High-precision calculations of In I and Sn II atomic properties

We use all-order relativistic many-body perturbation theory to study 5s^2 nl configurations of In I and Sn II. Energies, E1-amplitudes, and hyperfine constants are calculated using all-order method, which accounts for single and double excitations of the Dirac-Fock wave functions.Comment: 10 pages, accepted to PRA; v2: Introduction changed, references adde

Лапароскопічна герніопластика у лікуванні защемлених гриж у хворих похилого та старечого віку

Results of treatment of 118 (5.3 %) patients with strangulated hernia were analyzed. The age of patients ranged from 52to 92 years. Among them, 92 (69.0 %) patients underwent performed hernioplasty using polypropylene (PPI) implant; thesecond – 26 (31.0 %) patients who underwent autoplasty. Patients with strangulated hernia were divided into two groups:the fi rst included 60 (50.8 %) patients who underwent HP using the PPI for the "open" method; the second – 32 (27.1 %)patients who underwent laparoscopic alohernioplasty. 54 (45.8 %) patients were operated with strangulated inguinal hernia.Transabdominal preperitoneal endovideohernioplasty (TPEVH) was used in 12 (5.7 %) patients with strangulated inguinalhernia. In 39 (31.1 %) patients there was a strangulated femoral hernia, where 10th (8.5 %) performed TPEVH. 21 (17.8 %)patients with ventral hernias were operated on emergency indications. 14 (6.1 %) of them had strangulated umbilical hernia,6 (2.6 %) had a hernia linea alba, 1 (0.4 %) – hernia l. semilunaris. 2 (%) patients with hernia linea alba and 1 (0.4 %) patientswith hernia l. semilunaris were operated laparoscopically. In patients with postoperative and recurrent hernias of abdominalwall jamming was observed in 39 (33.1 %) cases in patients older than 60 years. Laparoscopic surgeries were 7 (5.9 %) patients.Postoperative complications of the wound were: Seroma – 12 (14.3 %) patients, festering wounds – in 5 (6.0 %) patients,evisceration – in 1 (1.2 %) patients. 2 died (2.4 %) patients from progression of peritonitis. In laparoscopic – 1 (1.2 %) in caseof bleeding from the lower epigastric artery and 1 (1.2 %) – intraoperative damage to the small intestine. Thus, the use ofendoscopic therapies strangulated hernia elderly patients may need further study and improvement.Проаналізовано результати хірургічного лікування 118 (5,3 %) хворих із защемленою грижею. Вік хворих склав від 52до 92 років. Із них 92 (69,0 %) хворим було виконано герніопластику із застосуванням поліпропіленового імплантата, 26(31,0 %) хворим було виконано аутопластику. Хворих із защемленою грижею поділили на дві групи: в першу увійшли60 (50,8 %) хворих, яким було виконано герніопластику із застосуванням поліпропіленового імплантата за “відкритим”способом; в другу – 32 (27,1 %) хворих, яким було виконано лапароскопічну алогерніопластику. 54 (45,8 %) пацієнтибули оперовані із защемленою пахвинною грижею, трансабдомінальна преперитонеальна ендовідеогерніопластика булазастосована 12 (5,7 %) хворим. У 39 (31,1 %) пацієнтів мало місце защемлення стегнової грижі, де 10-м (8,5 %) із них та-кож виконали трансабдомінальну преперитонеальну ендовідеогерніопластику. При первинній серединній локалізаціїгрижових дефектів, що були прооперовані за екстреними показаннями з приводу даної патології, був 21 (17,8 %) хворий,із них у 14 (6,1 %) пацієнтів мала місце защемлена пупкова грижа, у 6 (2,6 %) – грижа білої лінії живота, в 1 (0,4 %)– грижа спігелієвої лінії. Із них 2 (2,4 %) хворих із грижею білої лінії живота та 1 (0,4 %) – з грижею спігелієвої лініїбули прооперовані лапароскопічно. У групі хворих з післяопераційними та рецидивними грижами передньої черевноїстінки защемлення спостерігали в 39 (33,1 %) випадках у пацієнтів, старших 60 років. Лапароскопічно було проопе-ровано 7 (5,9 %) хворих. Ускладнення в групі з “відкритим” способом оперування в післяопераційному періоді з бокупісляопераційної рани були такі: серома – у 12 (14,3 %) хворих, нагноєння рани – у 5 (6,0 %) пацієнтів, евісцерація – у1 (1,2 %) хворого. Померли 2 (2,4 %) хворих від прогресування перитоніту. При лапароскопічних – 1 (1,2 %) випадоккровотечі з нижньої епігастральної артерії та 1 (1,2 %) – інтраопераційне пошкодження тонкої кишки. Отже, застосу-вання ендоскопічних методів лікування защемленої грижі хворих похилого віку можливе, потребує подальшого вив-чення та вдосконалення

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis

Identification of mutations in the PYRIN-containing NLR genes (NLRP) in head and neck squamous cell carcinoma

Head and Neck Squamous Cell Carcinoma (HNSCC) encompasses malignancies that arise in the mucosa of the upper aerodigestive tract. Recent high throughput DNA sequencing revealed HNSCC genes mutations that contribute to several cancer cell characteristics, including dysregulation of cell proliferation and death, intracellular proinflammatory signaling, and autophagy. The PYRIN-domain containing NLR (Nucleotide-binding domain, Leucine rich Repeats - containing) proteins have recently emerged as pivotal modulators of cell death, autophagy, inflammation, and metabolism. Their close physiologic association with cancer development prompted us to determine whether mutations within the NLRP (PYRIN-containing NLR ) gene family were associated with HNSCC genome instability and their clinicopathologic correlations. Catastrophic mutational events underlie cancer cell genome instability and mark a point-of-no-return in cancer cell development and generation of heterogeneity. The mutation profiles of 62 patients with primary conventional type HNSCC excluding other histologic variants were analyzed. Associations were tested using Fisher's Exact test or Mann-Whitney U test. Mutations in NLRP were associated with elevated genome instability as characterized by higher mutation rates. Clinically, NLRP mutations were more frequently found in HNSCC arising in the floor of mouth (50.0%) in comparison with HNSCC at other head and neck locations (14.8%). These mutations were clustered at the leucine rich repeats region of NLRP proteins, and affected NLRP genes were mostly localized at chromosomes 11p15.4 and 19q13.42-19q13.43. Twenty novel NLRP mutations were identified in HNSCC, and mutations in this group of genes were correlated with increased cancer cell genome mutation rates, and such features could be a potential molecular biomarker of HNSCC genome instability. © 2014 Lei et al

Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues

Defining the pharmacological target(s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC) is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61) or HadC (at Val85, Lys157 or Thr123), which are components of the bhydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

BACKGROUND: Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. METHODS: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. RESULTS: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/- , but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. CONCLUSIONS: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening

A Spatial Analysis of Rift Valley Fever Virus Seropositivity in Domestic Ruminants in Tanzania

Rift Valley fever (RVF) is an acute arthropod-borne viral zoonotic disease primarily occurring in Africa. Since RVF-like disease was reported in Tanzania in 1930, outbreaks of the disease have been reported mainly from the eastern ecosystem of the Great Rift Valley. This cross-sectional study was carried out to describe the variation in RVF virus (RVFV) seropositivity in domestic ruminants between selected villages in the eastern and western Rift Valley ecosystems in Tanzania, and identify potential risk factors. Three study villages were purposively selected from each of the two Rift Valley ecosystems. Serum samples from randomly selected domestic ruminants (n = 1,435) were tested for the presence of specific immunoglobulin G (IgG) and M (IgM), using RVF enzyme-linked immunosorbent assay methods. Mixed effects logistic regression modelling was used to investigate the association between potential risk factors and RVFV seropositivity. The overall RVFV seroprevalence (n = 1,435) in domestic ruminants was 25.8% and species specific seroprevalence was 29.7%, 27.7% and 22.0% in sheep (n = 148), cattle (n = 756) and goats (n = 531), respectively. The odds of seropositivity were significantly higher in animals sampled from the villages in the eastern than those in the western Rift Valley ecosystem (OR = 1.88, CI: 1.41, 2.51; p<0.001), in animals sampled from villages with soils of good than those with soils of poor water holding capacity (OR = 1.97; 95% CI: 1.58, 3.02; p< 0.001), and in animals which had been introduced than in animals born within the herd (OR = 5.08, CI: 2.74, 9.44; p< 0.001). Compared with animals aged 1-2 years, those aged 3 and 4-5 years had 3.40 (CI: 2.49, 4.64; p< 0.001) and 3.31 (CI: 2.27, 4.82, p< 0.001) times the odds of seropositivity. The findings confirm exposure to RVFV in all the study villages, but with a higher prevalence in the study villages from the eastern Rift Valley ecosystem

Adsorption and reaction of CO on (Pd–)Al2O3 and (Pd–)ZrO2: vibrational spectroscopy of carbonate formation

γ-Alumina is widely used as an oxide support in catalysis, and palladium nanoparticles supported by alumina represent one of the most frequently used dispersed metals. The surface sites of the catalysts are often probed via FTIR spectroscopy upon CO adsorption, which may result in the formation of surface carbonate species. We have examined this process in detail utilizing FTIR to monitor carbonate formation on γ-alumina and zirconia upon exposure to isotopically labelled and unlabelled CO and CO2. The same was carried out for well-defined Pd nanoparticles supported on Al2O3 or ZrO2. A water gas shift reaction of CO with surface hydroxyls was detected, which requires surface defect sites and adjacent OH groups. Furthermore, we have studied the effect of Cl synthesis residues, leading to strongly reduced carbonate formation and changes in the OH region (isolated OH groups were partly replaced or were even absent). To corroborate this finding, samples were deliberately poisoned with Cl to an extent comparable to that of synthesis residues, as confirmed by Auger electron spectroscopy. For catalysts prepared from Cl-containing precursors a new CO band at 2164 cm−1 was observed in the carbonyl region, which was ascribed to Pd interacting with Cl. Finally, the FTIR measurements were complemented by quantification of the amount of carbonates formed via chemisorption, which provides a tool to determine the concentration of reactive defect sites on the alumina surface