bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of a mass spectrometry-grade protease with PTM-directed specificity
Authors: Tran Duc T. , Cavett Valerie J. , Dang Vuong Q. , Torres Héctor L. , Paegel Brian M.
Published: December 2016

Significance

Protein posttranslational modifications (PTMs) regulate virtually every aspect of cellular function. Mapping PTMs is a key application of protein mass spectrometry (MS), which analyzes thousands of peptides generated in enzymatic protein digests. There are currently only about seven naturally occurring proteases for generating these digests, and with the exception of trypsin, most are poor or promiscuous enzymes that are not ideal for MS. This protease “toolbox” has remained essentially unchanged for decades. In this study, the directed evolution of trypsin’s proteolytic specificity resulted in the discovery of a mutant protease that efficiently cleaves at citrullinated arginines, affording a powerful PTM site identification tool and promising a Darwinian wellspring of new, custom proteases.
Hierarchical CRMP2 posttranslational modifications control NaV1.7 function
Authors: Dustrude Erik T. , Moutal Aubin , Yang Xiaofang , Wang Yuying , Khanna May , Khanna Rajesh
Published: December 2016

Significance

The voltage-gated sodium channel NaV1.7 is important for electrogenesis in sensory neurons. Insertion within the membrane is required for function of NaV1.7. However, the mechanisms determining how NaV1.7 is trafficked to neuronal cell membranes are poorly understood. Here, we elucidate a signaling program involving a complex and intriguing posttranslational modification regime of collapsin response mediator protein 2 (CRMP2), an NaV1.7-binding protein. NaV1.7 surface localization and currents are controlled by CRMP2 modifications. Activity of NaV1.7 is thought to modulate neuronal excitability that codes for several sensory modalities, including chronic pain, as inferred from human pain disorders caused by mutations in NaV1.7 channels. Understanding the role of cross-talk between CRMP2 modifications in modulation of NaV1.7 activity opens routes to exploit this system for pain.
Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4
Authors: Sagan Sharon A. , Winger Ryan C. , Cruz-Herranz Andrés , Nelson Patricia A. , Hagberg Sarah , Miller Corey N. , Spencer Collin M. , Ho Peggy P. , Bennett Jeffrey L. , Levy Michael , Levin Marc H. , Verkman Alan S. , Steinman Lawrence , Green Ari J. , Anderson Mark S. , Sobel Raymond A. , Zamvil Scott S.
Published: December 2016

Significance

Neuromyelitis optica (NMO) is a CNS autoimmune demyelinating disease involving aquaporin-4 (AQP4)-specific IgG1, a T-cell–dependent antibody subclass. The role of T cells in NMO is unclear. We evaluated AQP4-specific T cells in WT and AQP4
−/−
mice. AQP4 epitopes identified in WT mice were not pathogenic. AQP4 peptide (p) 135–153 and p201–220 elicited robust T-cell responses in AQP4
−/−
but not WT, mice. T-cell receptor repertoire utilization for these determinants in AQP4
−/−
mice was unique. Donor AQP4
−/−
p135–153- or p201–220-specific Th17 cells entered the CNS of recipient WT mice and induced CNS autoimmunity. Our findings indicate pathogenic AQP4-specific T cells are normally restrained by central tolerance, which could be relevant to understanding the origin of pathogenic T cells in NMO.
Robots and Gender
Authors: Nomura Tatsuya
Published: December 2016

This article provides an overview of the current research on gender in human-robot interaction (HRI) including a discussion of the effects of gender characteristics in robotics design (robot gender), gender differences on interaction with robots (human gender), and some interaction effects between the two. The article also reviews research that examined the impact of the interaction between humans and robots with regard to robot appearance and behaviors, and situational factors, such as tasks and roles. Although the current state of research findings is complicated, it appears that even simple gendering of robots by manipulation of voice and name can affect humans’ feelings and behaviors toward robots. These effects vary and are dependent on other factors, including human gender. Future research should focus on gender stereotypes, cultural influences, and robotic applications in various fields. At the same time, we should consider if gendering of robots, for given roles, is really necessary to encourage interactions between humans and robots.
CAME: identification of chromatin accessibility from nucleosome occupancy and methylome sequencing
Authors: Piao Yongjun , Lee Seong Keon , Lee Eun-Joon , Robertson Keith D , Shi Huidong , Ryu Keun Ho , Choi Jeong-Hyeon
Published: December 2016

Motivation

Chromatin accessibility plays a key role in epigenetic regulation of gene activation and silencing. Open chromatin regions allow regulatory elements such as transcription factors and polymerases to bind for gene expression while closed chromatin regions prevent the activity of transcriptional machinery. Recently, Methyltransferase Accessibility Protocol for individual templates-Bisulfite Genome Sequencing (MAPit-BGS) and nucleosome occupancy and methylome sequencing (NOMe-seq) have been developed for simultaneously profiling chromatin accessibility and DNA methylation on single molecules. Therefore, there is a great demand in developing computational methods to identify chromatin accessibility from MAPit-BGS and NOMe-seq.

Results

In this article, we present CAME (Chromatin Accessibility and Methylation), a seed-extension based approach that identifies chromatin accessibility from NOMe-seq. The efficiency and effectiveness of CAME were demonstrated through comparisons with other existing techniques on both simulated and real data, and the results show that our method not only can precisely identify chromatin accessibility but also outperforms other methods.

Availability and Implementation

CAME is implemented in java and the program is freely available online at http://sourceforge.net/projects/came/

Supplementary information

Supplementary data are available at Bioinformatics online.
PhosD: inferring kinase–substrate interactions based on protein domains
Authors: Qin Gui-Min , Li Rui-Yi , Zhao Xing-Ming
Published: December 2016

Motivation

Identifying the kinase–substrate relationships is vital to understanding the phosphorylation events and various biological processes, especially signal transductions. Although large amount of phosphorylation sites have been detected, unfortunately, it is rarely known which kinases activate those sites. Despite distinct computational approaches have been proposed to predict the kinase–substrate interactions, the prediction accuracy still needs to be improved.

Results

In this paper, we propose a novel probabilistic model named as PhosD to predict kinase–substrate relationships based on protein domains with the assumption that kinase–substrate interactions are accomplished with kinase–domain interactions. By further taking into account protein–protein interactions, our PhosD outperforms other popular approaches on several benchmark datasets with higher precision. In addition, some of our predicted kinase–substrate relationships are validated by signaling pathways, indicating the predictive power of our approach. Furthermore, we notice that given a kinase, the more substrates are known for the kinase the more accurate its predicted substrates will be, and the domains involved in kinase–substrate interactions are found to be more conserved across proteins phosphorylated by multiple kinases. These findings can help develop more efficient computational approaches in the future.

Availability and Implementation

The data and results are available at http://comp-sysbio.org/phosd

Supplementary information

Supplementary data are available at Bioinformatics online.
Gag-Specific CD8 T-Cell Proliferation Is Associated With Higher Peripheral Blood Levels of Transforming Growth Factor-β and Gut-Homing T Cells in Youths Perinatally Infected With Human Immunodeficiency Virus-1: The ANRS-EP38-IMMIP Study
Authors: Warszawski Josiane , Avettand-Fenoel Véronique , Rouzioux Christine , Scott-Algara Daniel , Montange Thomas , Didier Céline , Le Chenadec Jérôme , Viard Jean-Paul , Dollfus Catherine , Blanche Stéphane , Buseyne Florence
Published: December 2016

Background

Gag-specific T lymphocytes play a key role in the control of human immunodeficiency virus (HIV) replication. Their restoration will be important for future reservoir targeting strategies. In this study, we aimed to identify immune correlates of Gag-specific CD8 T-cell proliferation in youths with perinatally acquired HIV-1 infection.

Methods

The ANRS-EP38-IMMIP study included youths of 15 to 24 years of age. Fifty-three were taking combination anti-retroviral therapy and aviremic at the time of the study and had undergone valid 5-6-carboxyfluorescein diacetate succimidyl ester-based flow cytometry T-cell proliferation assays. Plasma analytes were quantified by enzyme-linked immunosorbent assay or multiplex assays. Peripheral blood cells were phenotyped by flow cytometry. Logistic regression was used to study the association between Gag-specific T-cell proliferation and immune markers.

Results

Patients with Gag-specific CD8 T-cell proliferation had higher levels of plasma transforming growth factor (TGF)-β1, a lower proportion of naive cells among regulatory T cells (Tregs), and higher percentages of CD4 and CD8 T cells expressing the α4β7 integrin or CD161 molecule than those without a Gag-specific response. These associations were significant based on analyses including potential confounders.

Conclusions

Preserved Gag-specific CD8 T-cell proliferation was associated with higher TGF-β1 levels and increased percentages of T cells with a gut-homing phenotype at least 15 years after HIV infection during the perinatal period.
Properdin Levels in Individuals with Chemotherapy-Induced Neutropenia
Authors: Tsyrkunou Artsiom , Agarwal Sarika , Koirala Bibek , Finberg Robert W. , Nath Rajneesh , Barton Bruce , Levitz Stuart M. , Wang Jennifer P. , Ram Sanjay
Published: December 2016

Background

Neutrophils produce and carry key components of the alternative pathway (AP) of complement, including properdin (P). The effect of chemotherapy-induced absolute neutropenia on circulating P levels and AP function has not been previously established.

Methods

We prospectively measured free P levels in serum from 27 individuals expected to develop neutropenia after administration of chemotherapy for hematological malignancies in preparation for hematopoietic stem cell transplantation and here describe the relationship between serum P levels and the neutrophil count over time.

Results

When the absolute neutrophil count (ANC) was >500 cells/mm3 pre-chemotherapy, P levels were significantly higher than P levels associated with an ANC ≤500 cells/mm3 (median values 8392 ng/mL and 6355 ng/mL, respectively; P = .001). Pairwise comparison between pre-chemotherapy P levels and P levels at initial or last documented neutropenia before recovery showed a significant decline (P < .0001). No correlation was observed between P levels during neutropenia and after recovery of neutropenia in 20 subjects for which postneutropenia samples were obtained. A small but significant (P = .02) decrease in AP hemolytic activity was noted between baseline (preneutropenia) and samples obtained at the onset of neutropenia, but only with low (6.25%) and not higher (12.5 or 25%) serum concentrations.

Conclusions

A decline in P levels and AP activity could contribute to the increased risk of infection in neutropenic patients and warrants further study.
Hepatitis B Virus Incidence and Risk Factors Among Human Immunodeficiency Virus-1 Negative Men Who Have Sex With Men in Kenya
Authors: Wahome Elizabeth , Ngetsa Caroline , Mwambi John , Gelderblom Huub C. , Manyonyi Gloria Omosa , Micheni Murugi , Hassan Amin , Price Matt A. , Graham Susan M. , Sanders Eduard J.
Published: December 2016

No data exist on hepatitis B virus (HBV) incidence among African men who have sex with men (MSM). We tested plasma samples archived between 2005 and 2014 for HBV core antibody or surface antigen seroconversion in a cohort of 312 initially human immunodeficiency virus (HIV)-1-negative MSM with no evidence of prior HBV infection. Hepatitis B virus incidence was 6.0/100 person-years (95% confidence interval [CI], 3.9–9.1). Hepatitis B virus acquisition was associated with being uncircumcised (adjusted incidence rate ratio [aIRR], 5.0; 95% CI, 1.5–16.8), recent HIV-1 acquisition (aIRR, 2.9; 95% CI, 1.1–7.7), rape (aIRR, 5.0; 95% CI, 1.2–20.4), and any tertiary education (aIRR, 3.2; 95% CI, 1.1–9.7). African MSM have a substantial risk of HBV acquisition and require vaccination urgently.
Oseltamivir Use Among Children and Adults Hospitalized With Community-Acquired Pneumonia
Authors: Oboho Ikwo K. , Bramley Anna , Finelli Lyn , Fry Alicia , Ampofo Krow , Arnold Sandra R. , Self Wesley H. , Williams Derek J. , Courtney D. Mark , Zhu Yuwei , Anderson Evan J. , Grijalva Carlos G. , McCullers Jonathan A. , Wunderink Richard G. , Pavia Andrew T. , Edwards Kathryn M. , Jain Seema
Published: December 2016

Background

Data on oseltamivir treatment among hospitalized community-acquired pneumonia (CAP) patients are limited.

Methods

Patients hospitalized with CAP at 6 hospitals during the 2010−2012 influenza seasons were included. We assessed factors associated with oseltamivir treatment using logistic regression.

Results

Oseltamivir treatment was provided to 89 of 1627 (5%) children (<18 years) and 143 of 1051 (14%) adults. Among those with positive clinician-ordered influenza tests, 39 of 61 (64%) children and 37 of 48 (77%) adults received oseltamivir. Among children, oseltamivir treatment was associated with hospital A (adjusted odds ratio [aOR], 2.76; 95% confidence interval [CI], 1.36−4.88), clinician-ordered testing performed (aOR, 2.44; 95% CI, 1.47−5.19), intensive care unit (ICU) admission (aOR, 2.09; 95% CI, 1.27−3.45), and age ≥2 years (aOR, 1.43; 95% CI, 1.16−1.76). Among adults, oseltamivir treatment was associated with clinician-ordered testing performed (aOR, 8.38; 95% CI, 4.64−15.12), hospitals D and E (aOR, 3.46−5.11; 95% CI, 1.75−11.01), Hispanic ethnicity (aOR, 2.06; 95% CI, 1.18−3.59), and ICU admission (aOR, 2.05; 95% CI, 1.34−3.13).

Conclusions

Among patients hospitalized with CAP during influenza season, oseltamivir treatment was moderate overall and associated with clinician-ordered testing, severe illness, and specific hospitals. Increased clinician education is needed to include influenza in the differential diagnosis for hospitalized CAP patients and to test and treat patients empirically if influenza is suspected.
An Uncommon Site of Streptococcus pneumoniae Colonization Leading to Recurrent Pneumococcal Disease
Authors: Sendi Parham , Moser Schaub Eva Maria , Nirgianakis Konstantinos , Hathaway Lucy J. , Bittel Pascal , Goldblatt David , Streit Sven
Published: December 2016

This report describes a case of relapsing pneumococcal peritonitis. The postulated source of infection was vaginal colonization and secondary adherence of pneumococci to an intrauterine contraceptive device. After immunization with a conjugate pneumococcal vaccine, her antibody levels were observed. She remained infection free at the 2-year follow-up investigation.
Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring
Authors: Yamamoto Yoshiaki , Takahashi Yukitoshi , Imai Katsumi , Kagawa Yoshiyuki , Inoue Yushi
Published: December 2016

Background:

This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy.

Methods:

A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan–Meier method.

Results:

Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 μmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days;P= 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P= 0.002).

Conclusions:

Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.
Treatment strategies for endometrial cancer: current practice and perspective
Authors: Lee Yeh C. , Lheureux Stephanie , Oza Amit M.
Published: December 2016

Purpose of review

Endometrial cancer incidence is increasing in North America and is a major cause of morbidity and mortality in women. We review recent literature published on treatment of endometrial cancer and highlight areas of active interest.

Recent findings

There has been movement toward minimal invasive surgery at diagnosis; lymph node staging remains controversial and continues to be investigated. Progress has been made to establish consensus on endometrial cancer risk classification to promote consistency for future trial design. Molecular characterization of endometrial cancer and its integration into clinicopathological profiling to develop predictive biomarkers for treatment selection are active areas of research. Optimal adjuvant treatment strategy in high-risk endometrial cancer remains to be defined with recognition of treatment-related toxicity. Despite encouraging results in drug development for treatment of advanced/recurrent endometrial cancer, no targeted therapies beyond hormonal therapy are approved. There is an urgent need for scientifically validated therapy with predictive biomarkers.

Our understanding of endometrial cancer has evolved through improvements in molecular biology, allowing improved definition of target-specific therapies. The precise role and sequence of conventional and targeted therapies, including immunotherapy, will require careful attention to the design of clinical trials with translational emphasis to allow the discovery, validation, and implementation of predictive biomarkers into clinical care.
Molecular characterization of endometrial cancer and therapeutic implications
Authors: Uppendahl Locke , Mullany Sally A. , Winterhoff Boris
Published: December 2016

Purpose of review

This article reviews the emerging comprehensive genomic classification of endometrial carcinoma and discusses the therapeutic implications of these subgroups.

Recent findings

Comprehensive, multiplatform evaluation of endometrial cancers by the Cancer Genome Atlas stratified the molecular aberrations into four distinct subtypes: POLE mutations, microsatellite instability, copy-number low/microsatellite stable, and copy-number high/‘serous-like.’ POLE-mutant tumors have a favorable prognosis and may often be overtreated. Microsatellite instability hypermutated tumors commonly have alterations in the phosphatidylinositide 3-kinases/AKT/mechanistic target of rapamycin pathway and limiting targeted therapy to this group may lead to greater response rates. Copy-number low/microsatellite stable tumors represent the majority of grade 1 and grade 2 endometrioid cancers and have an intermediate prognosis, few TP53 mutations, but frequent mutations in genes involved with Wingless-related integration site signaling. Approximately 25% of high-grade endometrioid tumors have mutational profiles that classify as copy-number high/‘serous-like’ and might benefit from treatment approaches similar to those for serous tumors.

Molecular characterization of endometrial cancer classifies tumors into prognostically significant subtypes with a broad range of therapeutic implications.
Comparison of Topical Low-Molecular-Weight Heparin–Taurocholate and Bevacizumab for Treatment and Prevention of Corneal Neovascularization
Authors: Moon Chan Hee , Moon Byung Gil , Kim Jae Yong , Kim Myoung Joon , Tchah Hungwon
Published: December 2016

Purpose:

To compare the therapeutic and preventive effects of topically administered 7-taurocholic acid–conjugated low-molecular-weight heparin (LHT7) and bevacizumab in experimentally induced corneal neovascularization (CoNV).

Methods:

CoNV was induced using sutures in the right eyes of 24 mice. To investigate the therapeutic effects, CoNV was allowed to develop for 1 week before treatment. To ascertain the preventive effects, the treatments were applied immediately after the suture. In each experiment, 12 eyes were divided into 3 groups and treated topically using bevacizumab (bevacizumab group), LHT7 (LHT7 group), and normal saline (control group). The treatments were instilled 3 times daily for 2 weeks. The CoNV area was measured before instillation and after 1 and 2 weeks after instillation.

Results:

In the investigation of therapeutic effects, the CoNV area had decreased significantly 1 week after treatment in the bevacizumab group (1.58–0.75 mm2; P = 0.036) and LHT7 group (1.38–0.74 mm2; P = 0.018). Two weeks after treatment, the CoNV area was significantly smaller in the bevacizumab groups (0.60 mm2; P = 0.005) and LHT7 group (0.64 mm2; P = 0.015) than in the control group (1.68 mm2), but the bevacizumab group did not differ significantly from the LHT7 group. In the experiment addressing the preventive effects, CoNV was less developed in the bevacizumab group (0.70 mm2; P = 0.003) and LHT7 group (0.54 mm2; P = 0.003) than in the control group (1.75 mm2), and the CoNV area was smaller in the LHT7 group than in the bevacizumab group (P = 0.021).

Conclusions:

The effects of LHT7 on CoNV regression are comparable to those of bevacizumab. Topical administration of LHT7 prevents CoNV more effectively than bevacizumab.
Autologous Blood Versus Fibrin Glue in Pterygium Excision With Conjunctival Autograft Surgery
Authors: Nadarajah Gaayathri , Ratnalingam Vanitha Hema , Mohd Isa Hazlita
Published: December 2016

Purpose:

To evaluate graft stability and recurrence rate between fibrin glue and autologous blood in pterygium conjunctival autograft surgery.

Methods:

A prospective, randomized, single-blinded clinical trial to assess the efficacy of autologous blood in place of fibrin glue in pterygium surgery. A total of 120 eyes of 111 patients were randomized according to pterygium morphology, to undergo pterygium surgery with autografting using either autologous blood or fibrin glue. All patients were operated by a single surgeon; 58 eyes were operated using fibrin glue and 62 eyes had a conjunctival autograft with autologous blood. Patients were seen on postoperative day 1, 1 week, 1 month, 6 months, and 1 year after surgery. Graft stability and pterygium recurrence were graded by an independent observer who was masked to the method of treatment.

Results:

All 120 eyes completed the 1-year follow-up. Graft loss was seen only in the autologous blood group. Of the 62 eyes in this group, a total of 15 (24.2%) grafts dislodged. Recurrence was calculated after excluding grafts that were dislodged. Of the 105 patients, there were a total of 7 recurrences, 2 (3.4%) from the fibrin adhesive method and 5 (10.6%) from the autologous blood method. This was not statistically significant (P = 0.238).

Conclusions:

Autologous blood does not exhibit similar graft stability seen with fibrin glue. Although the recurrence rate may not be significant, careful patient selection and a standard method needs to be laid out before the use of this method is widely accepted.
Ten-Year Clinical Outcome of the First Patient Undergoing Descemet Membrane Endothelial Keratoplasty
Authors: Baydoun Lamis , Müller Thomas , Lavy Itay , Parker Jack , Rodriguez-Calvo-de-Mora Marina , Liarakos Vasilios S. , Dapena Isabel , Melles Gerrit R. J.
Published: December 2016

Purpose:

To describe the 10-year clinical outcome of the first patient worldwide who underwent Descemet membrane endothelial keratoplasty (DMEK).

Methods:

In 2006, a 63-year-old man presented at the Melles Cornea Clinic, Rotterdam, with bilateral Fuchs endothelial dystrophy and cataract. After phacoemulsification, in vivo DMEK was performed in the left eye and 10 months later in the right eye. Best spectacle-corrected visual acuity (BSCVA), endothelial cell density, pachymetry, and complications were recorded every 6 months over a 10-year period.

Results:

BSCVA in the left eye improved from 20/60 (0.3) before surgery to 20/17 (1.2) at 1 month, and remained stable over 10 years, ranging from 20/20 (1.0) to 20/13 (1.5). BSCVA in the right eye improved from 20/50 (0.4) preoperative and 20/60 (0.3) at 1 month to 20/25 (0.8) at 3 months and 20/17 (1.2) at 6 months, ranging from 20/25 (0.8) to 20/17 (1.2) over 9 years. Both eyes underwent YAG-laser-capsulotomy to manage posterior capsule opacification at 5 and 4 years after DMEK, respectively. Endothelial cell density in the right and left eyes, respectively, decreased by 43% and 45% at 1 year, 52% and 59% at 5 years, and 72% and 68% at 10/9 years, respectively. No intraoperative or postoperative complications occurred; at the last follow-up, both corneas were clear.

Conclusions:

The first DMEK patient worldwide may show all short and long-term characteristics of this endothelial keratoplasty technique: outstanding patient satisfaction, quick visual recovery, low incidence of complications, and graft longevity. Published studies in the past decade would suggest that this case was the start of a new era in corneal transplantation.
Adjunctive Brexpiprazole as a Novel Effective Strategy for Treating Major Depressive Disorder
Authors: Yoon Seoyoung , Jeon Sang Won , Ko Young-Hoon , Patkar Ashwin A. , Masand Prakash S. , Pae Chi-Un , Han Changsu
Published: December 2016

Purpose/Background

Brexpiprazole was approved for adjunctive treatment of major depressive disorder (MDD) in 2015. Because only a small number of randomized controlled trials have investigated the use of brexpiprazole in MDD, we performed a meta-analysis.

Methods/Procedures

We systematically searched literatures in PubMed, Cochrane Library database, EMBASE, Google Scholar, and clinicaltrials.gov up to January 2016. The primary efficacy measure was the mean change in total Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline. Secondary efficacy measures were the mean change in total Hamilton Rating Scale for Depression (17 items) score from baseline and the response (≥50% reduction in MADRS total score) and remission (MADRS total score ≤ 10 with ≥50% reduction) rates.

Findings/Results

Four studies fulfilled the inclusion criteria and were included in the analysis. Brexpiprazole showed superior efficacy over placebo with effect sizes (mean differences) of −1.76 (95% confidence interval [CI], −2.45 to −1.07) for MADRS and −1.21 (95% CI, −1.71 to −0.72) for the 17-item Hamilton Rating Scale for Depression. The risk ratios for response and remission were 1.57 (95% CI, 1.29–1.91) and 1.55 (95% CI, 1.22–1.96), respectively. The incidences of discontinuation due to adverse events, akathisia, and weight increase were higher in the brexpiprazole group than in the placebo group, with risk ratios of 3.44 (95% CI, 1.52–7.80), 3.39 (95% CI, 2.08–5.51), and 4.36 (95% CI, 2.45–7.77), respectively, and the incidence of akathisia was related to the brexpiprazole dose.

Implications/Conclusions

Although our results suggest that brexpiprazole could be an effective adjunctive agent for MDD, they should be cautiously translated into clinical practice because the meta-analysis was based on only a handful of randomized controlled trials.
Influence Of Desire To Belong And Feelings Of Loneliness On Emotional Prosody Perception In Schizophrenia
Authors: Mitchell Rachel , Gamez Krystal , Kohler Christian , Calkins Monica E. , Turetsky Bruce I. , Leitman David I.
Published: December 2016

Objective: Humans are social creatures, with desires to connect or belong, producing loneliness when isolated. Individuals with schizophrenia are often more isolated than healthy adults and demonstrate profound social communication impairments such as vocal affect perception (prosody). Loneliness, levels of desire for social connectedness (need to belong, NTB), and their relationship to perception of social communications have not been investigated in schizophrenia.

Method: In a sample of 69 individuals (36 SZ), we measured endorsements of loneliness and NTB, and evaluated their putative relationships to clinical symptoms and social communication abilities, as indexed by emotional prosody and pitch perception.

Results: Loneliness endorsement was highly variable but particularly so in patients, whilst patients endorsed NTB at levels equivalent to healthy controls. In schizophrenia, pitch and prosody acuity were reduced, and prosody perception correlated with NTB. Loneliness, but not desire for social connectedness, correlated with negative symptoms.

Conclusion: Loneliness and negative symptoms likely exert bidirectional effects on each other. Loneliness and desire to form interpersonal attachments may be pivotal in shaping and stimulating social interactions and, subsequently, the ability to perceive social intent through prosody. Intact NTB levels in patients augurs well for cognitive remediation which, target vocal-communication processing to improve social skills.

Significant Outcomes

Patients with schizophrenia endorsed higher levels of loneliness than controls, but ratings of desire for social connectedness were at normal levels.

Pitch acuity and prosody perception were correlated, confirming the importance of basic sensory processing in recognizing prosodic emotions.

Socio-cognitive perceptual ability (emotional prosody perception) correlated with increased desire for social connections, implying that they may still be motivated to find social interactions reinforcing. Thus interventions to improve perceptual deficits could still be an effective means of improving social function.

Limitations

Causal relationships between desire for social connections, loneliness, and emotional prosody perception cannot be inferred through correlations and cross-sectional studies alone.

Subjective endorsements of loneliness through self-report are not the same thing as objective indices of loneliness. New and more extensive tools for measuring desire for both loneliness and social connectedness may be needed.

Direct experimental comparison of the interrelations between desire for social connectedness, loneliness, pitch acuity and emotional prosody perception in patients with schizophrenia and other populations such as autism will enable a more accurate comparison of the likely success of remediating socio-cognitive perceptual impairment in neuropsychiatric disorders.
A Resource for Assessing Information Processing in the Developing Brain Using EEG and Eye Tracking
Authors: Langer Nicolas , Ho Erica J. , Alexander Lindsay M. , Xu Helen Y. , Jozanovic Renee K. , Henin Simon , Cohen Samantha , Marcelle Enitan T. , Parra Lucas C. , Milham Michael P. , Kelly Simon P.
Published: December 2016

We present a dataset combining electrophysiology and eye tracking intended as a resource for the investigation of information processing in the developing brain. The dataset includes high-density task-based and task-free EEG, eye tracking, and cognitive and behavioral data collected from 126 individuals (ages: 6–44). The task battery spans both the simple/complex and passive/active dimensions to cover a range of approaches prevalent in modern cognitive neuroscience. The active task paradigms facilitate principled deconstruction of core components of task performance in the developing brain, whereas the passive paradigms permit the examination of intrinsic functional network activity during varying amounts of external stimulation. Alongside these neurophysiological data, we include an abbreviated cognitive test battery and questionnaire-based measures of psychiatric functioning. We hope that this dataset will lead to the development of novel assays of neural processes fundamental to information processing, which can be used to index healthy brain development as well as detect pathologic processes.
Hoxa1 and TALE proteins display cross-regulatory interactions and form a combinatorial binding code on Hoxa1 targets
Authors: De Kumar Bony , Parker Hugo J. , Paulson Ariel , Parrish Mark E. , Pushel Irina , Slaughter Brian D. , Unruh Jay R. , Zeitlinger Julia , Krumlauf Robb
Published: December 2016

Hoxa1has diverse functional roles in differentiation and development. We have identified and characterized properties of regions bound by Hoxa1 on a genome-wide basis in differentiating mouse ES cells. Hoxa1 bound regions are enriched for clusters of consensus binding motifs for Hox, Pbx and Meis and many display co-occupancy of Pbx and Meis. Pbx and Meis are members of the TALE family and genome-wide analysis of multiple TALE members (Pbx, Meis, TGIF, Prep1 and Prep2) show that nearly all Hoxa1 targets display occupancy of one or more TALE members. The combinatorial binding patterns of TALE proteins defines distinct classes of Hoxa1 targets and indicates a role as cofactors in modulating the specificity of Hox proteins. We also discovered extensive auto- and cross-regulatory interactions among the Hoxa1 and TALE genes. This study provides new insight into a regulatory network involving combinatorial interactions between Hoxa1 and TALE proteins.
Tracking the embryonic stem cell transition from ground state pluripotency
Authors: Kalkan Tüzer , Olova Nelly , Roode Mila , Mulas Carla , Lee Heather J. , Nett Isabelle , Marks Hendrik , Walker Rachael , Stunnenberg Hendrik G. , Lilley Kathryn S. , Nichols Jennifer , Reik Wolf , Bertone Paul , Smith Austin
Published: December 2016

Mouse embryonic stem (ES) cells are locked into self-renewal by shielding from inductive cues. Release from this ground state in minimal conditions offers a system for delineating developmental progression from naive pluripotency. Here we examined the initial transition of ES cells. The population behaves asynchronously. We therefore exploited a short-half-lifeRex1::GFPreporter to isolate cells either side of exit from naive status. Extinction of ES cell identity in single cells is acute. It occurs only after near-complete elimination of naïve pluripotency factors, but precedes appearance of lineage specification markers. Cells newly departed from the ES cell state exhibit global transcriptome features consistent with features of early post-implantation epiblast and distinct from primed epiblast. They also exhibit a genome-wide increase in DNA methylation, intermediate between early and late epiblast. These findings are consistent with the proposition that naïve cells transition to a discrete formative phase of pluripotency preparatory to lineage priming.

Highlights

The Rex1 destabilized GFP reporter demarcates naive pluripotency.

Exit from the naive state is asynchronous in the population.

Transition is relatively acute in individual cells and precedes lineage priming.

Transcriptome and DNA methylome reflect events in the pre-gastrulation embryo.
Flux through lipid synthesis dictates bacterial cell size
Authors: Vadia Stephen , Tse Jessica L. , Wang Jue D. , Levin Petra Anne
Published: December 2016

Nutrients—and by extension biosynthetic capacity—positively impact cell size in organisms throughout the tree of life. In bacteria, cell size is reduced three-fold in response to nutrient starvation or accumulation of the alarmone ppGpp, a global inhibitor of biosynthesis. However, whether biosynthetic capacity as a whole determines cell size or if particular anabolic pathways are more important than others remains an open question. Utilizing a top-down approach, here we identify flux through lipid synthesis as the primary biosynthetic determinant ofEscherichia colicell size. Altering flux through lipid synthesis recapitulated the impact of altering nutrients on cell size and morphology, while defects in other biosynthetic pathways either did not impact size or altered size in a lipid-dependent manner. Together our findings support a model in which lipid availability dictates cell envelope capacity and ppGpp functions as a linchpin linking surface area expansion with cytoplasmic volume to maintain cellular integrity.
IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer
Authors: Degrauwe Nils , Suvà Mario-Luca , Janiszewska Michalina , Riggi Nicolo , Stamenkovic Ivan
Published: December 2016

IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMP1–3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth.
RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1
Authors: Vélez-Cruz Renier , Manickavinayaham Swarnalatha , Biswas Anup K. , Clary Regina Weaks , Premkumar Tolkappiyan , Cole Francesca , Johnson David G.
Published: December 2016

The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss.
P13, the EMBL macromolecular crystallography beamline at the low-emittance PETRA III ring for high- and low-energy phasing with variable beam focusing
Authors: Cianci Michele , Bourenkov Gleb , Pompidor Guillaume , Karpics Ivars , Kallio Johanna , Bento Isabel , Roessle Manfred , Cipriani Florent , Fiedler Stefan , Schneider Thomas R.
Published: December 2016

The macromolecular crystallography P13 beamline is part of the European Molecular Biology Laboratory Integrated Facility for Structural Biology at PETRA III (DESY, Hamburg, Germany) and has been in user operation since mid-2013. P13 is tunable across the energy range from 4 to 17.5 keV to support crystallographic data acquisition exploiting a wide range of elemental absorption edges for experimental phase determination. An adaptive Kirkpatrick–Baez focusing system provides an X-ray beam with a high photon flux and tunable focus size to adapt to diverse experimental situations. Data collections at energies as low as 4 keV (λ = 3.1 Å) are possible due to a beamline design minimizing background and maximizing photon flux particularly at low energy (up to 1011 photons s−1 at 4 keV), a custom calibration of the PILATUS 6M-F detector for use at low energies, and the availability of a helium path. At high energies, the high photon flux (5.4 × 1011 photons s−1 at 17.5 keV) combined with a large area detector mounted on a 2θ arm allows data collection to sub-atomic resolution (0.55 Å). A peak flux of about 8.0 × 1012 photons s−1 is reached at 11 keV. Automated sample mounting is available by means of the robotic sample changer `MARVIN' with a dewar capacity of 160 samples. In close proximity to the beamline, laboratories have been set up for sample preparation and characterization; a laboratory specifically equipped for on-site heavy atom derivatization with a library of more than 150 compounds is available to beamline users.
Synchrotron radiation micro X-ray fluorescence spectroscopy of thin structures in bone samples: comparison of confocal and color X-ray camera setups
Authors: Rauwolf M. , Turyanskaya A. , Roschger A. , Prost J. , Simon R. , Scharf O. , Radtke M. , Schoonjans T. , Guilherme Buzanich A. , Klaushofer K. , Wobrauschek P. , Hofstaetter J. G. , Roschger P. , Streli C.
Published: December 2016

In the quest for finding the ideal synchrotron-radiation-induced imaging method for the investigation of trace element distributions in human bone samples, experiments were performed using both a scanning confocal synchrotron radiation micro X-ray fluorescence (SR-µXRF) (FLUO beamline at ANKA) setup and a full-field color X-ray camera (BAMline at BESSY-II) setup. As zinc is a trace element of special interest in bone, the setups were optimized for its detection. The setups were compared with respect to count rate, required measurement time and spatial resolution. It was demonstrated that the ideal method depends on the element of interest. Although for Ca (a major constituent of the bone with a low energy of 3.69 keV for its Kα XRF line) the color X-ray camera provided a higher resolution in the plane, for Zn (a trace element in bone) only the confocal SR-µXRF setup was able to sufficiently image the distribution.
Crystal structure of bis(μ-N-hydroxypicolinamidato)bis[bis(N-hydroxypicolinamide)sodium]
Authors: Safyanova Inna S. , Ohui Kateryna A. , Omelchenko Irina V.
Published: December 2016

The title compound, [Na2(C6H5N2O2)2(C6H6N2O2)4], is a centrosymmetric coordination dimer based on the sodium(I) salt ofN-hydroxypicolinamide. The molecule has an {Na2O6(μ-O)2} core with two bridging carbonyl O atoms and two hydroxamate O atoms of two mono-deprotonated residues ofN-hydroxypicolinamide, while two neutralN-hydroxypicolinamide molecules are coordinated in a monodentate manner to each sodium ionviathe carbonyl O atoms [the Na—O distances range from 2.3044 (2) to 2.3716 (2) Å]. The pentacoordinated sodium ion exhibits a distorted trigonal–pyramidal coordination polyhedron. In the crystal, the coordination dimers are linked into chains along thecaxisviaN—H...O and N—H...N hydrogen bonds; the chains are linked into a two-dimensional framework parallel to (100)viaweak C—H...O and π–π stacking interactions.
5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-amine
Authors: Naveen S. , Naveen P. , Zabiulla  , Manjunath H. R. , Lokanath N. K. , Khanum Shaukath Ara , Warad Ismail
Published: December 2016

In the title compound, C9H9N3O2, the dihedral angle between the aromatic rings is 8.64 (10)°. The crystal structure features inversion-related dimers linked by pairs of N—H...N hydrogen bonds, generatingR22(8) loops. A further N—H...N hydrogen bond links the dimers into (100) sheets.
(3Z)-3-Benzylidene-1H-benzimidazo[1,2-a]imidazol-2(3H)-one
Authors: Rida Mohammed , El Bakri Youness , Essassi El Mokhtar , Mague Joel T.
Published: December 2016

In the title compound, C16H11N3O, the molecular conformation is partially determined by an intramolecular C—H...π(ring) interaction. In the crystal, pairwise N—H...N hydrogen bonds form dimers, which associate into stacks through a combination of C—H...O, C—H...π(ring) and offset π–π stacking interactions.
(2-Benzoyl-1-phenylethenolato-κ2O,O′)bis[2-(1-phenyl-1H-benzimidazol-2-yl)phenyl-κC1]iridium(III) dichloromethane disolvate
Authors: Bezzubov Stanislav I. , Doljenko Vladimir D. , Kurnosov Nikon M. , Zharinova Irina S. , Kovalenko Ilya V. , Kiselev Yuri M.
Published: December 2016

We present here synthesis and crystal structure of a neutral IrIIIcomplex, [Ir(C19H13N2)2(C15H11O2)]·2CH2Cl2or [Ir(C^N)2O^O]·2CH2Cl2, where C^N is 1,2-diphenyl-1H-benzimidazole and O^O is 2-benzoyl-1-phenylethenolate. The coordination sphere of the IrIIIatom, located on a twofold rotation axis, is that of a slighlty distorted C2N2O2octahedron, with the N atoms in atransconfiguration. In the crystal, complex molecules assemble through weak C—H...π interactions in the range 2.699 (3)–2.892 (3) Å. The solvent CH2Cl2molecules reside in channels aligned along theaaxis and are connected to the complex molecules by C—H...O interactions.