Aims
To analyse the function of a putative lantibiotic gene cluster of Paenibacillus polymyxa E681 and to characterize its product, paenilan.
Methods and Results
Comparative analysis of the ...lantibiotic gene cluster of E681 revealed that the cluster, consisting of 11 open reading frames, is involved in the biosynthesis of a class I lantibiotic. The pnlA gene encoding the prepeptide PnlA was identified and P. polymyxa strain EPT14 producing only paenilan was constructed by knockout of the other five antibiotic biosynthetic gene clusters of E681. Paenilan was purified from EPT14 culture by solvent partitioning, ODS silica gel chromatography and reversed‐phase preparative HPLC. The molecular mass (2510·10 Da) and structure of paenilan analysed by Nanoelectrospray ionization mass spectrometry (MS) and MS/MS showed that paenilan is a novel class I lantibiotic. Paenilan exhibited antimicrobial activity against Gram‐positive bacteria such as Bacillus cereus, Micrococcus luteus and Paenibacillus durus. The paenilan gene is well‐conserved in different Paenibacillus sp. isolated from globally distant places.
Conclusions
The lantibiotic gene cluster of P. polymyxa E681 was analysed and its product, a novel and useful lantibiotic named paenilan that inhibits the growth of some Gram‐positive bacteria, was characterized.
Significance and Impact of the Study
Paenibacillus species are a good source of new lantibiotics, and the conservation of the paenilan gene among Paenibacillus sp. implies paenilan has an important function(s) for their survival.
Prediction of the
(IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our ...aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine
-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.
Ninety-three patients with World Health Organization grade II gliomas with known
mutation and 1p/19q-codeletion status (18
wild-type, 45
mutant and no 1p/19q codeletion, 30
mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the
-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for
wild-type tumors and 1p/19q-codeletion status in
-mutant subgroups were evaluated using the least absolute shrinkage and selection operator.
Various histogram and texture parameters differed significantly according to
-mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an
wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in
-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807.
Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the
-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.
We present results from an analysis of all data taken by the bicep2/Keck CMB polarization experiments up to and including the 2015 observing season. This includes the first Keck Array observations at ...220 GHz and additional observations at 95 and 150 GHz. The Q and U maps reach depths of 5.2, 2.9, and 26 μK_{CMB} arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈400 square degrees. The 220 GHz maps achieve a signal to noise on polarized dust emission approximately equal to that of Planck at 353 GHz. We take auto and cross spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz. We evaluate the joint likelihood of the spectra versus a multicomponent model of lensed-ΛCDM+r+dust+synchrotron+noise. The foreground model has seven parameters, and we impose priors on some of these using external information from Planck and WMAP derived from larger regions of sky. The model is shown to be an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r_{0.05}<0.07 at 95% confidence, which tightens to r_{0.05}<0.06 in conjunction with Planck temperature measurements and other data. The lensing signal is detected at 8.8σ significance. Running a maximum likelihood search on simulations we obtain unbiased results and find that σ(r)=0.020. These are the strongest constraints to date on primordial gravitational waves.
Aims/hypothesis
FTO
harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for
FTO
in obesity risk in Asians, its association with type 2 ...diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the
FTO
locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods
All studies published on the association between
FTO
-rs9939609 (or proxy
r
2
> 0.98) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results
The
FTO
-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (
p
= 9.0 × 10
−19
), overweight by 1.13-fold/allele (
p
= 1.0 × 10
−11
) and type 2 diabetes by 1.15-fold/allele (
p
= 5.5 × 10
−8
). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele,
p
= 6.6 × 10
−5
). The
FTO
-rs9939609 minor allele increased BMI by 0.26 kg/m
2
per allele (
p
= 2.8 × 10
−17
), WHR by 0.003/allele (
p
= 1.2 × 10
−6
), and body fat percentage by 0.31%/allele (
p
= 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of
FTO
variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation
FTO
is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore,
FTO
is also associated with type 2 diabetes independently of BMI.
A new model for the bending of a Bernoulli-Euler beam is developed using a modified couple stress theory. A variational formulation based on the principle of minimum total potential energy is ...employed. The new model contains an internal material length scale parameter and can capture the size effect, unlike the classical Bernoulli-Euler beam model. The former reduces to the latter in the absence of the material length scale parameter. As a direct application of the new model, a cantilever beam problem is solved. It is found that the bending rigidity of the cantilever beam predicted by the newly developed model is larger than that predicted by the classical beam model. The difference between the deflections predicted by the two models is very significant when the beam thickness is small, but is diminishing with the increase of the beam thickness. A comparison shows that the predicted size effect agrees fairly well with that observed experimentally.
Background and purpose
The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion‐weighted magnetic ...resonance imaging (DWI‐MRI) and whether ischaemic core size affects this rate remain to be investigated.
Methods
This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI‐MRI that was categorized into three groups: small Diffusion‐Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI‐ASPECTS) (8–10), moderate (5–7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0–2). The interaction between onset‐to‐groin puncture time (OTP) and DWI‐ASPECTS categories regarding functional outcomes was investigated.
Results
Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI‐ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction = 0.06). Every 60‐min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity = 0.15).
Conclusions
Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI‐ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.
This study investigated the clinical characteristics of diabetic ketoacidosis (DKA) and compared the DKA characteristics between patients treated with and without SGLT2 inhibitors.
Data were ...collected from patients aged ≥ 18 years admitted for DKA at nine centres in Korea between September 2014 and April 2017. The electronic medical records of these subjects were retrospectively reviewed. Based on their history of medications taken before admission, subjects were classified as either users or non-users of SGLT2 inhibitors and their clinical characteristics of DKA were compared.
During the study, the main subtype of DKA episodes (n = 523) was identified as type 2 diabetes (51%). Average hospitalization duration was 11 days, and average intensive care unit (ICU) time was 2.5 days. The in-hospital mortality rate was 3%, but no users of SGLT2 inhibitors died during DKA treatment. In patients taking SGLT2 inhibitors (n = 15), DKA manifested at 124 days, on average, after starting the inhibitors (range: 7–380 days). Also, SGLT2 inhibitors users had significantly lower plasma glucose levels (413 mg/dL) compared with non-users (554 mg/dL), and longer ICU stays (4 vs. 2 days; P = 0.019).
In this report of recent data on the clinical features of DKA in Korea, patients using SGLT2 inhibitors needed longer treatment in ICUs compared with non-users and had lower levels of blood glucose, whereas DKA associated with SGLT2 inhibitors was rare.
Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production ...and promotes tumour growth. Sirtuins are NAD(+)-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells.
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population ...aging. The primary feature of AD is progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment can substantially improve quality of life. Donepezil is an acetylcholinesterase inhibitor approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once‐daily sustained‐release 23‐mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose–response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild‐to‐moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability. This review presents an overview of the evidence for donepezil across the spectrum of AD, with a focus on dose optimization for disease progression.
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