The Kv7 subfamily of voltage-dependent potassium channels, distinct from other subfamilies by dint of its large intracellular COOH terminus, acts to regulate excitability in cardiac and neuronal ...tissues. KCNQ1 (Kv7.1), the founding subfamily member, encodes a channel subunit directly implicated in genetic disorders, such as the long QT syndrome, a cardiac pathology responsible for arrhythmias. We have used a recombinant protein preparation of the COOH terminus to probe the structure and function of this domain and its individual modules. The COOH-terminal proximal half associates with one calmodulin constitutively bound to each subunit where calmodulin is critical for proper folding of the whole intracellular domain. The distal half directs tetramerization, employing tandem coiled-coils. The first coiled-coil complex is dimeric and undergoes concentration-dependent self-association to form a dimer of dimers. The outer coiled-coil is parallel tetrameric, the details of which have been elucidated based on 2.0Å crystallographic data. Both coiled-coils act in a coordinate fashion to mediate the formation and stabilization of the tetrameric distal half. Functional studies, including characterization of structure-based and long QT mutants, prove the requirement for both modules and point to complex roles for these modules, including folding, assembly, trafficking, and regulation.
A strategy to create cooperative hydrogen‐bonding centers by using strong and directional intramolecular hydrogen‐bonding motifs that can survive in aqueous media is presented. In particular, ...glyco–oligoamides, a family of DNA minor groove binders, with cooperative and non‐cooperative hydrogen‐bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by means of NMR spectroscopy and molecular modeling methods. Indeed, two different sugar moieties, namely, β‐D‐Man‐Py‐γ‐Py‐Ind (1; Ind=indole, Man=mannose, Py=pyrrole) and β‐D‐Tal‐Py‐γ‐Py‐Ind (2; Tal=talose), were chosen according to our design. These sugar molecules should present one‐ or two‐directional intramolecular hydrogen bonds. The challenge has been to study the conformation of the glyco–oligoamides at low temperature in physiological media by detecting the exchangeable protons (amide NH and OH resonances) by means of NMR spectroscopic analysis. In addition, two more glyco–oligoamides with non‐cooperative hydrogen‐bonding centers, that is, β‐D‐Glc‐Py‐γ‐Py‐Ind (3; Glc=glucose), β‐D‐Gal‐Py‐γ‐Py‐Ind (4; Gal=galactose), and the model compounds β‐D‐Man‐Py‐NHAc (5) and β‐D‐Tal‐Py‐NHAc (6) were synthesized and studied for comparison. We have demonstrated the existence of directional intramolecular hydrogen bonds in 1 and 2 in aqueous media. The unexpected differences in terms of stabilization of the intramolecular hydrogen bonds in 1 and 2 relative to 5 and 6 promoted us to evaluate the influence of CH—π interactions on the establishment of intramolecular hydrogen bonds by using computational methods. Initial binding studies of 1 and 2 with calf‐thymus DNA and poly(dA‐dT)2 by NMR spectroscopic analysis and molecular dynamics simulations were also carried out. Both new sugar–oligoamides are bound in the minor groove of DNA, thus keeping a stable hairpin structure, as in the free state, in which both intramolecular hydrogen‐bonding and CH—π interactions are present.
A stable influence: Glyco–oligoamides, a family of DNA minor groove binders, with cooperative and non‐cooperative hydrogen‐bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by NMR spectroscopy and molecular modeling methods. Both intramolecular hydrogen‐bonding and CH—π interactions are present in the binding of these new sugar–oligoamides.
Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, ...their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.
Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact of endocrine disruptor ...chemicals on reproductive function and other reproductive system complications that cause high economic losses in livestock species. The present study aimed to generate an innovative, reproducible, and functional 3D scaffold-based model of the bovine endometrium structurally robust for long term-culture. We developed a multicellular model containing both endometrial epithelial and stromal cells. Epithelial cells organized to form a luminal-like epithelial layer on the surface of the scaffold. Stromal cells produced their own extracellular matrix forming a stable subepithelial compartment that physiologically resembles the normal endometrium. Both cell types released prostaglandin E
2
and prostaglandin F
2α
following a treatment with oxytocin and arachidonic acid. Additionally signal pathways mediating oxytocin and arachidonic acid stimulation of prostaglandin synthesis were analyzed by real time PCR (RT-PCR).
Oxytocin receptor
(
OXTR
),
prostaglandin E
2
receptor 2
(
EP2
),
prostaglandin E
2
receptor 4
(
EP4
),
prostaglandin F receptor
(
PTGFR
),
prostaglandin E synthase
(
PTGES
), PGF-synthase (
PGFS
) and prostaglandin-endoperoxide synthase 2 (
COX-2
) expression was detected in both control and treatment groups, however, only significant changes in abundance of
OXTR
mRNA transcripts were found. The results obtained by this study are a step forward in bovine in vitro culture technology. This 3D scaffold-based model provides a platform to study regulatory mechanisms involved in endometrial physiology and can set the basis for a broader tool for designing and testing novel therapeutic strategies for recurrent uterine pathologies.
The preparation of previously unknown (indol-3-yl)-α-allenols and -allenones was accomplished from indole-3-carbaldehydes, through indium-mediated Barbier allenylation reaction taking advantage of ...the N-(2-pyridyl)sulfonyl group. Metal-catalyzed cyclizations of oxyallenyl C3-linked indoles proceeded in two ways depending on the presence or absence of the N-(2-pyridyl)sulfonyl group. For allenols, gold-catalyzed oxycyclization occurred in the presence of the protecting group; in the absence of the protecting group, palladium- and gold-catalyzed benzannulations operated. On the contrary, under gold catalysis furyl-indoles were obtained as exclusive products from NH-allenones, while 5-endo carbocyclization adducts were the major components starting from N-SO2py-protected allenones. These cyclization reactions have been developed experimentally, and their mechanisms have additionally been investigated by a computational study.
The acaricidal effects of 55 strains of Metarhizium anisopliae (Metschnikoff) Sorokin, 1883 (Hypocreales: Clavicipitaceae) isolated from paddocks of cattle farms were evaluated in two Rhipicephalus ...microplus (Canestrini 1887) (Ixodida: Ixodidae) populations, of which one was multi‐resistant and one was susceptible to chemical acaricides. Percentage mortality and reproductive efficiency indices in R. microplus were evaluated by adult immersion tests at a dose of 1 × 108 conidia/mL for each fungal strain. Some strains were selected to calculate lethal concentrations to kill 50% (LC50) and 99% (LC99) of engorged ticks. Strains MaV22, MaV26 and MaV55 induced 100% mortality in R. microplus on day 14. Strains MaV05, MaV09 and MaV22 caused mortality of >90% from day 12 onward in both tick populations. The most effective acaricidal fungal strain, MaV55, inhibited egg laying by 54.86 and 55.86% in acaricide‐resistant and ‐susceptible R. microplus populations, respectively. None of the fungal strains had statistically significant effects on larval hatching. In conclusion, nine strains of M. anisopliae demonstrated high acaricidal effects against R. microplus and reduced its egg laying. No differences in acaricidal effects were observed between the two populations of ticks tested.
There is evidence regarding the presence of alterations in both the stress response and the endogenous pain modulation systems of people with fibromyalgia (FM). However, research on pain modulation ...under induced stress on FM patients is scarce and contradictory. The present study analyzes stress-induced changes in pain and intolerance thresholds among FM patients, examining the possible existence of differences linked to PTSD comorbidity and gaining insights into the role of cardiovascular reactivity. Eighteen women diagnosed with FM and comorbid PTSD (FM + PTSD), 18 women diagnosed with FM and no PTSD (FM-PTSD), and 38 healthy women (HC) were exposed to the Social Stress Test task. Pressure pain thresholds and intolerance thresholds were measured before and during stress induction, and after a recovery period, while systolic blood pressure and heart rate were simultaneously recorded. Overall, while pain thresholds decreased during stress and recovery for HC, no significant changes were observed for women with FM. The intolerance threshold decreased for HC during stress, but was maintained at basal level during recovery. FM-PTSD women exhibited a delayed response, with a drop at recovery. For FM + PTSD, tolerance levels remained unchanged. In addition, cardiovascular reactivity did not seem to explain these results. This performance of the pain modulation system seems to follow the same pattern of hypoactive responsiveness under stressors that has previously been observed in FM patients on the autonomic and neuroendocrine axes. Such a hypoactive pattern may involve a non-adaptive response that may contribute to the development and maintenance of chronic pain.
We present a new catalog of TeV gamma-ray sources using 1523 days of data from the High-Altitude Water Cherenkov (HAWC) Observatory. The catalog represents the most sensitive survey of the northern ...gamma-ray sky at energies above several TeV, with three times the exposure compared to the previous HAWC catalog, 2HWC. We report 65 sources detected at ≥5 significance, along with the positions and spectral fits for each source. The catalog contains eight sources that have no counterpart in the 2HWC catalog, but are within 1° of previously detected TeV emitters, and 20 sources that are more than 1° away from any previously detected TeV source. Of these 20 new sources, 14 have a potential counterpart in the fourth Fermi Large Area Telescope catalog of gamma-ray sources. We also explore potential associations of 3HWC sources with pulsars in the Australia Telescope National Facility (ATNF) pulsar catalog and supernova remnants in the Galactic supernova remnant catalog.
Abstract
Health care-related infections are frequent and among them surgical site infection (SSI) are the most frequent in hospitals. The objective was to evaluate the adequacy of antibiotic ...prophylaxis in patients undergoing neck surgery and its relationship with the incidence of surgical site infection (SSI). Prospective cohort study. The adequacy of antibiotic prophylaxis in patients undergoing neck surgery was evaluated. Antibiotic prophylaxis was considered adequate when it conformed to all items of the protocol (antibiotic used, time of administration, administration route, dose and duration). The cumulative incidence of SSI was calculated, and the relationship between SSI and antibiotic prophylaxis adequacy was determined using adjusted relative risk (RR). Antibiotic prophylaxis was administered in 63 patients and was adequate in 85.7% (95% CI 75.0–92.3) of them. The cumulative incidence of SSI was 6.4% (95% CI 3.4–11.8). There was no significant relationship between antibiotic prophylaxis inadequacy and the incidence of SSI (RR = 2.4, 95% CI 0.6–10.6). Adequacy of antibiotic prophylaxis was high and it did not affect the incidence of SSIs.
► The Mesoproterozoic Karagwe-Ankole Belt (KAB) has a Western (WD) and Eastern (ED) domain. ► WD and ED are underlain respectively by Eburnean-age and Archaean units. ► KAB reflects an ...intracontinental history under a transtensional regime with intermittent periods of sedimentation and magmatism. ► Detrital and volcanic rocks identify three distinct sedimentation periods: (c. 1.8Ga, c. 1.4Ga and c. 1.2Ga). ► KAB records compressional events at c. 1.0Ga (Rodinia amalgamation) and c. 0.55Ga (Gondwana amalgamation).
The Mesoproterozoic Kibara Belt (also Kibaran Belt or Kibarides in some references) of Central Africa was often portrayed as a continuous, c. 1500km long orogenic belt, trending NE to NNE from Katanga, Democratic Republic of Congo (DRC) in the south, up into SW Uganda in the north. Recently however, the Karagwe-Ankole Belt (KAB; formerly the NE Kibara Belt) has been redefined as the part north of a NW oriented Palaeoproterozoic basement high of the Ubende-Rusizi Belts, while the Kibara Belt (KIB) is now limited to the part south of this rise.
We present a lithostratigraphy for the KAB that takes into account two rheologically contrasting structural domains (Western and Eastern Domain); each of them being characterised by independent sedimentary sub basin(s) and depositional conditions: the ED with Archaean basement versus the WD with Palaeoproterozoic basement. We document new volcanic and detrital U–Pb SHRIMP zircon data which provide new constraints on the timing of deposition and on the detrital provenance of the sedimentary sequences in the KAB. We discuss the evolution of the KAB in a wider regional context, comparing it to other Mesoproterozoic units and with reference to the general geodynamic history of this part of the African continent in Proterozoic times.
The lithostratigraphic successions of the KAB are only valid respectively in the ED (Kagera Supergroup) or in the WD (Akanyaru Supergroup), with no correlations between them. Deposition of the Kagera Supergroup in the ED is bracketed between 1.78Ga and 1.37Ga and the deposits have to be considered an Eburnean-age “molasse”. Detrital components comprise material only of Archaean and Palaeoproterozoic age, consistent with derivation from nearby source regions. In the WD, deposition of the two lowermost groups of the Akanyaru Supergroup is bracketed between 1.42Ga and 1.37Ga. The large contribution of detrital Palaeoproterozoic components in the WD strengthens the view that this domain is underlain by Palaeoproterozoic basement and supports the concept that part of the Akanyaru Supergroup sediments consists of reworked Eburnean-aged molasse. In the WD of the Kivu-Maniema area (DRC), later sedimentation periods are documented at respectively 1222Ma and 710Ma. The KAB documents a long-lived period of intracratonic intermittent depositional activity (with periods of interruption of deposition, erosion and magmatism) showing a recurrent subsidence trend controlled by structural activity moving with time from E to W.
On a regional scale, we postulate that since 1.8Ga, following the amalgamation of Archaean and Palaeoproterozoic landmasses into a single coherent ‘proto-Congo Craton’, various long-lived shallow-water intracratonic basins (aulacogenes) developed. These basins underwent a comparable Mesoproterozoic geodynamic evolution, as shown not only in the sequences of the KAB and of the relatively close Kibara (KIB), Bangweulu Block and Northern Irumide Belts, but even in more distant sequences located in SW Angola and E Brazil.
The long-lived aulacogene history of the KAB within the proto-Congo Craton is interrupted only twice by short-lived compressional deformation reflecting far-field effects of global orogenic events, external to the proto-Congo Craton. The first event at 1.0Ga is related to Rodinia amalgamation. The second event at 550Ma results from Gondwana amalgamation and develops a N–S Pan African overprint in the KAB which has previously been underestimated or even overlooked. Three mineralisation provinces occurring in the KAB, respectively the Bushveld-type, the tin-coltan-wolfram and the gold province, can be ascribed successively to the 1375Ma Kibaran magmatic event, the 1.0Ga Rodinia and the 550Ma Gondwana amalgamation events.
Our results give additional weight to the recent redefinition of the KAB and the KIB, forming two distinct Belts respectively north and south of the Palaeoproterozoic basement high of the Ubende-Rusizi Belts, the more that within this basement rise local Mesoproterozoic strike-slip basins, with their own unique lithostratigraphic and geodynamic characteristics (e.g. Itiaso Group) are documented, which differ from those of the KAB or the KIB.
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