The complete genome sequence of Geobacter sulfurreducens, a δ-proteobacterium, reveals unsuspected capabilities, including evidence of aerobic metabolism, one-carbon and complex carbon metabolism, ...motility, and chemotactic behavior. These characteristics, coupled with the possession of many two-component sensors and many c-type cytochromes, reveal an ability to create alternative, redundant, electron transport networks and offer insights into the process of metal ion reduction in subsurface environments. As well as playing roles in the global cycling of metals and carbon, this organism clearly has the potential for use in bioremediation of radioactive metals and in the generation of electricity.
Bacteria residing in the guts of pollinating insects play a key role in nutrient acquisition, digestion, and resistance to pests and diseases. Imbalances in microbial flora in response to ...environmental change and stress can therefore impact insect health and resilience. This study is aimed at defining the core gut microbiome of the Australian native stingless bee,
Tetragonula carbonaria
, and exploring the impact of colony transplantation on gut health. The gut microbiomes of nine forager bees from natural (log) and manufactured (box) hives were examined via 16S rRNA gene amplicon sequencing. Some differences were observed at the ASV level between the microbiomes of log and box hive bees. However, a core microbiome, dominated by
Lactobacillus
spp., unclassified Acetobacteraceae spp., and
Bombella
spp., was maintained. Further, the inferred functional potential of the microbiomes was consistent across all individuals. This study highlights that although hive transplantation has an impact on the overall diversity of stingless bee gut microbiomes, it is unlikely to have a significant negative impact on the overall health and resilience of the colony.
Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) ...alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach.
We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%).
PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
J. M. Quayle, M. T. Nelson and N. B. Standen
Department of Cell Physiology and Pharmacology, University of Leicester, United Kingdom.
The properties and roles of ATP-sensitive (KATP) and inwardly ...rectifying
(KIR) potassium channels are reviewed. Potassium channels regulate the
membrane potential of smooth muscle, which controls calcium entry through
voltage-dependent calcium channels, and thereby contractility through
changes in intracellular calcium. The KATP channel is likely to be composed
of members of the inward rectifier channel gene family (Kir6) and
sulfonylurea receptor proteins. The KIR channels do not appear to be as
widely distributed as KATP channels in smooth muscle and may provide a
mechanism by which changes in extracellular K+ can alter smooth muscle
membrane potential, and thereby arterial diameter. The KATP channels
contribute to the resting membrane conductance of some types of smooth
muscle and can open under situations of metabolic compromise. The KATP
channels are targets of a wide variety of vasodilators and constrictors,
which act, respectively, through adenosine 3',5'-cyclic
monophosphate/protein kinase A and protein kinase C. The KATP channels are
also activated by a number of synthetic vasodilators (e.g., diazoxide and
pinacidil) and are inhibited by the oral hypoglycemic sulfonylurea drugs
(e.g., glibenclamide). Together, KATP and KIR channels are important
regulators of smooth muscle function and represent important therapeutic
targets.
Low cardiac output syndrome (LCOS), affecting up to 25% of neonates and young children after cardiac surgery, contributes to postoperative morbidity and mortality. This study evaluated the efficacy ...and safety of prophylactic milrinone in pediatric patients at high risk for developing LCOS.
The study was a double-blind, placebo-controlled trial with 3 parallel groups (low dose, 25- microg/kg bolus over 60 minutes followed by a 0.25- microg/kg per min infusion for 35 hours; high dose, 75- microg/kg bolus followed by a 0.75- microg/kg per min infusion for 35 hours; or placebo). The composite end point of death or the development of LCOS was evaluated at 36 hours and up to 30 days after randomization. Among 238 treated patients, 25.9%, 17.5%, and 11.7% in the placebo, low-dose milrinone, and high-dose milrinone groups, respectively, developed LCOS in the first 36 hours after surgery. High-dose milrinone significantly reduced the risk the development of LCOS compared with placebo, with a relative risk reduction of 55% (P=0.023) in 238 treated patients and 64% (P=0.007) in 227 patients without major protocol violations. There were 2 deaths, both after infusion of study drug. The use of high-dose milrinone reduced the risk of the LCOS through the final visit by 48% (P=0.049).
The use of high-dose milrinone after pediatric congenital heart surgery reduces the risk of LCOS.
The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy ...number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.
This paper aims to (i) identify differences in measures of hip morphology between four racial groups using anteroposterior (AP) hip x-rays, and (ii) examine whether these differences vary by sex.
912 ...hip x-rays (456 individuals) from four racial groups (European Caucasians, American Caucasians, African Americans and Chinese) were obtained. Males and females (45–75 years) with no radiographic hip OA (Kellgren and Lawrence < Grade 2 or Croft < Grade 1) were included. Eleven features of hip joint morphology were analysed. Linear regression with generalised estimating equations (GEE) was used to determine race and sex differences in hip morphology. Post-hoc Bonferroni procedure was used to adjust for multiple comparisons.
The final analysis included 875 hips. Chinese hips showed significant differences for the majority of measures to other racial groups. Chinese were characterised by more shallow and narrow acetabular sockets, reduced femoral head coverage, smaller femoral head diameter, and a lesser angle of alignment between the femoral neck and shaft. Variation was found between other racial groups, but with few statistically significant differences. The average of lateral centre edge angle, minimum neck width and neck length differed between race and sex (p-value for interaction < 0.05).
Significant differences were found in measures of morphology between Chinese hips compared to African Americans or Caucasian groups; these may explain variation in hip OA prevalence rates between these groups and the lower rate of hip OA in Chinese. Sex differences were also identified, which may further explain male-female prevalence differences for OA.
The 1,995,275-bp genome of Coxiella burnetii, Nine Mile phase I RSA493, a highly virulent zoonotic pathogen and category B bioterrorism agent, was sequenced by the random shotgun method. This ...bacterium is an obligate intracellular acidophile that is highly adapted for life within the eukaryotic phagolysosome. Genome analysis revealed many genes with potential roles in adhesion, invasion, intracellular trafficking, host-cell modulation, and detoxification. A previously uncharacterized 13-member family of ankyrin repeat-containing proteins is implicated in the pathogenesis of this organism. Although the lifestyle and parasitic strategies of C. burnetii resemble that of Rickettsiae and Chlamydiae, their genome architectures differ considerably in terms of presence of mobile elements, extent of genome reduction, metabolic capabilities, and transporter profiles. The presence of 83 pseudogenes displays an ongoing process of gene degradation. Unlike other obligate intracellular bacteria, 32 insertion sequences are found dispersed in the chromosome, indicating some plasticity in the C. burnetii genome. These analyses suggest that the obligate intracellular lifestyle of C. burnetii may be a relatively recent innovation.
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