bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of a Lay Counselor–Led Combination Intervention for Retention of Mothers and Infants in HIV Care: A Randomized Trial in Kenya
Authors: Fayorsey Ruby N. , Wang Chunhui , Chege Duncan , Reidy William , Syengo Masila , Owino Samuel O. , Koech Emily , Sirengo Martin , Hawken Mark P. , Abrams Elaine J. 
Published: November 2018

Background:
Retention of mothers and infants across the prevention of mother-to-child HIV transmission (PMTCT) continuum remains challenging. We assessed the effectiveness of a lay worker administered combination intervention compared with the standard of care (SOC) on mother–infant attrition.

Methods:
HIV-positive pregnant women starting antenatal care at 10 facilities in western Kenya were randomized using simple randomization to receive individualized health education, retention/adherence support, appointment reminders, and missed visit tracking vs. routine care per guidelines. The primary endpoint was attrition of mother–infant pairs at 6 months postpartum. Attrition was defined as the proportion of mother–infant pairs not retained in the clinic at 6 months postpartum because of mother or infant death or lost to follow-up. Intent-to-treat analysis was used to assess the difference in attrition. This trial is registered with ClinicalTrials.gov; NCT01962220.

Results:
From September 2013 to June 2014, 361 HIV-positive pregnant women were screened, and 340 were randomized to the intervention (n = 170) or SOC (n = 170). Median age at enrollment was 26 years (interquartile range 22–30); median gestational age was 24 weeks (interquartile range 17–28). Overall attrition of mother–infant pairs was 23.5% at 6 months postpartum. Attrition was significantly lower in the intervention arm compared with SOC (18.8% vs. 28.2%, relative risk (RR) = 0.67, 95% confidence interval: 0.45 to 0.99, P = 0.04). Overall, the proportion of mothers who were retained and virally suppressed (<1000 copies/mL) at 6 months postpartum was 54.4%, with no difference between study arms.

Conclusions:
Provision of a combination intervention by lay counselors can decrease attrition along the PMTCT cascade in low-resource settings.
Outcomes for popliteal artery injury repair after discharge: A large-scale population-based analysis
Authors: Butler William J. , Calvo Richard Y. , Sise Michael J. , Bowie Jason M. , Wessels Lyndsey E. , Bansal Vishal , Beth Sise C. 
Published: November 2018

BACKGROUND
Although short-term outcomes for popliteal artery injury after endovascular versus open repair appear similar, studies on outcomes after discharge are limited. We evaluated popliteal artery injury repair in a population-based data set. We hypothesized that postdischarge outcomes for open repair are superior to endovascular repair.

METHODS
Patients with popliteal artery injury were identified in the California Office of Statewide Health Planning and Development 2007–2014 discharge database. Popliteal artery injury and other lower-extremity injuries were identified using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Procedure codes were evaluated to identify open repair, endovascular repair, fasciotomy, and amputation. Primary outcomes were mortality or amputation. The association between repair method and each outcome was evaluated with logistic regression. Postdischarge amputation and all-cause mortality were evaluated using survival analysis.

RESULTS
Among 769 patients with popliteal artery injury, open repair occurred in 456 (59.3%), endovascular repair in 37 (4.3%), combined endovascular and open in 18 (2.3%), and nonoperative management in 258 (33.6%). Fasciotomy was performed more frequently in open than endovascular repair (p = 0.001) during index admission. Amputation rate was also increased in open repair, but this was not significant (p = 0.196). Arterial thromboembolus during index admission was more likely after endovascular or combined endovascular and open compared with open (24.3%, 55.6%, 16.7%, respectively, p < 0.001). Patients requiring both endovascular and open were more likely to undergo amputation postdischarge (hazard ratio, 4.11; 95% confidence interval, 1.16–14.53). Patients undergoing endovascular repair were more likely to die postdischarge (hazard ratio, 4.43; 95% confidence interval, 1.06–18.56) compared with patients who had open repair (median, 98.5 days postdischarge).

CONCLUSIONS
In a large cohort with popliteal artery injury, open repair was associated with lower rates of index admission arterial thromboembolus as well as postdischarge amputation and all-cause mortality. We recommend conducting a prospective multicenter study to examine the appropriate use of endovascular repair for this injury.

LEVEL OF EVIDENCE
Therapeutic, level IV.
Isoform 6–selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock
Authors: Nikolian Vahagn C. , Dennahy Isabel S. , Weykamp Michael , Williams Aaron M. , Bhatti Umar F. , Eidy Hassan , Ghandour Mohamed H. , Chtraklin Kiril , Li Yongqing , Alam Hasan B. 
Published: November 2018

BACKGROUND
Nonselective histone deacetylase (pan-HDAC) inhibitors, such as valproic acid (VPA), have demonstrated neuroprotective properties in trauma models. However, isoform-specific HDAC inhibitors may provide opportunity for more effective drug administration with fewer adverse effects. We investigated HDAC6 inhibition with ACY-1083 in an in vitro and an in vivo large animal model of injury.

METHODS
Mouse hippocampal cells were subjected to oxygen-glucose deprivation (0% O2, glucose-free and serum-free medium, 18 hours) and reoxygenation (21% O2, normal culture media, 4 hours) with/without VPA (4 mmol/L) or ACY-1083 (30 nmol/L, 300 nmol/L). Cell viability was measured by methylthiazolyl tetrazolium assay. Expression of hypoxia-inducible factor-1α, heat shock protein 70, and effectors in the phosphoinositide-3 kinase/mammalian target of rapamycin pathway were measured by Western blot analysis. Additionally, swine were subjected to combined traumatic brain injury and hemorrhagic shock and randomized to three treatment groups (n = 5/group): (i) normal saline (NS; 3× hemorrhage volume); (ii) NS + VPA (NS; 3× hemorrhage volume, VPA; 150 mg/kg), and (iii) NS + ACY-1083 (NS; 3× hemorrhage volume, ACY-1083; 30 mg/kg). After 6 hours, brain tissue was harvested to assess lesion size and brain swelling.

RESULTS
Significant improvement in cell viability was seen with both HDAC inhibitors in the in vitro study. ACY-1083 suppressed hypoxia-inducible factor-1α expression and up-regulated phosphorylated mammalian target of rapamycin and heat shock protein 70 in a dose-dependent manner. Lesion size and brain swelling in animals treated with pharmacologic agents (VPA and ACY-1083) were both smaller than in the NS group. No differences were observed between the VPA and ACY-1083 treatment groups.

CONCLUSIONS
In conclusion, selective inhibition of HDAC6 is as neuroprotective as nonselective HDAC inhibition in large animal models of traumatic brain injury and hemorrhagic shock.
NF-κB mediates early blood-brain barrier disruption in a rat model of traumatic shock
Authors: Deng Zhe , Liu Dehong , Fu Tingping , Jiang Wenqiang , Qiu Min , Xiao Xiaoyong , Xu Ji , Feng Yongwen , Li Danhui , Zeng Hongke 
Published: November 2018

BACKGROUND
Blood-brain barrier (BBB) disruption is associated with a large number of central nervous system and systemic disorders. The aim of the present study was to investigate the dynamic change of BBB changes during traumatic shock and resuscitation as well as the mechanisms involved.

METHODS
The experiments were performed on male Sprague-Dawley rats anesthetized with pentobarbital sodium. To produce traumatic shock, the rats were subjected to bilateral femoral traumatic fracture and blood withdrawal from the femoral artery to decrease mean arterial pressure (MAP) to 35 mm Hg. Hypovolemic status (at a MAP of 35 to 40 mm Hg) was sustained for 1 hour followed by fluid resuscitation with shed blood and 20 mL/kg of lactated Ringer's solution.

RESULTS
The rats were sacrificed at 1 hour, 2 hours, or 6 hours after fluid resuscitation. Blood-brain barrier permeability studies showed that traumatic shock significantly increased brain water contents and sodium fluorescein leakage, which was aggravated by fluid resuscitation. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses revealed that Na+-K+-Cl− cotransporter-1 and vascular endothelial growth factor (VEGF) expression were upregulated in cortical brain tissue of traumatic shock rats, and this change was accompanied by downregulation of occludin and claudin-5. Traumatic shock also significantly increased the protein levels of NF-κB-p65 subunit. Of note, administration of NF-κB inhibitor PDTC effectively attenuated augmentation of the above changes.

CONCLUSION
Our results suggest that traumatic shock is associated with early BBB disruption, and inhibition of NF-κB may be an effective therapeutic strategy in protecting the BBB under traumatic shock conditions.
FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain
Authors: Gingrich Ellen C. , Shepard Katherine A. , Mitchell Molly E. , Sawicka Kirsty , Darnell Jennifer C. , Akins Michael R. 
Published: November 2018

AbstractThe localization and translation of mRNAs is controlled by a diverse array of ribonucleoprotein particles (RNPs), multimolecular complexes containing mRNAs and RNA binding proteins. Fragile X granules (FXGs) are a family of RNPs that exemplify the diversity of RNA granules in the mammalian nervous system. FXGs are found in a conserved subset of neurons, where they localize exclusively to the axonal compartment. Notably, the specific RNA binding proteins and mRNAs found in FXGs depend on brain circuit and neuron type, with all forebrain FXGs containing Fragile X mental retardation protein (FMRP), the protein mutated in the human autism-related disorder Fragile X syndrome. FMRP negatively regulates FXG abundance but is not required for their association with ribosomes or mRNA. To better understand the circuit-dependent mechanisms whereby FMRP associates with and regulates FXGs, we asked how a disease-causing point mutation, I304N, in the KH2 RNA binding domain of FMRP affects these granules in two brain regions – cortex and hippocampus. We found that FMRPI304N had a reduced association with FXGs, as it was absent from approximately half of FXGs in cortex and nearly all FXGs in hippocampus. FXG abundance correlated with the number of FMRP-containing FXGs, suggesting that FMRP regulates FXG abundance by KH2-independent mechanisms that occur locally within the granules. Together, these findings illustrate that cell type-dependent mechanisms guide the assembly of similar RNA granules. Further, point mutations in RNA granule components may lead to cell type-dependent phenotypes that produce atypical forms of disorders that normally arise from more severe mutations.
Whole cell response to receptor stimulation involves many deep and distributed subcellular processes
Authors: Hansen Jens , Yadaw Arjun Singh , Siddiq Mustafa M. , Tolentino Rosa , Rabinovich Vera , Jayaraman Gomathi , Jain Mohit , Liu Tong , Li Hong , Goldfarb Joseph , Iyengar Ravi 
Published: November 2018

AbstractNeurite outgrowth is an integrated whole cell response regulated by cannabinoid-1 receptor. To understand underlying mechanisms, we identified subcellular processes (SCPs) and their interactions required for the response. Differentially expressed genes and proteins upon receptor stimulation of neuronal cells were used informatically to build networks of SCPs and their interactions. From SCP networks we identified additional genes, which when ablated validated the SCP involvement in neurite outgrowth. The experiments and informatics analyses identified diverse SCPs such as those involved in pyrimidine metabolism, lipid biosynthesis, mRNA splicing and stability along with membrane vesicle and microtubule dynamics. We find that SCPs required for neurite outgrowth are widely distributed among constitutive cellular functions. Several of these SCPs are deep since they are distal to cell signaling pathways and proximal SCPs involved in microtubule growth and membrane vesicle dynamics. We conclude that receptor regulation of SCPs for neurite outgrowth is distributed and deep.
Intramolecular domain dynamics regulate synaptic MAGUK protein interactions
Authors: Rademacher Nils , Kuropka Benno , Kunde Stella-Amrei , Wahl Markus C. , Freund Christian , Shoichet Sarah A. 
Published: November 2018

AbstractPSD-95 MAGUK family scaffold proteins are multi-domain organisers of synaptic transmission that contain three PDZ domains followed by an SH3-GK domain tandem. This domain architecture allows coordinated assembly of protein complexes composed of neurotransmitter receptors, synaptic adhesion molecules, cytoskeletal proteins and downstream signalling effectors. Here we show that binding of monomeric PDZ3ligands to the third PDZ domain of PSD-95 induces functional changes in the intramolecular SH3-GK domain assembly that influence subsequent homotypic and heterotypic complex formation. We identify PSD-95 interactors that differentially bind to the SH3-GK domain tandem depending on its conformational state. Among these interactors we further establish the heterotrimeric G protein subunit Gnb5 as a PSD-95 complex partner at dendritic spines. The PSD-95 GK domain binds to Gnb5 and this interaction is triggered by PDZ3ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation.
CMT disease 2A and demyelination decouple ATP and ROS production by axonal mitochondria
Authors: van Hameren Gerben , Campbell Graham , Deck Marie , Berthelot Jade , Chrast Roman , Tricaud Nicolas 
Published: November 2018

AbstractMitochondria are critical for the function and maintenance of myelinated axons notably through ATP production. A by-product of this activity is reactive oxygen species (ROS), which are highly deleterious for neurons. While ROS and metabolism are involved in several neurodegenerative diseases, it is still unclear how axonal activity or myelin modulates ATP and ROS production in axonal mitochondria. We imaged and quantified mitochondrial ATP and hydrogen peroxide (H2O2) in resting or stimulated peripheral nerve myelinated axonsin vivo, using genetically-encoded fluorescent probes, two-photon time-lapse and CARS imaging. ATP and H2O2productions are intrinsically higher in nodes of Ranvier even in resting conditions. Axonal firing increased both ATP and H2O2productions but with different dynamics. In neuropathic MFN2R94Qmice, mimicking Charcot-Marie-Tooth 2A disease, defective mitochondria failed to upregulate ATP production following axonal activity. However, H2O2production was dramatically sustained. Mimicking demyelinating peripheral neuropathy resulted in a reduced production of ATP while H2O2level soared. Taken together, our results suggest that ATP and ROS productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity.
How does genome size affect the evolution of pollen tube growth rate, a haploid performance trait?
Authors: Reese John B. , Williams Joseph H. 
Published: November 2018

ABSTRACTPremise of the StudyMale gametophytes of most seed plants deliver sperm to eggs via a pollen tube. Pollen tube growth rates (PTGRs) of angiosperms are exceptionally rapid, a pattern attributed to more effective haploid selection under stronger pollen competition. Paradoxically, whole genome duplication (WGD) has been common in angiosperms but rare in gymnosperms. Pollen tube polyploidy should initially acceleratePTGRbecause increased heterozygosity and gene dosage should increase metabolic rates, however polyploidy should also independently increase tube cell size, causing more work which should decelerate growth. We asked how genome size changes have affected the evolution of seed plantPTGRs.MethodsWe assembled a phylogenetic tree of 451 species with knownPTGRs. We then used comparative phylogenetic methods to detect effects of neo-polyploidy (within-genus origins), DNA content, and WGD history onPTGR, and correlated evolution ofPTGRand DNA content.Key ResultsGymnosperms had significantly higher DNA content and slowerPTGRoptima than angiosperms, and theirPTGRand DNA content were negatively correlated. For angiosperms, 89% of model weight favored Ornstein-Uhlenbeck models with a fasterPTGRoptimum for neo-polyploids, butPTGRand DNA content were not correlated. In comparisons of within-genus and intraspecific-cytotype pairs,PTGRsof neo-polyploids ≤ paleo-polyploids.ConclusionsGenome size increases should negatively affectPTGRwhen genetic consequences of WGDs are minimized, as found in intra-specific autopolyploids (low heterosis) and gymnosperms (few WGDs). But in angiosperms, the higherPTGRoptimum of neo-polyploids and non-negativePTGR-DNA content correlation suggest that recurrent WGDs have caused substantialPTGRevolution in a non-haploid state.
The unstructured linker arms of MutL enable GATC site incision beyond roadblocks during initiation of DNA mismatch repair
Authors: Mardenborough Yannicka SN , Nitsenko Katerina , Laffeber Charlie , Duboc Camille , Sahin Enes , Quessada-Vial Audrey , Winterwerp Herrie HK , Sixma Titia K , Kanaar Roland , Friedhoff Peter , Strick Terence R , Lebbink Joyce HG 
Published: November 2018

AbstractDNA mismatch repair (MMR) maintains genome stability through repair of DNA replication errors. InEscherichia coli, initiation of MMR involves recognition of the mismatch by MutS, recruitment of MutL, activation of endonuclease MutH and DNA strand incision at a hemimethylated GATC site. Here we studied the mechanism of communication that couples mismatch recognition to daughter strand incision. We investigated the effect of catalytically-deficient Cas9 as well as stalled RNA polymerase as roadblocks placed on DNA in between the mismatch and GATC site in ensemble and single molecule nanomanipulation incision assays. The MMR proteins were observed to incise GATC sites beyond a roadblock, albeit with reduced efficiency. This residual incision is completely abolished upon shortening the disordered linker regions of MutL. These results indicate that roadblock bypass can be fully attributed to the long, disordered linker regions in MutL and establish that communication during MMR initiation occurs along the DNA backbone.
PerSort facilitates characterization and elimination of persister subpopulation in mycobacteria
Authors: Srinivas Vivek , Arrieta-Ortiz Mario L. , Peterson Eliza J.R. , Baliga Nitin S. 
Published: November 2018

AbstractMycobacterium tuberculosis(MTB) generates phenotypic diversity to persist and survive the harsh conditions encountered during infection. MTB avoids immune effectors and antibacterial killing by entering into distinct physiological states. The surviving cells, persisters, are a major barrier to the timely and relapse-free treatment of tuberculosis (TB). We present for the first time, PerSort, a method to isolate and characterize persisters in the absence of antibiotic, or other pressure. We demonstrate the value of PerSort to isolate translationally dormant cells that pre-exist in small numbers withinMycobacterium spp. cultures growing under optimal conditions, but which dramatically increased in proportion under stress conditions. The translationally dormant subpopulation exhibited multidrug tolerance and regrowth properties consistent with persister cells. Furthermore, PerSort enabled single-cell transcriptional profiling that provided evidence that the translationally dormant persisters were generated through a variety of mechanisms, includingvapC30, mazF, andrelA/spoToverexpression. Finally, we demonstrate that notwithstanding the varied mechanisms by which the persister cells were generated, they converge on a similar low oxygen metabolic state that was reversed through activation of respiration to rapidly eliminate persisters fostered under host-relevant stress conditions. We conclude that PerSort provides a new tool to study MTB persisters, enabling targeted strategies to improve and shorten the treatment of TB.SummaryWe have developed a novel method, PerSort, to isolate translationally dormant cells that pre-exist in small numbers withinMycobacterium spp. cultures growing under naïve conditions (i.e., absence of antibiotic treatment), but dramatically increase in proportion under stress conditions. The translationally dormant cells have high tolerance to isoniazid and rifampicin, and can regenerate the parental population structure in standard media, albeit after a significantly longer lag phase, indicating they are persister cells. Single-cell expression profiling demonstrated that the translationally dormant persister subpopulation is a mixture ofvapC30, mazF, andrelA/spoToverexpressing cells, indicating there are multiple pathways to become a persister cell. Regardless of the mechanism by which they are generated, the persister cells have reduced oxidative metabolism, which is reversed upon addition of L-cysteine to effect complete clearance by INH and RIF under host-related stress.
Differential phase partition of a PICS complex is required for piRNA processing and chromosome segregation in C. elegans
Authors: Zeng Chenming , Weng Chenchun , Wang Xiaoyang , Yan Yong-Hong , Li Wen-Jun , Xu Demin , Hong Minjie , Liao Shanhui , Feng Xuezhu , Dong Meng-Qiu , Xu Chao , Guang Shouhong 
Published: November 2018

AbstractPiwi-interacting RNAs (piRNAs) play significant roles in suppressing transposons and non-self nucleic acids, maintaining genome integrity, defending against viral infections, and are essential for fertility in a variety of organisms. In C. elegans, most piRNA precursors are transcribed by RNA polymerase II in the nucleus and are subjected to a number of processing and maturation steps. However, the biogenesis of piRNAs are still not fully understood. We used functional proteomics to study piRNA biogenesis in C. elegans and identified a PICS complex that is required for piRNA processing and chromosome segregation. The PICS complex contains two known piRNA biogenesis factors TOFU-6 and PID-1, and three new proteins PICS-1, TOST-1, and ERH-2, which exhibit dynamic localization among different subcellular compartments. In the germline of gravid animals, the PICS complex contains TOFU-6/PICS-1/ERH-2/PID-1 and largely concentrate at the perinuclear granule zone and engages in piRNA processing. During early embryogenesis, the TOFU-6/PICS-1/ERH-2/TOST-1 complex accumulates in the nucleus and play essential roles in chromosome segregation and cell division. Interestingly, the function of these factors in mediating chromosome segregation is independent of piRNA production. Therefore, we speculate that a differential phase partition of PICS factors may help cells to coordinate distinct cellular processes.