bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roles of the Essential Protein FtsA in Cell Growth and Division in Streptococcus pneumoniae
Authors: Mura Andrea , Fadda Daniela , Perez Amilcar J. , Danforth Madeline L. , Musu Daniela , Rico Ana Isabel , Krupka Marcin , Denapaite Dalia , Tsui Ho-Ching T. , Winkler Malcolm E. , Branny Pavel , Vicente Miguel , Margolin William , Massidda Orietta 
Published: November 2016

ABSTRACT

Streptococcus pneumoniae
is an ovoid-shaped Gram-positive bacterium that grows by carrying out peripheral and septal peptidoglycan (PG) synthesis, analogous to model bacilli, such as
Escherichia coli
and
Bacillus subtilis
. In the model bacilli, FtsZ and FtsA proteins assemble into a ring at midcell and are dedicated to septal PG synthesis but not peripheral PG synthesis; hence, inactivation of FtsZ or FtsA results in long filamentous cells unable to divide. Here, we demonstrate that FtsA and FtsZ colocalize at midcell in
S. pneumoniae
and that partial depletion of FtsA perturbs septum synthesis, resulting in elongated cells with multiple FtsZ rings that fail to complete septation. Unexpectedly, complete depletion of FtsA resulted in the delocalization of FtsZ rings and ultimately cell ballooning and lysis. In contrast, depletion or deletion of
gpsB
and
sepF
, which in
B. subtilis
are synthetically lethal with
ftsA
, resulted in enlarged and elongated cells with multiple FtsZ rings, with deletion of
sepF
mimicking partial depletion of FtsA. Notably, cell ballooning was not observed, consistent with later recruitment of these proteins to midcell after Z-ring assembly. The overproduction of FtsA stimulates septation and suppresses the cell division defects caused by the deletion of
sepF
and
gpsB
under some conditions, supporting the notion that FtsA shares overlapping functions with GpsB and SepF at later steps in the division process. Our results indicate that, in
S. pneumoniae
, both GpsB and SepF are involved in septal PG synthesis, whereas FtsA and FtsZ coordinate both peripheral and septal PG synthesis and are codependent for localization at midcell.

IMPORTANCE
Streptococcus pneumoniae
(pneumococcus) is a clinically important human pathogen for which more therapies against unexploited essential targets, like cell growth and division proteins, are needed. Pneumococcus is an ovoid-shaped Gram-positive bacterium with cell growth and division properties that have important distinctions from those of rod-shaped bacteria. Gaining insights into these processes can thus provide valuable information to develop novel antimicrobials. Whereas rods use distinctly localized protein machines at different cellular locations to synthesize peripheral and septal peptidoglycans, we present evidence that
S. pneumoniae
organizes these two machines at a single location in the middle of dividing cells. Here, we focus on the properties of the actin-like protein FtsA as an essential orchestrator of peripheral and septal growth in this bacterium.
Impact of a community-based package of interventions on child development in Zambia: a cluster-randomised controlled trial
Authors: Rockers Peter C , Fink Günther , Zanolini Arianna , Banda Bowen , Biemba Godfrey , Sullivan Cierra , Mutembo Simon , Silavwe Vichaels , Hamer Davidson H 
Published: November 2016

BackgroundCommunity-based programmes are a critical platform for improving child health and development. We tested the impact of a community-based early childhood intervention package in rural Zambia.MethodsWe conducted a non-blinded cluster randomised controlled trial in Southern Province, Zambia. 30 clusters of villages were matched based on population density and distance from the nearest health centre, and randomly assigned to intervention (15 clusters and 268 caregiver–child dyads) or control (15 clusters and 258 caregiver–child dyads). Caregivers were eligible if they had a child aged 6–12 months at baseline. In intervention clusters, health workers screened children for infections and malnutrition, and invited caregivers to attend fortnightly group meetings covering a nutrition and child development curriculum. 220 intervention and 215 control dyads were evaluated after 1 year. The primary outcomes were stunting and INTERGROWTH-21st neurodevelopmental assessment (NDA) scores. Weight-for-age and height-for-age z-scores based on WHO growth standards were also analysed. Secondary outcomes were child illness symptoms, dietary intake and caregiver–child interactions based on self-report. Impact was estimated using intention-to-treat analysis.ResultsThe intervention package was associated with a 0.12 SD increase in weight-for-age (95% CI −0.14 to 0.38), a 0.15 SD increase in height-for-age (95% CI −0.18 to 0.48) and a reduction in stunting (OR 0.68; 95% CI 0.36 to 1.28), whereas there was no measurable impact on NDA score. Children receiving the intervention package had fewer symptoms, a more diverse diet and more caregiver interactions.ConclusionsIn settings like Zambia, community-based early childhood programmes appear to be feasible and appreciated by caregivers, as evidenced by high rates of uptake. The intervention package improved parenting behaviours and had a small positive, though statistically insignificant, impact on child development. Given the short time frame of the project, larger developmental impact is likely if differential parenting behaviours persist.Trial registration numberNCT02234726; Results.
Independent association of glucocorticoids with damage accrual in SLE
Authors: Apostolopoulos Diane , Kandane-Rathnayake Rangi , Raghunath Sudha , Hoi Alberta , Nikpour Mandana , Morand Eric F 
Published: November 2016

ObjectivesTo determine factors associated with damage accrual in a prospective cohort of patients with SLE.MethodsPatients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual.ResultsA total of 162 patients were observed over a median (IQR) 3.6 (2.0–4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non-glucocorticoid related domains of the SDI.ConclusionsGlucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.
Interferon (IFN)-λ is a potential mediator in lupus nephritis
Authors: Zickert Agneta , Oke Vilija , Parodis Ioannis , Svenungsson Elisabet , Sundström Yvonne , Gunnarsson Iva 
Published: November 2016

ObjectivesInterferon (IFN)-α is thought to be central in the pathogenesis for lupus nephritis (LN) and recent studies also indicate a role for IFNλ. Little is known about these cytokines in the context of treatment response. We studied levels of IFNα and IFNλ in patients with LN in association with clinical and histological response (HR) to treatment.MethodsFifty-six patients with active LN were included. Renal biopsies were performed at baseline and after immunosuppressive therapy. Serum levels of IFNα and IFNλ were analysed at both biopsy occasions and in 163 controls. The biopsies were evaluated according to the International Society of Nephrology/Renal Pathology Society classification. Clinical response was defined according to recent definitions. HR was defined as class I, II or III/IV-C on repeat biopsies. The expression of IFNλ in renal tissue was assessed by immunohistochemistry.ResultsAt baseline, serum levels of both IFNα and IFNλ were higher in patients versus controls (p=0.01 and p=0.03, respectively). There was no correlation between IFNα and IFNλ. Overall, IFNα decreased after treatment (p=0.003) but IFNλ remained unchanged. However in patients with HR, IFNλ decreased (p=0.01). The highest levels of IFNλ were seen in patients with poor HR. Immunostaining of renal tissue revealed expression of IFNλ, particularly in crescent formations, inflammatory infiltrates and tubular cells.ConclusionsThe study supports a role for IFNλ in LN, both in circulation and at a tissue level. Levels of IFNα and IFNλ did not correlate and were affected differently by immunosuppression, indicating that they are differently involved in subgroups of LN. Persistent increased levels of IFNλ were associated to an unfavourable HR to treatment.
Effective radium-226 concentration in rocks, soils, plants and bones
Authors: Perrier Frédéric , Girault Frédéric , Bouquerel Hélène 
Published: November 2016

Abstract

Effective radium-226 concentration,
EC
Ra
, is the product of radium activity concentration,
C
Ra
, multiplied by the emanation coefficient,
E
, which is probability of producing a radon-222 atom in the pore spaces. It is measured by accumulation experiments in the laboratory, achieved routinely for a sample mass >50 g using scintillation flasks to measure the radon concentration. We report on 3370
EC
Ra
values obtained from more than 11 800 such experiments. Rocks (
n
=1351) have a mean
EC
Ra
value of 1.9±0.1 Bq kg
−1
(90% of data in the range 0.11–35 Bq kg
−1
), while soils (
n
=1524) have a mean
EC
Ra
value of 7.5±0.2 Bq kg
−1
(90% of data between 1.4 and 28 Bq kg
−1
). Using this large dataset, we establish that the spatial structure of
EC
Ra
is meaningful in geology or sedimentology. For plants (
n
=85),
EC
Ra
is generally <1 Bq kg
−1
, but values of larger than 10 Bq kg
−1
are also observed. Dedicated experiments were performed to measure emanation,
E
, in plants, and we obtained values of 0.86±0.04 compared with 0.24±0.04 for sands, which leads to estimates of the radium-226 soil-to-plant transfer ratio. For most measured animal bones (
n
=26),
EC
Ra
is >1 Bq kg
−1
. Therefore,
EC
Ra
appears essential for radon modelling, health hazard assessment and also in evaluating the transfer of radium-226 to the biosphere.
Intraspinal microstimulation and diaphragm activation after cervical spinal cord injury
Authors: Mercier L. M. , Gonzalez-Rothi E. J. , Streeter K. A. , Posgai S. S. , Poirier A. S. , Fuller D. D. , Reier P. J. , Baekey D. M. 
Published: November 2016

Intraspinal microstimulation (ISMS) using implanted electrodes can evoke locomotor movements after spinal cord injury (SCI) but has not been explored in the context of respiratory motor output. An advantage over epidural and direct muscle stimulation is the potential of ISMS to selectively stimulate components of the spinal respiratory network. The present study tested the hypothesis that medullary respiratory activity could be used to trigger midcervical ISMS and diaphragm motor unit activation in rats with cervical SCI. Studies were conducted after acute (hours) and subacute (5–21 days) C2 hemisection (C2Hx) injury in adult rats. Inspiratory bursting in the genioglossus (tongue) muscle was used to trigger a 250-ms train stimulus (100 Hz, 100–200 μA) to the ventral C4 spinal cord, targeting the phrenic motor nucleus. After both acute and subacute injury, genioglossus EMG activity effectively triggered ISMS and activated diaphragm motor units during the inspiratory phase. The ISMS paradigm also evoked short-term potentiation of spontaneous inspiratory activity in the previously paralyzed hemidiaphragm (i.e., bursting persisting beyond the stimulus period) in ∼70% of the C2Hx animals. We conclude that medullary inspiratory output can be used to trigger cervical ISMS and diaphragm activity after SCI. Further refinement of this method may enable “closed-loop-like” ISMS approaches to sustain ventilation after severe SCI. NEW & NOTEWORTHY We examined the feasibility of using intraspinal microstimulation (ISMS) of the cervical spinal cord to evoke diaphragm activity ipsilateral to acute and subacute hemisection of the upper cervical spinal cord of the rat. This proof-of-concept study demonstrated the efficacy of diaphragm activation, using an upper airway respiratory EMG signal to trigger ISMS at the level of the ipsilesional phrenic nucleus during acute and advanced postinjury intervals.
Transcriptional Selectivity of Epigenetic Therapy in Cancer
Authors: Sato Takahiro , Cesaroni Matteo , Chung Woonbok , Panjarian Shoghag , Tran Anthony , Madzo Jozef , Okamoto Yasuyuki , Zhang Hanghang , Chen Xiaowei , Jelinek Jaroslav , Issa Jean-Pierre J. 
Published: November 2016

Abstract
A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation, and ChIP-seq analyses the epigenetic response of a set of colon, breast, and leukemia cancer cell lines to small-molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models used, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA-methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity. Cancer Res; 77(2); 470–81. ©2016 AACR.
H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences
Authors: Drosten Matthias , Simón-Carrasco Lucía , Hernández-Porras Isabel , Lechuga Carmen G. , Blasco María T. , Jacob Harrys K.C. , Fabbiano Salvatore , Potenza Nicoletta , Bustelo Xosé R. , Guerra Carmen , Barbacid Mariano 
Published: November 2016

AbstractGenetic studies in mice have provided evidence that H-Ras and K-Ras proteins are bioequivalent. However, human tumors display marked differences in the association of RAS oncogenes with tumor type. Thus, to further assess the bioequivalence of oncogenic H-Ras and K-Ras, we replaced the coding region of the murine K-Ras locus with H-RasG12V oncogene sequences. Germline expression of H-RasG12V or K-RasG12V from the K-Ras locus resulted in embryonic lethality. However, expression of these genes in adult mice led to different tumor phenotypes. Whereas H-RasG12V elicited papillomas and hematopoietic tumors, K-RasG12V induced lung tumors and gastric lesions. Pulmonary expression of H-RasG12V created a senescence-like state caused by excessive MAPK signaling. Likewise, H-RasG12V but not K-RasG12V induced senescence in mouse embryonic fibroblasts. Label-free quantitative analysis revealed that minor differences in H-RasG12V expression levels led to drastically different biological outputs, suggesting that subtle differences in MAPK signaling confer nonequivalent functions that influence tumor spectra induced by RAS oncoproteins. Cancer Res; 77(3); 707–18. ©2016 AACR.
Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer
Authors: Chen Ke , Xiao Haibing , Zeng Jin , Yu Gan , Zhou Hui , Huang Chunhua , Yao Weimin , Xiao Wei , Hu Junhui , Guan Wei , Wu Lily , Huang Jiaoti , Huang Qihong , Xu Hua , Ye Zhangqun 
Published: November 2016

Abstract

Purpose:
Deregulation or mutation of the EZH2 gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). Although several splice variants of EZH2 have been identified, little is known about how EZH2 splicing is regulated or the contribution of alternative splicing to its protumorigenic functions.

Experimental Design:
We conducted RT-PCR, Western blot analysis, and IHC techniques to examine EZH2 and its alternative splicing transcript expression in renal cancer tissue and renal cancer cell lines. Proliferation, migration, clonogenicity, and tumorigenicity of renal cancer cells either exhibiting knockdown of EZH2 or its splicing factor SF3B3 were assessed by CCK8, Transwell assay, and murine xenograft experiments.

Results:
We found that the inclusion of alternative EZH2 exon 14 was significantly increased in ccRCC samples and renal cancer cell lines. In ccRCC lines, enforced expression of EZH2Δ14 inhibited, and EZH2 promoted, cell growth, migration, proliferation, and tumorigenicity in a xenograft model. Mechanistic studies demonstrated that EZH2Δ14 isoform functions as a dominant-negative inhibitor of full-length EZH2. Coexpression of EZH2Δ14 variant with full-length EZH2 not only abrogated DAB2IP and HOXA9 suppression but also inhibited EZH2-driven tumorigenesis. Strikingly, the splicing factor SF3B3 stimulates inclusion of exon14 and has pro-proliferative activity. Importantly, the upregulation of SF3B3 expression observed in clinical ccRCC samples parallels the increased inclusion of EZH2 exon14, and the SF3B3 level is associated with higher tumor stage and poor overall survival.

Conclusions:
These results suggest SF3B3 as a key regulator of EZH2 pre-mRNA splicing and SF3B3 may represent a novel prognostic factor and potential therapeutic target in ccRCC.
СУЧАСНІ ВІТЧИЗНЯНІ ЗАСАДИ НАДАННЯ МЕДИЧНОЇ ДОПОМОГИ ДІТЯМ ПЕРШИХ РОКІВ ЖИТТЯ ІЗ ПОРУШЕННЯМ ЗОРОВИХ ФУНКЦІЙ
Authors: Rykov S. O. , Barynov Yu. V. 
Published: November 2016

У публікації проведено науковий аналіз описаних у вітчизняній та зарубіжній літературі досліджень щодо організації надання медичної допомоги дітям перших років життя з порушенням зорових функційю. А також етапи, зміни та нововведення у зв’язку із зростаючими тенденціями кількості випадків виникнення сліпоти й слабобачення в ранньому дитячому віці як у світі та у країнах Європейського регіону, так і в Україні зокрема. Проаналізовано особливості організації надання лікувально-профілактичної допомоги дітям із порушеннями зорових функцій у ранньому віці (з перших років життя) як первинної медичної допомоги в амбулаторно-поліклінічних умовах, так і в стаціонарах з наданням вторинної медичної та третинної високоспеціалізованої медичної допомоги. Обґрунтовано доцільність міжсекторального підходу із залученням батьків, родини, в якій виховується дитина з порушенням зорових функцій в ранньому віці, медичного персоналу, фахівців освіти, тифлопедагогів у вирішенні складної медико-соціальної проблеми організації процесу лікування, реабілітації, виховання та розвитку дітей із порушеннями зорових функцій.
RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations
Authors: Shenkar Robert , Shi Changbin , Austin Cecilia , Moore Thomas , Lightle Rhonda , Cao Ying , Zhang Lingjiao , Wu Meijing , Zeineddine Hussein A. , Girard Romuald , McDonald David A. , Rorrer Autumn , Gallione Carol , Pytel Peter , Liao James K. , Marchuk Douglas A. , Awad Issam A. 
Published: November 2016

Background and Purpose—
We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease.

Methods—

Two heterozygous murine models,
Ccm1
+/−
Msh2
−
/−
and
Ccm2
+/−
Trp53
−/−
, were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity.

Results—

Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in
Ccm1
+/−
Msh2
−/−
mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in
Ccm1
+/−
Msh2
−/−
mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of
Ccm1
+/−
Msh2
−/−
mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in
Ccm1
+/−
Msh2
−/−
mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in
Ccm2
+/−
Trp53
−/−
mice alone, and Fasudil benefit seemed limited to males.

Conclusions—
ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.
Intercomparisons of Rainfall Estimates from TRMM and GPM Multisatellite Products over the Upper Mekong River Basin
Authors: He Zhihua , Yang Long , Tian Fuqiang , Ni Guangheng , Hou Aizhong , Lu Hui 
Published: November 2016

Abstract
The aim of this study is to evaluate the accuracy of daily rainfall estimates based on the GPM level-3 final product derived from the IMERG algorithm (abbreviated as IMERG) and TRMM 3B42, version 7 (abbreviated as 3B42), in the upper Mekong River basin, a mountainous region in southwestern China. High-density rain gauges provide exceptional resources for ground validation of satellite rainfall estimates over this region. The performance of the two satellite rainfall products is evaluated during two rainy seasons (May–October) over the period 2014–15, as well as their applications in hydrological simulations. Results indicate that 1) IMERG systematically reduces the bias value in rainfall estimates at the gridbox scale and presents a greater ability to capture rainfall variability at the local domain scale compared with 3B42; 2) IMERG improves the ability to capture rain events with moderate intensities and presents higher capability in detecting occurrences of extreme rain events, but significantly overestimates the amounts of these extreme events; and 3) IMERG generally produces comparable daily streamflow simulations to 3B42 and tends to outperform 3B42 in driving hydrological simulations when calibrating model parameters using each rainfall input. This study provides an early evaluation of the IMERG rainfall product over a mountainous region. The findings indicate the potential of the IMERG product in overestimating extreme rain events, which could serve as the basis for further improvement of IMERG rainfall retrieval algorithms. The hydrological evaluations described here could shed light on the emerging application of retrospectively generated IMERG products back to the TRMM era.