mortality from cardiovascular causes. Inhalation of PM is known to increase endothelin (ET)-1 levels. Yet, less is known about particle composition-related changes at the molecular level including the endothelinergic system and relationship with cardiovascular function changes. In this work, adult Wistar male rats were exposed for 4 h by nose-only inhalation to clean air, Ottawa urban particles (EHC-93, 48 mg/m3) and water-leached (EHC-93L, 49 mg/m3) particles, to examine the effect of particle compositional changes on oxidative stress, circulating ETs, blood pressure, and heart electrophysiology. Particle deposition in the respiratory compartment was estimated at 85 μg (25 ng/cm2). Lung cell proliferation was low in both treatment groups, indicating absence of acute injury. Inhalation of EHC-93 caused statistically significant elevations (p < 0.05) of oxidative stress markers, ET-1, ET-3, blood pressure, and a decrease of ST-segment duration in the ECG at 1.5 days post-exposure. Leached particles (EHC-93L) caused rapid but transient elevation (p < 0.05) of oxidative stress, ET-1, ET-2, and ET-3 at earlier time points, with no changes in blood pressure or ST-segment. These results demonstrate that inhalation of urban particles at an internal dose inadequate to cause acute lung injury can induce oxidative stress, enhance vasoactive endothelins, leading to vasopressor response, affecting cardiac electrophysiology in Wistar rats, consistent with the cardiovascular impacts of ambient particles in human populations. Change in particle potency after removal of soluble species, notably cadmium, zinc and polar organics suggests that the toxicodynamics of cardiovascular effects can be modified by physicochemical properties of particles.


Abnormal gallbladder nuclear ejection fraction predicts success of cholecystectomy in patients with biliary dyskinesia.
The management of patients with symptoms consistent with biliary tract disease who do not have gallstones is difficult. We retrospectively reviewed the charts of 18 patients who underwent cholecystokinin cholescintigraphy at our institution to determine if this procedure was reliable in identifying patients who would benefit from cholecystectomy. All patients underwent biliary screening, and a gallbladder ejection fraction of less than or equal to 35% was considered abnormal. None of the patients had evidence of gallstones by ultrasound. There were 11 patients with abnormal ejection fractions. All 11 patients (100%) had "classic" biliary colic and underwent cholecystectomy. The pathologic diagnosis was chronic cholecystitis in every patient. All patients had complete relief of their symptoms postoperatively with a mean follow-up of 10 months. There were six patients with normal ejection fractions. Only one patient in this group had "classic" biliary colic. This patient had a gallbladder ejection fraction of 38% and endoscopic evidence of gastritis. This patient remains symptomatic despite H2 blockade. The remaining five patients had nonspecific right upper quadrant or epigastric pain. These patients had endoscopic evidence of gastritis, and symptoms were relieved with H2 blockade. The remaining patient had an indeterminate scan due to radioactivity in the duodenum overlying the gallbladder and was excluded from this analysis. Cholecystokinin cholescintigraphy is a useful test in identifying those patients with biliary dyskinesia or acalculous cholecystitis who will benefit from cholecystectomy.


Circulating N-terminal pro-B-type natriuretic peptide in fetal anemia before and after treatment.
N-terminal pro-B-type natriuretic peptide (ntproBNP) is an established marker of heart failure in adult cardiology. We analyzed nt-proBNP in the circulation of fetuses with increased volume load secondary to anemia and investigated the effect of treatment on nt-proBNP concentration. Fetuses undergoing intrauterine transfusion (IUT) were examined. nt-proBNP was measured before IUT and correlated with hemoglobin concentrations, ultrasonographic findings, and Doppler measurements of the peak systolic velocity of the middle cerebral artery (MCA-PSV). A total of 27 patients (7 with hydrops) and 78 controls were examined. nt-proBNP was markedly elevated in anemia (P < 0.001). Concentrations were highest in hydropic fetuses (P < 0.03); no differences were present in hemoglobin and MCA-PSV values between hydropic and nonhydropic cases. In fetuses undergoing multiple IUTs nt-proBNP normalized after the third IUT, whereas hemoglobin and MCA-PSV remained abnormal. Levels of circulating nt-proBNP correlate well with the degree of myocardial workload in the hyperdynamic state of fetal anemia. We hypothesize that normalization of nt-proBNP after serial transfusions is an indicator of myocardial adjustment to chronic anemia. nt-proBNP measurement may be useful in the management of fetal anemia, particularly in cases at risk of hydrops and fetuses requiring multiple transfusions.


Cervical spine injuries requiring surgery in a Level I trauma centre in a major German city.
Cervical spine injuries (CSI) are rare in trauma patients, at about 9.2-16.5/100,000 inhabitants in Scandinavia and Canada, and the annual incidence of CSI surgeries in Norway is around 3.0/100,000 inhabitants. However, despite their rarity, the incidence of CSI has increased, thereby assuming an increasing need for surgery. Outside of Scandinavia, no data about the incidence of CSI and subsequent surgeries exist. Therefore, this study aimed to analyse CSI epidemiology and surgery in a German city with a Level I trauma centre both to understand the injury and improve needs-based planning. This retrospective, monocentre study included all patients who presented with CSI from 2012-2017 at a university hospital with a Level I trauma centre in a major German city and had permanent residency within the city. Based on the assumption that the patients represented all CSI injuries in the city, as they were treated at the only available Level I trauma centre, the annual incidence of surgeries and neurologic deficits due to CSI were calculated. A total of 465 patients with 609 CSI were identified. Of these patients, 61 both received surgery and resided in the city (mean age, 68.1 ± 18.3 years; 26 female, 35 male). The incidence of CSI surgeries was calculated as 3.24/100,000 person years (1.75/100,000 in the upper and 1.54/100,000 in the subaxial cervical spine). Neurologic deficits occurred in 0.64/100,000 person years. The incidence of both surgeries and neurologic deficits showed no significant changes over the 6-year study period. Compared to Scandinavia, an increasing annual incidence for CSI surgeries and neurologic deficits were found. For long-term demand planning with adaptability to demographic changes, cross-regional studies including long-term follow-up are necessary.


Determination of anti-carcinogenic polyphenols present in green tea using capillary electrophoresis coupled to a flow injection system.
A capillary electrophoresis (CE) method was developed for the simultaneous determination of a number of major ingredients of green tea. The components analysed were caffeine, adenine, theophylline, epigallocatechin-3 gallate, epigallocatechin, epicatechin-3 gallate, (-)-epicatechin, (+)-catechin, gallic acid, quercetin and caffeic acid. Separation was achieved using a fused capillary column with 0.15 M H3BO3 as buffer at a pH of 8.5, UV detection at 210 nm and 20 kV of voltage. Analysis was carried out after treatment (extraction, filtration and dilution) of the samples in a flow injection system which was coupled to a CE equipment via a programmable arm. The procedure allows the determination of these compounds in less than 20 min. Quantitative analysis was performed by the standard addition method. Limits of detection ranged between 0.04 microgram ml-1 for flavonols and 1.2 micrograms ml-1 for caffeine.


The ketogenic diet increases mitochondrial glutathione levels.
The ketogenic diet (KD) is a high-fat, low carbohydrate diet that is used as a therapy for intractable epilepsy. However, the mechanism(s) by which the KD achieves neuroprotection and/or seizure control are not yet known. We sought to determine whether the KD improves mitochondrial redox status. Adolescent Sprague-Dawley rats (P28) were fed a KD or control diet for 3 weeks and ketosis was confirmed by plasma levels of beta-hydroxybutyrate (BHB). KD-fed rats showed a twofold increase in hippocampal mitochondrial GSH and GSH/GSSG ratios compared with control diet-fed rats. To determine whether elevated mitochondrial GSH was associated with increased de novo synthesis, the enzymatic activity of glutamate cysteine ligase (GCL) (the rate-limiting enzyme in GSH biosynthesis) and protein levels of the catalytic (GCLC) and modulatory (GCLM) subunits of GCL were analyzed. Increased GCL activity was observed in KD-fed rats, as well as up-regulated protein levels of GCL subunits. Reduced CoA (CoASH), an indicator of mitochondrial redox status, and lipoic acid, a thiol antioxidant, were also significantly increased in the hippocampus of KD-fed rats compared with controls. As GSH is a major mitochondrial antioxidant that protects mitochondrial DNA (mtDNA) against oxidative damage, we measured mitochondrial H2O2 production and H2O2-induced mtDNA damage. Isolated hippocampal mitochondria from KD-fed rats showed functional consequences consistent with the improvement of mitochondrial redox status i.e. decreased H2O2 production and mtDNA damage. Together, the results demonstrate that the KD up-regulates GSH biosynthesis, enhances mitochondrial antioxidant status, and protects mtDNA from oxidant-induced damage.


Unusually aggressive osteomyelitis of the jaws. A report of two cases.
Two cases of unusually aggressive osteomyelitis of the jaws are reported. Both cases manifested severe, rapidly progressive lytic destruction of the maxilla in spite of the fact that patients were young, healthy adults with no local or systemic factors that would predispose them to severe infection in either case. Characteristic historical, clinical, radiographic, and histologic features are elaborated. Also, theoretical aspects of this disease entity are discussed in an effort to explain the unusually aggressive manner in which these cases presented.


Special Issue: "Genetic Counseling and Genetic Testing in Precision Medicine".
Progress in genomic technologies has spurred innovation in healthcare and medicine, contributing to improved health and well-being [...].


Organization of serotonergic system in Sphaerotheca breviceps (Dicroglossidae) tadpole brain.
The monoaminergic neurotransmitter 5-hydroxytryptamine (5-HT) is known to be involved in several physiological, behavioural and neuroendocrine functions in vertebrates. In this study, we investigated the distribution of 5-HT neuronal system in the central nervous system (CNS) of Sphaerotheca breviceps tadpoles at metamorphic climax stage. In the telencephalon, there was no 5-HT-immunoreactive (5-HT-ir) perikarya, but conspicuous fibres were observed in the olfactory bulb, pallium, subpallium and amygdala complexes. The preoptic area showed dense 5-HT-ir somata and cerebrospinal fluid contacting fibres, whereas a few varicose 5-HT-ir fibres were noticed in the suprachiasmatic nucleus. 5-HT-ir cells and fibres were found in the ventral, lateral dorsal subdivisions of the hypothalamus and in the nucleus tuberculi posterioris, but only 5-HT-ir fibres were localised in the periventricular area and pituitary gland. Numerous 5-HT-ir cells and/or fibres were detected in the thalamus, entopeduncular area and mesencephalic subdivisions. In the rhombencephalon, although 5-HT-ir cells and fibres were noticed in the subdivisions of the raphe nucleus and reticular formation, a moderate plexus of fibres was observed in the cerebellum, parabrachial nucleus and solitary tract. Distinct 5-HT-ir fibres, but no perikarya, were observed in the rostral spinal cord. Overall, extensively labelled 5-HT-ir cells and fibres in the CNS of the metamorphic tadpole suggest possible roles for the involvement of 5-HT in various somatosensory, behavioural and neuroendocrine functions during final stages of development.


Ampelopsin attenuates Staphylococcus aureus Alpha-Toxin-Induced Lung Injury.
Staphylococcus aureus is a prevalent cause of lung infections in hospitals and communities, and can cause a wide spectrum of human infections. Due to the bottleneck caused by antibiotic resistance and substantial increases in morbidity and mortality, targeting the virulence factors released by S. aureus as an alternative prevention and treatment method has become a promising approach. Ampelopsin, a component of vine tea, has promising potential for treating S. aureus-induced acute lung injury. In this study, the effects of ampelopsin were investigated on a mouse model of acute lung injury established using S. aureus 8325-4 and the α-hemolysin (hla) silent strain DU1090. The hla silent strain did not cause mortality in mice, whereas lethal and sublethal concentrations of S. aureus 8325-4 caused high mortality. Notably, ampelopsin treatment protected against mortality stemming from S. aureus infection. Ampelopsin yielded enhancements in lung barrier function, decreased total protein leakage in the alveolar lavage fluid, and modulated inflammatory signaling pathway-related proteins, thereby reducing the release of pro-inflammatory factors and improving respiratory dysfunction. Moreover, ampelopsin prevented the upregulation of ADAM10 activity, leading to E-cadherin mucin cleavage. In conclusion, our findings establish the key role of alpha -toxin in infectious lung injury in S. aureus and provide support for ampelopsin as an effective therapeutic approach to improve lung injury.


Biotechnological production of L(+)-lactic acid from wood hydrolyzate by batch fermentation of Enterococcus faecalis.
The inhibition of lactic acid fermentation by wood hydrolyzate was decreased (approx. 20%) by adaptation of Enterococcus faecalis RKY1 to wood hydrolyzate-based medium whereby lactic acid productivity and cell growth were enhanced by 0.5 g l(-1) h(-1) and 2.1 g l(-1), respectively. When the diluted or concentrated wood hydrolyzate (equivalent to 25-100 g glucose l(-1)) was supplemented with 15 g yeast extract l(-1), 24-93 g lactic acid l(-1) was produced at a rate between 1.7 g l(-1) h(-1) and 3.2 g l(-1) h(-1).


Surface-bound basement membrane components accelerate amyloid-β peptide nucleation in air-free wells: an in vitro model of cerebral amyloid angiopathy.
Cerebral amyloid angiopathy is caused by deposition of the amyloid β-peptide which consists of mainly 39-40 residues to the cortical and leptomeningeal vessel walls. There are no definite in vitro systems to support the hypothesis that the vascular basement membrane may act as a scaffold of amyloid β-peptide carried by perivascular drainage flow and accelerate its amyloid fibril formation in vivo. We previously reported the critical roles of interfaces and agitation on the nucleation of amyloid fibrils at low concentrations of amyloid β-peptide monomers. Here, we reproduced the perivascular drainage flow in vitro by using N-hydroxysuccinimide-Sepharose 4 Fast flow beads as an inert stirrer in air-free wells rotated at 1rpm. We then reproduced the basement membranes in the media of cerebral arteries in vitro by conjugating Matrigel and other proteins on the surface of Sepharose beads. These beads were incubated with 5μM amyloid β(1-40) at 37°C without air, where amyloid β(1-40) alone does not form amyloid fibrils. Using the initiation time of fibril growth kinetics (i.e., the lag time of fibril growth during which nuclei, on-pathway oligomers and protofibrils are successively formed) as a parameter of the efficiency of biological molecules to induce amyloid fibril formation, we found that basement membrane components including Matrigel, laminin, fibronectin, collagen type IV and fibrinogen accelerate the initiation of amyloid β-peptide fibril growth in vitro. These data support the essential role of vascular basement membranes in the development of cerebral amyloid angiopathy.


High efficiency carbon nanotubes-based single-atom catalysts for nitrogen reduction.
Carbon-based single-atom catalysts (SACs) for electrochemical nitrogen reduction reaction (NRR) have received increasing attention due to their sustainable, efficient, and green advantages. However, at present, the research on carbon nanotubes (CNTs)-based NRR catalysts is very limited. In this paper, using FeN3@(n, 0) CNTs (n = 3 ~ 10) as the representative catalysts, we demonstrate that the CNT curvatures will affect the spin polarization of the catalytic active centers, the activation of the adsorbed N2 molecules and the Gibbs free energy barriers for the formation of the critical intermediates in the NRR processes, thus changing the catalytic performance of CNT-based catalysts. Zigzag (8, 0) CNT was taken as the optimal substrate, and twenty transition metal atoms (Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Nb, Mo, Tc, Ru, Rh, Pd, W, Re, Ir, and Pt) were embedded into (8, 0) CNT via N3 group to construct the NRR catalysts. Their electrocatalytic performance for NRR were examined using DFT calculations, and TcN3@(8, 0) CNT was screened out as the best candidate with a low onset potential of - 0.53 V via the distal mechanism, which is superior to the molecules- or graphene-support Tc catalysts. Further electronic properties analysis shows that the high NRR performance of TcN3@(8, 0) CNT originates from the strong d-2π* interaction between the N2 molecule and Tc atom. TcN3@(8, 0) CNT also exhibits higher selectivity for NRR than the competing hydrogen evolution reaction (HER) process. The present work not only provides a promising catalyst for NRR, but also open up opportunities for further exploring of low-dimensional carbon-based high efficiency electrochemical NRR catalysts.


The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats.
Mechanical and metabolic stimuli from contracting muscles evoke reflex increases in blood pressure, heart rate and sympathetic nerve activity. Little is known, however, about the nature of the mechano-gated channels on the thin fibre muscle afferents that contribute to evoke this reflex, termed the exercise pressor reflex. We determined the effect of GsMTx4, an inhibitor of mechano-gated Piezo channels, on the exercise pressor reflex evoked by intermittent contraction of the triceps surae muscles in decerebrated, unanaesthetized rats. GsMTx4 reduced the pressor, cardioaccelerator and renal sympathetic nerve responses to intermittent contraction but did not reduce the pressor responses to femoral arterial injection of compounds that stimulate the metabolically-sensitive thin fibre muscle afferents. Expression levels of Piezo2 channels were greater than Piezo1 channels in rat dorsal root ganglia. Our findings suggest that mechanically-sensitive Piezo proteins contribute to the generation of the mechanical component of the exercise pressor reflex in rats. Mechanical and metabolic stimuli within contracting skeletal muscles evoke reflex autonomic and cardiovascular adjustments. In cats and rats, gadolinium has been used to investigate the role played by the mechanical component of this reflex, termed the exercise pressor reflex. Gadolinium, however, has poor selectivity for mechano-gated channels and exerts multiple off-target effects. We tested the hypothesis that GsMTX4, a more selective mechano-gated channel inhibitor than gadolinium and a particularly potent inhibitor of mechano-gated Piezo channels, reduced the exercise pressor reflex in decerebrate rats. Injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 ± 5, GsMTx4: 12 ± 5 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to tendon stretch, a purely mechanical stimulus, but had no effect on the pressor responses to intra-arterial injection of α,β-methylene ATP or lactic acid. Moreover, injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 ± 2, GsMTx4: 14 ± 3 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to electrically-induced intermittent hindlimb muscle contractions. By contrast, injection of 10 μg of GsMTx4 into the jugular vein had no effect on the pressor, cardioaccelerator, or renal sympathetic nerve responses to contraction. Quantitative RT-PCR and western blot analyses indicated that both Piezo1 and Piezo2 channel isoforms were natively expressed in rat dorsal root ganglia tissue. We conclude that GsMTx4 reduced the exercise pressor reflex in decerebrate rats and that the reduction was attributable, at least in part, to its effect on mechano-gated Piezo channels.


Psychological well-being of identity-release egg donation parents with infants.
What are the psychological health, relationship quality and perceived social support outcomes of heterosexual couples who have conceived an infant through identity-release egg donation? Parents' scores on all measures were within the normal range. Egg donation mothers had poorer perceived social support, and egg donation fathers had less optimal psychological health than a comparison group of IVF parents, although these differences were associated with the older age of egg donation parents, rather than being an effect of family type. There is limited understanding of the psychological health and couple relationship quality of egg donation parents, and no empirical data on parents' social support, during the first year of parenthood. No studies have included families who have used an identity-release egg donor. The study offers the first examination of the psychological well-being of identity-release egg donation parents. This study included 57 families created through identity-release egg donation, and a comparison group of 56 families who had used IVF with their own gametes, recruited through UK fertility clinics. Families were visited at home between October 2013 and June 2015. The sample forms part of a larger study examining family functioning in families created following fertility treatment. All families were heterosexual two-parent families with an infant aged 6-18 months. Mothers and fathers were administered standardised questionnaires assessing psychological health (Edinburgh Postnatal Depression Scale, Trait Anxiety Inventory and Parenting Stress Index-short form), couple relationship quality (Golombok Rust Inventory of Marital State) and perceived social support (Multidimensional Scale of Perceived Social Support). Scores from the egg donation and IVF parents were within the normal range on all measures. Significant differences were found between the groups indicating less optimal social support in egg donation mothers compared to IVF mothers, and poorer psychological health in egg donation fathers compared to IVF fathers. These differences appeared to be related to the older age of egg donation parents or to twin parenthood, rather than to egg donation per se. No differences were found between the groups in the parents' relationship quality. It is possible that families who were managing the transition to parenthood less well may have been less likely to participate in research. Fewer IVF than egg donation fathers participated in the study, so the statistical power was lower for comparisons between fathers. The findings are of relevance to UK clinics offering identity-release egg donation. That scores of egg donation parents on measures of psychological well-being were more similar than different to those of IVF parents should prove reassuring to individuals considering this treatment type. As less optimal outcomes were found for egg donation parents on several measures, and these were associated with parental age rather than conception type, it is recommended that clinics discuss with older patients how they may establish a social support network and signpost patients to appropriate post-natal support. This research was supported by a Wellcome Trust Senior Investigator Award [097857/Z/11/Z] and a CHESS-ESRC studentship. The authors have no conflicts of interest to declare. N/A.


Green synthesis of copper oxide nanoparticles and its efficiency in degradation of rifampicin antibiotic.
In recent ages, green nanotechnology has gained attraction in the synthesis of metallic nanoparticles due to their cost-effectiveness, simple preparation steps, and environmentally-friendly. In the present study, copper oxide nanoparticles (CuO NPs) were prepared using Parthenium hysterophorus whole plant aqueous extract as a reducing, stabilizing, and capping agent. The CuO NPs were characterized via UV-Vis Spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), powder X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS). The UV-Vis spectra of CuO NPs showed a surface plasmonic resonance band to occur at 340 nm. FTIR analysis revealed the presence of secondary metabolites on the surface of CuO NPs, with a characteristic Cu-O stretching band being identified at 522 cm-1. Scanning electron micrographs and transmission electron micrographs showed that CuO NPs were nearly spherical, with an average particle of 59.99 nm obtained from the SEM micrograph. The monoclinic crystalline structure of CuO NPs was confirmed using XRD, and crystallite size calculated using the Scherrer-Debye equation was found to be 31.58 nm. DLS showed the presence of nanoparticle agglomeration, which revealed uniformity of the CuO NPs. Furthermore, the degradation ability of biosynthesized nanoparticles was investigated against rifampicin antibiotic. The results showed that the optimum degradation efficiency of rifampicin at 98.43% was obtained at 65℃ temperature, 50 mg dosage of CuO NPs, 10 mg/L concentration of rifampicin solution, and rifampicin solution at pH 2 in 8 min. From this study, it can be concluded that CuO NPs synthesized from Parthenium hysterophorus aqueous extract are promising in the remediation of environmental pollution from antibiotics. In this light, the study reports that Parthenium hysterophorus-mediated green synthesis of CuO NPs can effectively address environmental pollution in cost-effective, eco-friendly, and sustainable ways.


Effects of enhanced coronary flow during cardiopulmonary bypass: development of myocardial edema.
Coronary blood flow, left ventricular diastolic stiffness, ventricular water content and ventricular thiocyanate space were investigated in empty fibrillating and empty beating dog hearts during cardiopulmonary bypass. In empty fibrillating hearts coronary blood flow was considerably enhanced even at levels of normal perfusion pressure. A close correlation was demonstrated between enhanced coronary flow, left ventricular diastolic stiffness, tissue water content and thiocyanate space.


A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.
A Phase II trial of TCN-P was conducted in metastatic or recurrent squamous cell carcinoma of the cervix using a 5-day continuous infusion schedule. The starting dose was 35 mg/m2 x 5 days and courses were repeated every 6 weeks. Among 21 evaluable patients, 2 responses were observed. One patient had a complete response for 19+ months. Another patient had a partial response for 5+ months, but developed symptomatic hypocalcemia, requiring discontinuation of the drug. Using this dose and schedule TCN-P appears to have limited activity in metastatic or recurrent squamous cell cancer of the cervix.


Stochastic representation of many-body quantum states.
The quantum many-body problem is ultimately a curse of dimensionality: the state of a system with many particles is determined by a function with many dimensions, which rapidly becomes difficult to efficiently store, evaluate and manipulate numerically. On the other hand, modern machine learning models like deep neural networks can express highly correlated functions in extremely large-dimensional spaces, including those describing quantum mechanical problems. We show that if one represents wavefunctions as a stochastically generated set of sample points, the problem of finding ground states can be reduced to one where the most technically challenging step is that of performing regression-a standard supervised learning task. In the stochastic representation the (anti)symmetric property of fermionic/bosonic wavefunction can be used for data augmentation and learned rather than explicitly enforced. We further demonstrate that propagation of an ansatz towards the ground state can then be performed in a more robust and computationally scalable fashion than traditional variational approaches allow.


Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites.
Theoretical and experimental studies on the computation of neural networks suggest that neural computation results from a dynamic interplay of excitatory and inhibitory (E/I) synaptic inputs. Precisely how E/I synapses are organized structurally and functionally to facilitate meaningful interaction remains elusive. Here we show that E/I synapses are regulated across dendritic trees to maintain a constant ratio of inputs in cultured rat hippocampal neurons. This structural arrangement is accompanied by an E/I functional balance maintained by a 'push-pull' feedback regulatory mechanism that is capable of adjusting E/I efficacies in a coordinated fashion. We also found that during activity, inhibitory synapses can determine the impact of adjacent excitatory synapses only if they are colocalized on the same dendritic branch and are activated simultaneously. These fundamental relationships among E/I synapses provide organizational principles relevant to deciphering the structural and functional basis for neural computation within dendritic branches.


What's wrong with the global migration of health care professionals? Individual rights and international justice.
When health care workers migrate from poor countries to rich countries, they are exercising an important human right and helping rich countries fulfill obligations of social justice. They are also, however, creating problems of social justice in the countries they leave. Solving these problems requires balancing social needs against individual rights and studying the relationship of social justice to international justice.


Field emission scanning electron microscopic, X-ray diffraction and ultraviolet spectroscopic analysis of Terminalia bellerica based silver nanoparticles and evaluation of their antioxidant, catalytic and antibacterial activity.
In recent years, scientists have come up with ways to make nanoparticles that are inexpensive and good for the environment. Terminalia bellerica-based silver nanoparticles (TBAgNPs) were made in this study using methanol extract from T. bellerica fruits. This method was quick, economical, and good for the environment. The biosynthesized TBAgNPs were used as antioxidants, antibacterial agents, and anti-catalytic agents. Analytical techniques like XRD, FESEM, and UV-Vis were used to find out more about the spherical TBAgNPs that were made. Also, Cefotaxime-resistant bacteria found in hospitals were used to test how well the TBAgNPs killed bacteria. With the Bauer-agar Kirby's gel diffusion and Mueller-Hinton broth methods, the ability of the synthesized TBAgNPs to stop bacterial growth was tested. After the TBAgNPs were studied, it was found that the average size of their crystals was between 10 and 25 nm. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) reducing tests showed that these AgNPs could act as antioxidants, and TBAgNPs (%inhibition = 20.90% to 94.94%) were better antioxidant than ascorbic acid (%inhibition = 13.80% to 86.10%) and extract (%inhibition = 16.90% to 80.50%). The reduction of methylene blue (MB) to leucomethylene blue (LMB) with sodium borohydride (NaBH4) was used as a model to test the catalytic potential of TBAgNPs. On UV spectroscopic analysis at room temperature, TBAgNPs at different concentrations were able to reduce methylene blue effectively. For Escherichia coli and Klebsiella pneumoniae, the minimum inhibitory concentration (MIC) for TBAgNPs was 0.625 μg/mL and 1.25 μg/mL, respectively. Based on these results, silver nanoparticles made with Terminalia bellerica extract may have much biological importance and could be used in making useful therapeutic applications.


Detection of Wolfgram W1 protein, myelin basic proteins and proteolipids in cultured oligodendrocytes by the electro-immunoblotting method.
Oligodendrocytes, mechanically obtained from primary cultures of newborn rat brain, were investigated by a sensitive electro-immunoblotting method for the presence of the characteristic myelin proteins: Wolfgram W1 protein, basic proteins and proteolipids. These three major myelin protein types were detectable from the 20th to the 40th day in culture. The present biochemical findings are in accordance with previous immunohistochemical data and provide additional evidence that oligodendrocytes in culture are capable of synthesizing every myelin and oligodendrocyte marker found in vivo, in the absence of neurones.


miR-1301 promotes prostate cancer proliferation through directly targeting PPP2R2C.
Prostate cancer is the leading cause of cancer deaths among men in the worldwide, it's important to find new prognostic factors and therapeutic targets. microRNAs play critical roles in the development and progression of prostate cancer. Here we revealed miR-1301 promoted prostate cancer progression. miR-1301 was upregulated in prostate cancer tissues and cells, overexpression of miR-1301 promoted anchorage-dependent and -independent growth using MTT analysis, colony formation analysis and soft agar growth analysis, whereas knockdown of miR-1301 suppressed anchorage-dependent and -independent growth. We also found overexpression of miR-1301 inhibited p27 expression and promoted Cyclin D1 expression, whereas knockdown of miR-1301 reduced this effect, suggesting miR-1301 promoted the G1/S transition. These results suggested miR-1301 promoted cell proliferation of prostate cancer. microRNAs can inhibit target mRNA translation or/and induce mRNA degradation, we found tumor suppresser PPP2R2C was the target of miR-1301, simultaneous downregualtion of PPP2R2C and miR-1301 promoted anchorage-dependent and -independent growth. These findings suggested miR-1301 promoted prostate cancer proliferation by inhibiting PPP2R2C, and might a therapeutic target for prostate cancer.


A reappraisal of alcoholic psychoses.
A retrospective study of alcoholic psychoses is reported. The phenomena of the illnesses corresponded poorly with classical descriptions of alcoholic hallucinosis, delirium tremens and alcoholic paranoia. Alternative diagnostic approaches were tried (Catego, restrictive definition of alcoholic hallucinosis). The problems of distinguishing psychoses with associated organic factors from 'idiopathic' forms are discussed.


Expression of 67-kDa elastin receptor in annular elastolytic giant cell granuloma: elastin peptides induce monocyte-derived dendritic cells or macrophages to form granuloma in vitro.
Annular elastolytic giant cell granuloma (AEGCG) is characterized by non-palisading granuloma and elastophagocytic giant cells. Granulomas consist of structured masses of macrophages, dendritic cells, and T lymphocytes which play an essential role in granuloma formation. Two lineage systems of dendritic cells and macrophages originated from peripheral blood monocytes have been established in vitro. To know how elastin fragments are involved in the granuloma formation in AEGCG, we tested in vitro whether elastin fragments potentially induce monocyte-derived macrophages or dendritic cells to form granuloma and multinucleated giant cells. Immunohistochemical studies of the lesional skins of AEGCG (n = 5) revealed that the 67-kDa elastin receptor was specifically expressed in the epithelioid or multinucleated giant cells. Proliferation of factor XIIIa(+) cells and CD68(+) cells was also seen in the lesional skins of AEGCG. Factor XIIIa(+) dendritic cells or CD68(+) macrophages were established by the treatment of granulocyte/macrophage-colony stimulating factor (GM-CSF)/interleukin-4 or M-CSF, respectively. Further treatments of these dendritic cells or macrophages with elastin peptide resulted in the formation of granuloma or multinucleated giant cells which were immunoreactive with anti-67-kDa elastin receptor antibody. These findings suggest that elastic tissue induces factor XIIIa(+) cells and CD68(+) macrophages to form granuloma or multinucleated giant cells and plays an essential role in the formation of granuloma in AEGCG.


Coordinated synthesis of the two ClpB isoforms improves the ability of Escherichia coli to survive thermal stress.
Eubacteria synthesize a full-length (ClpB95) and a N-terminally truncated (ClpB80) version of the ClpB disaggregase owing to the presence of a translation initiation site within the clpB transcript. Why these two isoforms have been evolutionary conserved is poorly understood. Here, we constructed a series of E. coli strains and plasmids allowing production of the ClpB95/ClpB80 pair, ClpB95 alone, or ClpB80 alone from near physiological concentrations to a 6-10-fold excess over normal cellular levels. We found that although overexpressed ClpB95 or ClpB80 can independently restore basal thermotolerance to DeltaclpB cells, strains expressing ClpB80 from the clpB chromosomal locus do not exhibit increased resistance to thermal killing at 50 degrees C relative to clpB null cells. Furthermore, synthesis of physiological levels of ClpB95 is less effective than coordinated expression of ClpB95/ClpB80 in protecting E. coli from thermal killing. These results provide an explanation for the conservation of the two ClpB isoforms in eubacteria and are consistent with the fact that wild type E. coli maintains the ClpB80 to ClpB95 ratio at a nearly constant value of 0.4-0.5 under a variety of stress conditions.


Review of brachytherapy complications - Upper gastrointestinal tract.
While brachytherapy applications are not widely used for cancer diagnoses in the upper GI tract (including the esophagus, liver, stomach, and pancreas), they have a clear role in palliation and symptom management and occasionally definitive locoregional treatment. With the increasing use of image-guided techniques, the incidence of side effects and complications has shown to be lower than many other alternative treatment modalities, making brachytherapy approaches a preferred treatment option. This review examines procedural complications and acute and chronic adverse effects from radiation associated with esophageal, hepatobiliary, and pancreatic brachytherapy and their management.


Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats.
1. Flosequinan (BTS 49 465, 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg-1 and 20 mg kg-1 flosequinan causing similar falls in mean blood pressure to 1 mg kg-1 and 3 mg kg-1 hydralazine respectively. In normotensive cats, 5 mg kg-1 flosequinan caused similar falls to 0.5 and 1.0 mg kg-1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat. 2. The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P less than 0.05). 3. In normotensive dogs, flosequinan, 10 and 20 mg kg-1 orally, caused a small but non-significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg-1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P less than 0.01). 4. Neither flosequinan, 10 mg kg-1 orally, nor hydralazine 1 mg kg-1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p-aminohippuric acid clearance in normotensive dogs. 5. The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.


Severe neonatal hyperbilirubinemia in the southeast region of Turkey
Severe neonatal hyperbilirubinemia is an important cause of morbidity and mortality in developing countries. The aim was to assess etiologic reasons for development of severe hyperbilirubinemia and define risk factors for exchange transfusion and acute bilirubin encephalopathy (ABE) in Şanlıurfa located in the southeast region of Turkey. An observational cohort study included 115 infants with ≥35 weeks of gestation admitted with diagnosis of severe hyperbilirubinemia in a period of 18 months. Potential risk factors associated with exchange transfusion and development of ABE were analyzed. Among 115 infants, 67 (58.3%) received exchange transfusion and 45 (39.1%) developed ABE. Rh isoimmunization (OR: 24.6, 95% CI = 2.2–271, P = 0.009), glucose-6-phosphate dehydrogenase deficiency (G6PD) (OR: 21.1, 95% CI = 1.8–238.4, P = 0.01), early discharge (OR: 14.4, 95% CI = 4.2–48.9, P ≤ 0.001), and male sex (OR: 4.3, 95% CI = 1.3–14.1, P = 0.02) were independently associated with an increased risk for exchange transfusion. Being a refugee (OR: 6.8, 95% CI = 1.8–25.8, P = 0.005) and G6PD deficiency (OR: 9.9, 95% CI = 1.3–71.9, P = 0.02) were associated with development of ABE. Early discharge, Rh isoimmunization, and G6PD deficiency are significant risk factors for severe hyperbilirubinemia and exchange transfusion. Prevention of early hospital discharges, family education to increase awareness for hazardous effects of hyperbilirubinemia, and early follow-up visits after discharge would reduce the disease burden.


Facilitating the Voice of Adolescents in Hospitals Through Art: A Case Report.
Adolescence can be a challenging time, but even more so when diagnosed with a serious or chronic illness. Starlight Children's Foundation established the Livewire program after recognizing the unique needs of adolescents in hospitals. This article describes our experience of implementing an art-based project within the Livewire program, designed to facilitate the voice of adolescents with a serious or chronic illness and their siblings. We invited young people across Australia to contribute their artwork which would be used as the design for a deck of playing cards. The final 54 cards were a creative reflection of the unique interests, personalities, and experiences of 45 young people. In this article, we also share the experiences of two young people who contributed to this project. We conclude with our learnings in delivering an art-based project for young people that is not presented directly as "therapy".


First Complete Genome Sequence of Cherry virus A.
The 5'-terminal genomic sequence of Cherry virus A (CVA) has long been unknown. We determined the first complete genome sequence of an apricot isolate of CVA (7,434 nucleotides [nt]). The 5'-untranslated region was 107 nt in length, which was 53 nt longer than those of known CVA sequences.


Compliance With Fluoxetine Use in Men With Primary Premature Ejaculation.
Premature ejaculation (PE) is a common sexual dysfunction for which selective serotonin reuptake inhibitors (SSRIs) have been used effectively for treatment. However, compliance with therapy and predictors of long-term SSRI use in the treatment of PE are not well known. To analyze our experience with drop-out rates with fluoxetine in the primary PE population and to identify predictors of continued use of this agent. Men with primary PE constituted who used fluoxetine and had at least 12 months follow-up constituted the study population. Subjects underwent a comprehensive interview to ascertain self-reported (non-stopwatch) intravaginal ejaculatory latency time (IELT), self-rated control over ejaculation, and personal and patient-reported partner distress due to PE. Patients were treated with fluoxetine 20 mg daily, with the possibility of dose titration up or down based on efficacy and side effects. The PE parameters of interest included self-reported IELT, self-rated control over ejaculation, personal and partner distress due to PE, and medication adherence. 130 men were included in the study. Dropout rates at 6 and 12 months were 56% and 72%. Self-rated "poor" ejaculatory control decreased from 98%-41% (P < .01), high personal distress from 47%-11% (P < .01), and high partner distress rates from 72%-27% (P < .01). Predictors of continued use at 12 months included high partner distress, being unpartnered, and having a post-treatment IELT ≥5 minutes (P < .01). Overall side effects included headache (5%), dizziness (4%), nausea (5%), nervousness (5%), and sleepiness (8%); however, moderate to severe side effects reported included nausea (2%), sleepiness (2%), headache (2%), and dizziness (2%). Compliance with SSRIs is a well-described problem in the depression literature, but data are sparse regarding continued use of SSRIs in the treatment of PE. We report on 12-month compliance with SSRIs for the treatment of PE. Our early compliance rates were more encouraging than what has been reported in the past. However, IELT was self-reported and not measured objectively, and we did not use validated patient-reported outcomes but rather self-reported ejaculatory control and distress levels, which have limitations. Fluoxetine is an effective agent for the treatment of PE with significant improvement realized in IELT, ejaculatory control, and distress levels for both men and their partners. Despite its efficacy, continued use of fluoxetine beyond 6 months is poor. Jenkins LC, Gonzalez J, Tal R, et al. Compliance with Fluoxetine Use in Men with Primary Premature Ejaculation. J Sex Med 2020;16:1895-1899.


Pulmonary Function Tests in Sickle Cell Disease.
To determine pulmonary function abnormalities in children with Sickle Cell Disease (SCD) from Western India. In this cross sectional study conducted at Surat, Gujarat, India; equal number of age and gender matched children i.e., 99 in the age group of 6-18 y was recruited in case (children with SCD) and control (non-SCD healthy children) groups respectively. Weight, height, body mass index (BMI) and hemoglobin (Hb) were assessed as baseline characteristics and spirometry was performed to assess the pulmonary function. The two groups of children were comparable in the baseline characteristics such as weight, height and BMI, however mean hemoglobin was significantly low in SCD as compared to healthy controls [9.1 ± 1.52 vs. 11.4 ± 1.04 (p=0.001)]. Mean (% predicted) Forced expiratory volume in 1 s (FEV1) (86.79 ± 11.6 vs. 94.3 ± 16.1) and FVC (84.4 ± 11.5 vs. 91.75 ± 15.2) values were significantly low (p < 0.001) in cases. The present study revealed that the difference of pulmonary function tests between sickle cell patients and normal age matched controls were statistically significant but this difference was not clinically significant.


Correction to: Trends of change in the individual contribution of risk factors for small for gestational age over more than 2 decades.
In the original article published, the name of the corresponding author is published incorrectly.


Plasma somatomedin activity in normal and scoliotic children.
In a study of plasma somatomedin activity in childhood scoliosis a group of five patients with congenital scoliosis was found to have significantly lower plasma somatomedin levels compared with a group of 20 normal children. A group of 52 patients with "idiopathic" scoliosis had normal plasma somatomedin levels. There is no apparent difference in the plasma somatomedin activity between the sexes, and no change in plasma somatomedin activity with chronologic age in these children, suggesting that normal adult somatomedin levels have been reached.


Acoustic and perceptual comparison of chronic and incipient spastic dysphonia.
Vocal symptoms of patients with chronic and incipient spastic dysphonia were compared on a number of acoustic and perceptual parameters. Patients with incipient spastic dysphonia displayed less severe strain-strangle phonation, effort, rhythm, and stress. Harshness was the only perceptual parameter on which incipient spastic dysphonics were rated higher than chronic spastic dysphonics. Changes in the acoustic measures of laryngealization, harmonic change, mean vowel duration, and duration ratio between stressed and unstressed vowels accompanied changes in listeners' perception of strain-strangle phonation and effort. The variation in acoustic characteristics such as laryngealization and harmonic change as well as normal phonation indicated that both groups were characterized by a variety of phonatory modes.


Reduced substance P in hereditary sensory neuropathy in the mf rat.
Mutilated foot (mf) is a mutant rat with an autosomal recessive sensory neuropathy. Affected animals become ataxic and their feet become mutilated. Morphological and quantitative studies have shown a reduced number of sensory ganglion cells and of cells of secondary sensory neurons. No degeneration was seen in the peripheral nervous system. Substance P (SP) is an undecapeptide which is thought to be involved in transmission of nociceptive information. Since mf rats show, in addition to ataxia, a decreased response to painful stimuli, SP immunoreactivity was examined. The density of SP staining was decreased at all levels of the spinal cord, mainly at cervical and lumbar levels and only in areas related to sensory pathways. In other areas of the spinal cord and in the substantia gelatinosa of the trigeminal tract, no reduction of SP staining was observed. The results further support the relationship between SP and transmission of pain stimuli. There are also many similarities between the appearance in mf rats and those in animals in which sensory afferents from dorsal root ganglia had been impaired with various methods, particularly in those treated from birth with capsaicin.


KMnCuTe2: a layered antiferromagnetic semiconductor with long metal-metal distance.
The magnetic semiconductor in a two-dimensional system is a major subject for both theoretical and experimental investigations. Here we report the synthesis of a new quaternary manganese chalcogenide KMnCuTe2, which shows layered structure and antiferromagnetic (AFM) semiconducting features. Single crystals of KMnCuTe2 were obtained using a self-flux method and based on single-crystal X-ray diffraction, KMnCuTe2 adopts the ThCr2Si2-type structure composed of edge-sharing tetrahedral layers separated by K+ cations. The Mn and Cu atoms randomly distribute in the centre of tetrahedral units. Attributed to the large radius of Te, KMnCuTe2 has large lattice parameters (a = 4.3115(3) Å and c = 14.9360(20) Å), leading to a long metal-metal distance (3.049 Å) in the tetrahedral layers. Based on the experiments and theoretical calculations, KMnCuTe2 exhibits a G-type AFM interaction with the transition temperature at around 225 K and an indirect semiconducting nature with the band gap of 0.95 eV. The magnetic semiconducting property of KMnCuTe2 is unique in AMnMCh2 systems (A = Li, Na, K, M = Cu, Ag and Ch = S, Se, Te), which could be associated with the large metal-metal distance. Our work not only highlights the role of metal-metal interactions on regulating the properties of ThCr2Si2-type compounds, but also provides a feasible strategy to obtain the layered magnetic semiconductor.


Superarming the S-benzoxazolyl glycosyl donors by simple 2-O-benzoyl-3,4,6-tri-O-benzyl protection.
The strategic placement of common protecting groups led to the discovery of a new method for "superarming" glycosyl donors. Conceptualized from our previous studies on the O-2/O-5 Cooperative Effect, it was determined that S-benzoxazolyl glycosyl donors possessing both a participating moiety at C-2 and an electronically armed lone pair at O-5, such as the superarmed glycosyl donor shown above, were exceptionally reactive.


Rapid diagnosis of tuberculosis. Detection of drug resistance mechanisms.
Tuberculosis is still a serious public health problem, with 10.8 million new cases and 1.8 million deaths worldwide in 2015. The diversity among members of the Mycobacterium tuberculosis complex, the causal agent of tuberculosis, is conducive to the design of different methods for rapid diagnosis. Mutations in the genes involved in resistance mechanisms enable the bacteria to elude the treatment. We have reviewed the methods for the rapid diagnosis of M. tuberculosis complex and the detection of susceptibility to drugs, both of which are necessary to prevent the onset of new resistance and to establish early, appropriate treatment.


Cationic β-cyclodextrin polymer applied to a dual cyclodextrin polyelectrolyte multilayer system.
A polyelectrolyte multilayer film (PEM) based on cationic and anionic β-cyclodextrin polyelectrolytes was coated onto a textile substrate for future drug delivery purposes. We firstly synthesized a novel cationic β-cyclodextrin polymer (polyEPG-CD) by crosslinking β-cyclodextrin (βCD) with epichlorohydrin (EP) under basic conditions, in the presence of glycidyltrimetrylammonium chloride (GTMAC) as cationizing group. The influence of preparation conditions has been investigated in order to preferably obtain a water soluble fraction whose charge density and molecular weights were optimal for the layer-by-layer (LbL) deposition process. The different cationic cyclodextrin polymers obtained were characterized by FTIR, NMR, colloidal titration, conductimetry, thermogravimetric analysis and size exclusion chromatography. Besides, the counterpart polyelectrolyte was a β-cyclodextrin polymer crosslinked with citric acid, polyCTR-CD, whose synthesis and characterization have been previously reported. Finally we realized the Layer by Layer (LbL) build-up of the PEM coating onto the textile support, using the dip coating method, by alternatively soaking it in cationic polyEPG-CD and anionic polyCTR-CD solutions. This multilayer self-assembly was monitored by SEM, gravimetry and OWLS in function of both polyelectrolytes concentrations and ratios. Solutions parameters such as pH, ionic strenght were also discussed.


The immune reconstitution inflammatory syndrome related to HIV co-infections: a review.
The immune reconstitution inflammatory syndrome (IRIS) is a consequence of an excessive pathogen-specific immune recovery reaction and occurs in a subset of patients on antiretroviral therapy (ART). Infective forms of IRIS may present either as an 'unmasking' of a previously subclinical infection or the paradoxical clinical deterioration of an infection for which the patient received appropriate antimicrobial therapy. The most important risk factors for IRIS are a low CD4+ T-cell count and a short time between treatment of the infection and the commencement of ART. The general approach to the treatment of IRIS is to continue ART and provide antimicrobial therapy for the provoking infection. The majority of cases are self-limiting; however, mortality and hospitalisation rates are particularly high when tuberculosis- or cryptococcal-IRIS affects the central nervous system (CNS). Corticosteroid therapy should be considered in certain forms of IRIS after the exclusion of other conditions that could explain the inflammatory manifestations in the patients. Given that a low CD4+ T-cell count is a major risk factor for the development of IRIS, commencing ART at a CD4+ T-cell count of >350/μL will prevent most cases.


A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth.
Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). We show here, using both Xenopus laevis embryonic neuronal culture and intact X. laevis embryos, that the nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue. Expression of a mutated form of synapsin that prevents phosphorylation at this site, or introduction of phospho-specific antibodies directed against this site, decreased basal and dibutyryl cAMP-stimulated neurite outgrowth. Expression of a mutation mimicking constitutive phosphorylation at this site increased neurite outgrowth, both under basal conditions and in the presence of a PKA inhibitor. These results provide a potential molecular approach for stimulating neuron regeneration, after injury and in neurodegenerative diseases.


Investigation of the Serum Level of Vitamin D in Patients with Ear Cholesteatoma.
This study aimed to investigate the serum level of vitamin D in patients with ear cholesteatoma. This cross-sectional study was performed on 62 patients with middle ear cholesteatoma (case group) and 62 patients with simple chronic otitis media (control group). Both groups had the same age (32±1 in the case group and 34±1 in the control group; P=0.973) and gender. Vitamin D serum level was measured in the two groups. Data analysis was conducted using t-test and ANOVA. According to the statistical analysis, a significant relationship was observed between the serum level of vitamin D and middle ear cholesteatoma (P=0.000). The results showed that the serum level of vitamin D was lower in the case group, compared to the control group. Vitamin D serum level was lower in the cholesteatoma group. Moreover, it was strongly associated with hearing loss, tinnitus, and vertigo.


Performance reduction in finger amputees when reaching and operating common control devices: a pilot experimental investigation using a simulated finger disability.
This paper reports results of an experimental laboratory investigation to determine if finger amputations (most pervasive upper extremity injury in the United States) result in significant work performance deterioration in tasks requiring operation of common control devices found in industrial settings. Ten male student volunteers from the University of Cincinnati participated in this study. The finger disability simulated was of an extreme nature, and was defined as the loss of four fingers in the preferred hand and the thumb in the nonpreferred hand. While being seated, participants activated 5 types of industrial control devices (a rotary dial, a push button, a toggle switch, a castor wheel, and a rocker switch). The controls were assembled on a device attached to a cylindrical pole, such that the control assembly could move up and down the cylindrical pole. The vertical height of control location (15, 20, and 30 in. from the seat reference point) and angle of control location in vertical plane (0 degree, 45 degrees, 90 degrees, and 135 degrees) were varied in the experiment. Participants also had their torso restrained or unrestrained while reaching and activating controls, in addition to the presence or absence of the simulated disability in each participant. Functional reaches and arm reaches from the wall were measured for participants in the sample to determine the distances at which to place the control pole assembly. If a participant was able to reach the control, the time taken to activate and operate the control was recorded. Overall results indicate that participants took significantly longer (p < 0.05) to activate controls in the presence of the simulated disability. Physical restraint did not significantly alter performance provided the participant was able to reach the control. The type of control and the height of location of the control also significantly affected work performance.


Comparison of ciprofol (HSK3486) versus propofol for the induction of deep sedation during gastroscopy and colonoscopy procedures: A multi-centre, non-inferiority, randomized, controlled phase 3 clinical trial.
Ciprofol is a propofol analogue with improved pharmacokinetic properties. A multi-centre, non-inferiority trial was conducted to compare the deep sedation properties of ciprofol and propofol with a non-inferiority margin of 8% in patients undergoing gastroscopy and colonoscopy. In total, 289 patients were randomly allocated for surgery (259 colonoscopy and 30 gastroscopy) at a 1:1 ratio to be given intravenous injections of ciprofol (0.4 mg/kg) or propofol (1.5 mg/kg). The primary outcome was the success rate of colonoscopy defined as colonoscopy completion with no need for an alternative sedative or >5 ciprofol or propofol top up doses within any 15-min time period. The success rate of colonoscopy was 100% in the ciprofol group vs. 99.2% in the propofol group (mean difference 0.8%, 95% CI: -2.2% to 4.2%). Except for the gastrointestinal lesions found during the gastroscopy and colonoscopy procedures, the occurrence rates of adverse drug reactions in the ciprofol and propofol groups were 31.3% and 62.8%, respectively (P < 0.001). Pain on injection was less common in the ciprofol group (4.9% vs. 52.4%, P < 0.001). The outcomes demonstrated that ciprofol was non-inferior to propofol with regard to successful sedation for gastroscopy or colonoscopy procedures and no obvious important adverse events occurred.


Differential binding of nonhistone chromosomal proteins to the putative mouse origin of replication.
Ehrlich ascites tumour (EAT) cells were treated with trioxsalen and ultraviolet light to crosslink DNA in vivo. After the treatment initiation of DNA replication can still occur but elongation is blocked by the crosslinks and this leads to the formation of short DNA fragments containing the origin of replication that can be isolated in double-stranded form after S1 nuclease cutting of the crosslinked DNA (Russev, G. and Vassilev, L. (1982) J. Mol. Biol. 161, 77-87). To assess the affinity of these DNA fragments toward different chromosomal proteins, chromatin was fractionated by SDS-polyacrylamide gel electrophoresis, proteins were transferred to nitrocellulose filters and allowed to interact with in vivo labelled [32P]DNA. The autoradiography of the filters showed that the DNA fraction synthesized between crosslinks and containing the putative mouse origin of replication bound preferentially to several nonhistone proteins, the most strongly binding ones having molecular weights of 64, 68, 72 and 150 kDa.


Teaching of the Society for Fetal Urology grading system for pediatric hydronephrosis is improved by e-Learning using Computer Enhanced Visual Learning (CEVL): A multi-institutional trial.
It is unclear how clinicians learn to grade pediatric hydronephrosis (HN) and how effective their training has been. We sought to: 1. Assess how clinicians learn to grade HN and their confidence in their training and abilities and 2. To assess Computer Enhanced Visual Learning (CEVL) e-Learning to learn the Society for Fetal Urology (SFU) grading system for pediatric HN. A multi-institutional online survey was distributed to pediatric urologists, nephrologists, and radiologists. Respondents used a 6-point Likert scale (0 = not confident to 5 = very confident) to assess their confidence in knowledge of the criteria, indications, and ability to grade HN, and how they learned to grade. Participants assigned SFU grades to 15 neonatal ultrasounds (US). A CEVL module on the SFU grading system was accessed and a post-CEVL survey completed. Changes in confidence and accuracy of grading were compared before and after CEVL e-Learning. The most common method of learning was "casually during training" (44.5%). Significant increases in confidence in knowledge of criteria, indications, and ability to grade, as well as the accuracy of grading were seen following CEVL e-Learning (Figure A and B). Although the SFU grading system is considered the predominant grading system for HN, its application in clinical practice has been inconsistent. While this may be due to the grading system itself, it is possible that deficient training and confidence are the root causes. Our data supports this by demonstrating that most clinicians receive only casual training and accordingly, report low confidence in their knowledge and ability to grade HN. Therefore, we conclude that there exists a strong need to improve the teaching of the SFU grading system. e-Learning has been shown to be effective in teaching difficult topics and skills. We demonstrate that e-Learning with CEVL is effective in increasing both the confidence and accuracy of SFU grading of pediatric HN. Limitations of our study include a small sample size, low response rate, and discrepant participation. Furthermore, we did not assess the extent to which the CEVL module was used or include a control group learning through traditional means. Therefore, we were unable to evaluate the efficiency of learning or be certain that the improvements seen were derived exclusively from CEVL. Current training in SFU grading of HN is mostly unstructured and inaccurate grading is common. Learners who use CEVL show improvements in their confidence and ability to SFU grade HN.


Growth in short term primary cell cultures derived from pregnancy-dependent mammary tumors.
The behavior of cells in primary cultures derived from autonomous and pregnancy-dependent mouse mammary tumors was studied. Despite initial growth both dependent and autonomous mammary tumors produced only short-term primary cultures. Initial plating density had a marked effect on growth with only cultures plated at greater than or equal to 2 X 10(5) cells/cm2 showing any short-termed growth. Time lapse analysis showed that the lack of growth was due to failures of cytokinesis and increased death rate and intermitotic time in cultures plated at less than 2 X 10(5) cells/cm2. Using continuous label autoradiographic techniques, a partial synchronous wave of DNA synthesis was observed with newly plated and restimulated cultures. DNA synthesis reached a peak 24-48 hrs. after plating or restimulation and then dropped to low values for the next few days. Attempts to maintain the initial high rate of DNA synthesis or to induce another round of DNA synthesis by enriched media, increased serum concentrations, or other types of serum and plasma were at best only partially successful. Important hormones necessary for growth of mammary tissue in vivo may be necessary for sustained growth in vitro.


Evolutionary game analysis between employees and employers about working overtime from the perspective of information asymmetry.
Overtime is an international phenomenon, especially in some Chinese Internet technology companies, the 996 work regime is a common corporate atmosphere. This paper holds that overtime work is the result of a long-term dynamic game between employees and employers. In such a dynamic evolution process, employers and employees both cooperate and conflict, they will choose a strategy conducive to their own development through long-term learning and improvement. Based on the evolutionary game theory and principal-agent theory, this paper constructs a [Formula: see text] evolutionary game matrix. The strategies of employees can be divided into voluntary overtime and involuntary overtime, while the strategies of employers can be divided into providing overtime pay and not providing overtime pay. The stability of the system is related to four parameters: resource consumption, information asymmetry coefficient, trust coefficient, and moral hazard coefficient. Through an in-depth study of the model and data simulation, the system has five equilibrium points, an ESS point, and a saddle point in any case. Accordingly, we put forward two theorems and three propositions, which are verified not only theoretically but also by data simulation. Besides, the strategies of the employees and the employers will evolve from the initial state to (Involuntarily, Not pay) or (Voluntarily, Pay) under different situations. This is closely related to the initial parameters of the evolutionary game model and the payment matrix. By summarizing the influence of each parameter on the evolutionary path, we believe that fairness and information equivalence between employees and employers can effectively promote both parties to reach the Pareto optimal state. In other words, employees and employers need to communicate and share information promptly to ensure the unity of information acquired by each other and achieve a win-win situation. This paper contributes to providing theoretical guidance and practical enlightenment for organizations to manage employees' overtime behavior scientifically and improve their work psychology reasonably.


Smouldering wildfires in peatlands, forests and the arctic: Challenges and perspectives.
Wildfires can be divided into two types, flaming or smouldering, depending on the dominant combustion processes. Both types are present in most wildfires, and despite being fundamentally different in chemical and physical terms, one transitions to the other. Traditionally, science has focused on flames, while smouldering is often misinterpreted. But smouldering wildfires are emerging as a global concern because they cause extensive air pollution, emit very large amounts of carbon, are difficult to detect and suppress, and could accelerate climate change. Central to the topic are smouldering peat fires that lead to the largest fires on Earth. Smouldering also dominates the residual burning after flames have died out and firebrand ignition. Finally, smouldering is an important part of Arctic wildfires, which are increasing in frequency. Here, we present a scientific overview of smouldering wildfires, the associated environmental and health issues, including climate change, and the challenges in prevention and mitigation.


Dynamics of self-excited thermoacoustic instability in a combustion system: Pseudo-periodic and high-dimensional nature.
We have examined the dynamics of self-excited thermoacoustic instability in a fundamentally and practically important gas-turbine model combustion system on the basis of complex network approaches. We have incorporated sophisticated complex networks consisting of cycle networks and phase space networks, neither of which has been considered in the areas of combustion physics and science. Pseudo-periodicity and high-dimensionality exist in the dynamics of thermoacoustic instability, including the possible presence of a clear power-law distribution and small-world-like nature.


Sequences and homology analysis of two genes encoding beta-glucosidases from Bacillus polymyxa.
The nucleotide sequences of the bglA and bglB genes encoding beta-glucosidases from Bacillus polymyxa have been determined. Both genes contain coding regions of 1344 bp, corresponding to polypeptides with Mrs of 51,643 and 51,547, respectively. Patterns of codon usage indicate that both genes are expressed at a low frequency. Previous data suggested that the proteins encoded by bglA and bglB were intra- and extracellular enzymes, respectively; however, neither of the two deduced amino acid sequences has N termini with the typical features of a leader peptide. The proteins encoded by bglA and bglB show remarkable homology to each other and to other beta-glucosidases (Bgl) and beta-galactosidases (beta Gal). On the basis of the observed homologies, we can define two groups of microbial Bgl: one of them, type I, including most bacterial Bgl, and type II, including enzymes from different yeast species and one from Clostridium thermocellum. Likewise, at least two groups of beta Gal can be distinguished: type I, including enzymes homologous to type-I Bgl, and type II, showing no homology to any of the previous groups.


The irreplaceable role of medical massive open online courses in China during the COVID-19 pandemic.
Massive open online courses (MOOCs) have become innovative open-learning approach in medical education. This study aimed to evaluate the dynamic changes in the construction and application of medical MOOCs before and after the coronavirus disease 2019 (COVID-19) pandemic in China. The dynamic changes of usages about medical MOOCs before and after 2020 were mainly searched on the Smart Education of China Higher Education platform, and the detailed learning profiles and outcome indicators were further analyzed using 40 national first-class medical MOOCs from 'zhihuishu' platform. A total of 2,405 medical MOOCs were exported from the Smart Education of China Higher Education platform, of which 1,313 (54.6%) were launched since 2020. The total and average numbers of participants of 141 national first-class medical MOOCs peaked during the initial spread of COVID-19 in 2020. We further analyzed the dynamic usage of MOOCs from 2018 to 2022 based on 40 national first-class medical MOOCs launched on the 'Zhihuishu' platform. The findings revealed that the number of registered learners (3,240 versus 2,654), questions and answers (27,005 versus 5,116) and students taking the final examination (2,782 versus 1,995) per semester were significantly higher since 2020 compared to these before 2020. Especially, the number of registered learners, registered schools, questions and answers, and students participating in online discussion, taking the unit quiz, taking final examinations and passing final examinations all peaked in the 2020 spring-summer semester. Pearson's correlation analysis found that the number of questions and answers and the number of learners who participated in online discussion were both positively correlated with the number of students who passed the final examination, and the correlation was especially strong since 2020. Moreover, the number of publications on medical MOOC research has soared since 2020 and has maintained a continuous upward trend. High-quality medical MOOCs have been launched rapidly since the COVID-19 pandemic in China. The number of participants and online interactions of medical MOOCs peaked during the initial spread of COVID-19 in 2020. MOOCs are reliable and valid digital sources that facilitate medical higher education and play irreplaceable roles in emergency management.


The Role of Pharmacists in Managing Adverse Events Related to Immune Checkpoint Inhibitor Therapy.
To provide an overview of immune checkpoint inhibitor (ICI) therapy-associated immune-related adverse events (irAEs) and their management, focusing on the key responsibilities for pharmacists in recognizing, distinguishing, and treating irAEs and in educating patients about irAEs and their management. Literature published from January 2000 to March 2018 available from online sources. Relevant English-language studies, guidelines, and articles. ICI therapies have been approved for the treatment of several cancers as single-agent therapies, combined ICI therapies, or in combination with other agents. ICI therapies increase the activity of the immune system and consequently can have autoimmune-like adverse effects that are often termed irAEs. irAE management can be challenging as irAEs can vary in their frequency and severity among patients, according to the specific agent, and can occur at any time during treatment or after therapy discontinuation. Additionally, for patients treated with ICI therapies in combination with other therapies, ICI-associated irAEs must be distinguished from adverse events associated with chemotherapy or targeted therapies, which often require different management. Pharmacists can provide essential support to diagnose and manage irAEs. Early and accurate diagnosis and prompt management of irAEs by pharmacists are critical to reduce the risk of severe or life-threatening complications and prevent premature ICI discontinuation. Pharmacists have a key role in the recognition, monitoring, and management of irAEs and in educating patients about irAEs associated with ICI therapies and the agents used to manage them.


Evolution of the noncoding regions in Drosophila mitochondrial DNA: two intergenic regions.
The sequences of the mitochondrial DNA (mtDNA) segment containing the two intergenic regions were determined for six species belonging to the Drosophila immigrans species group and compared to the corresponding segments of Drosophila species which had been studied previously. We found remarkable differences in the evolutionary rates of the two intergenic regions. The Intergenic I region, which lies between the tRNA(gln) and the tRNA(ile) genes, was found to be highly conserved in terms of both size (30 ntp) and nucleotide sequence among the species studied. In contrast, the sequences of the Intergenic II region, which lies between the tRNA(f-met) and the tRNA(ile) genes, showed considerable variation. The size of the Intergenic II region ranged from 0 to 88 ntp, and accurate alignment was possible only among sequences from geographical strains or very closely related species in the nasuta species subgroup. The observed differences in conservation of the two mtDNA intergenic regions are discussed in light of functional constraints on mtDNA sequences.


Two new putative susceptibility loci for ADNFLE.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) has been up to now considered a simple Mendelian trait caused by mutations in neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. We previously demonstrated that in a three-generation Italian family the disease was unlinked to all known ADNFLE loci as well as to all known brain-expressed nAChR subunits. The genome-wide linkage analysis here presented performed on this family points to the existence of two new putative ADNFLE loci on chromosomes 3p22-p24 and 8q11.2-q21.1. These findings, together with several ADNFLE characteristics, suggest that this epilepsy could be, at least in the above family, a complex disorder. In particular, we propose and discuss the hypothesis of a digenic transmission of the disease.


The Effect of Timing of Tetanus-Diphtheria-Acellular Pertussis Vaccine Administration in Pregnancy on the Avidity of Pertussis Antibodies.
Background: Optimal timing of gestational tetanus-diphtheria-acellular pertussis (Tdap) vaccination is not well-defined. No well-established specific anti-pertussis antibody level correlates with protection, suggesting the importance of antibody quality such as avidity. We aimed to determine the effect of timing of vaccination with Tdap in pregnancy on the avidity of cord anti-pertussis toxin (PT) immunoglobulin G (IgG). Methods: Prospective study of newborns in a tertiary hospital (Melbourne, Australia) born to women vaccinated with Tdap in pregnancy. Ammonium thiocyanate was used as a bond-breaking agent to measure the avidity of anti-PT IgG using concentrations between 0.25 M (to measure low avidity antibodies) and 3 M (to measure very high avidity antibodies). Anti-PT IgG levels achieved at each ammonium thiocyanate concentration in cord samples of women vaccinated during 28-32 weeks gestation (WG) vs. 33-36 WG, and women vaccinated 5-12 vs. 1-4 weeks prior to delivery were compared using t-tests. Results: Newborns of women vaccinated with Tdap during 28-32 WG (n = 43) had statistically significant higher concentrations of medium and high avidity anti-PT IgG compared with newborns of women vaccinated during 33-36 WG (n = 47), 11.6 IU/ml (95% CI, 8.8-15.2) IU/ml vs. 6.7 IU/ml (95% CI, 5.2-8.6) and 10.1 IU/ml (95% CI, 7.4-13.8) vs. 5.7 (95% CI, 3.6-8.9) IU/ml (p = 0.007 and p = 0.035), respectively. Newborns of women vaccinated 5-12 weeks before delivery (n = 64) had statistically significant higher concentrations of high and very high avidity anti-PT IgG compared with newborns of women vaccinated within 4 weeks before delivery (n = 25), 10.3 IU/mL (95% CI, 7.9-13.4) vs. 3.3 IU/mL (95% CI, 1.7-6.4), 12.6 IU/mL (95% CI, 9.4-16.9) vs. 4.3 IU/mL (95% CI, 2.2-8.5) (all p < 0.03), respectively. Conclusions: Quantification of levels of anti-PT IgG with different avidities demonstrated that pertussis vaccination 5-12 weeks before delivery was associated with higher anti-PT IgG avidity compared with vaccination within 4 weeks before delivery. Pertussis vaccination during 28-32 WG was associated with higher anti-PT IgG avidity compared with vaccination during 33-36 WG, supporting vaccination at 28-32 over 33-36 WG for optimal protection against pertussis in infancy.


Targeted Therapy and Immunotherapy for Lung Cancer.
Targeted therapy and immunotherapy have changed the treatment paradigm of non-small cell lung cancer (NSCLC). Distinct molecular subtypes of NSCLC have been described over the past 20 years, enabling the emergence of treatments specific to that subtype. Agents targeting the driver mutations in NSCLC have revolutionized the approach to patients with metastatic disease, because oncologists now select a treatment based on the profile of that particular tumor. More recently, an understanding of immune checkpoints has led to the development of checkpoint inhibitors that enable the host immune system to better recognize tumor cells as foreign and to destroy them.


Graft patency evaluation with colour-Doppler ultrasonography after bypass surgery in Takayasu's arteritis: a direct colour-flow lumen imaging method.
To assess the feasibility and potential diagnostic usefulness of colour-Doppler flow imaging (CDFI) to detect complications of supra-aortic vascular bypass grafts in Takayasu's arteritis (TA). A prospective study. Nine supra-aortic grafts in six patients with Takayasu's arteritis. The minimal, maximal, and true colour-flow image diameters of the lumens of the grafts were measured and stenoses, occlusions, and dilatations were evaluated and compared with angiographic findings. The sensitivity for detection in > 50% stenoses and in total occlusions was 75% while specificity was 100%. Only one 40% stenosis had been overlooked in whole. The maximal difference of stenosis by two methods was otherwise 20%. CDFI was in general able to expose stenoses in supra-aortic grafts, but the lack of visibility of some grafts throughout their length cause the false results. It appears that some angiographies can be replaced by CDFI and that this is a suitable method for follow-up in symptom-free patients with grafts.


Association of urinary phthalate metabolites with all-cause and cardiovascular disease mortality among adults with diabetes mellitus: National Health and Nutrition Examination Survey 2005-2014.
The study regarding phthalate metabolites and mortality among diabetes mellitus (DM) is limited. We aimed to examine the association of urinary phthalate metabolites with all-cause and cardiovascular disease (CVD) mortality among adults with DM. This study included 8,931 adults from the National Health and Nutrition Examination Survey (NHANES) from 2005-2006 to 2013-2014. Mortality data were linked to National Death Index public access files through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidences (CIs) for mortality. We identified 1,603 adults with DM [mean ± SE age, 47.08 ± 0.30 years; 50.5% (833) were men]. Mono-(carboxynonyl) phthalate (MCNP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of Di (2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHP) were positively associated with DM (MCNP: OR = 1.53, 95%CI = 1.16-2.01; MECPP: OR = 1.17, 95% CI = 1.03-1.32; ∑DEHP: OR = 1.14, 95% CI = 1.00-1.29). Among DM patients, mono-(3-carboxypropyl) phthalate (MCPP) was associated with a 34% (HR 1.34, 95% CI 1.12-1.61) increased risk of all-cause mortality while the HRs (95%CI) of CVD mortality were 2.02 (1.13-3.64) for MCPP, 2.17 (1.26-3.75) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), 2.47 (1.43-4.28) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 2.65 (1.51-4.63) for MECPP, and 2.56 (1.46-4.46) for ∑DEHP, respectively. This study is an academic exploration of the association between urinary phthalate metabolites and mortality among adults with DM, suggesting that exposure to phthalates might be associated with an increased risk of all-cause and CVD mortality in DM. These findings suggest that patients with DM should carefully use plastics products.


Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow.
Bone marrow contains mesenchymal stem cells (MSCs) that can differentiate along multiple mesenchymal lineages. In this capacity they are thought to be important in the intrinsic turnover and repair of connective tissues while also serving as a basis for tissue engineering and regenerative medicine. However, little is known of the biological responses of human MSCs to inflammatory conditions. When cultured with IL-1β, marrow-derived MSCs from 8 of 10 human subjects deposited copious hydroxyapatite, in which authenticity was confirmed by Fourier transform infrared spectroscopy. Transmission electron microscopy revealed the production of fine needles of hydroxyapatite in conjunction with matrix vesicles. Alkaline phosphatase activity did not increase in response to inflammatory mediators, but PPi production fell, reflecting lower ectonucleotide pyrophosphatase activity in cells and matrix vesicles. Because PPi is the major physiological inhibitor of mineralization, its decline generated permissive conditions for hydroxyapatite formation. This is in contrast to MSCs treated with dexamethasone, where PPi levels did not fall and mineralization was fuelled by a large and rapid increase in alkaline phosphatase activity. Bone sialoprotein was the only osteoblast marker strongly induced by IL-1β; thus these cells do not become osteoblasts despite depositing abundant mineral. RT-PCR did not detect transcripts indicative of alternative mesenchymal lineages, including chondrocytes, myoblasts, adipocytes, ligament, tendon, or vascular smooth muscle cells. IL-1β phosphorylated multiple MAPKs and activated nuclear factor-κB (NF-κB). Certain inhibitors of MAPK and PI3K, but not NF-κB, prevented mineralization. The findings are of importance to soft tissue mineralization, tissue engineering, and regenerative medicine.