bluuebunny/crossref_metadata_2025 huggingface dataset:
Disaster Scenarios in Spine Surgery
Authors: Abdul-Jabbar Amir , Yilmaz Emre , Fisahn Christian , Drazin Doniel , Blecher Ronen , Uppal Maninderdip , Phernetton Brandi L. , Altafulla Juan , Oskouian Rod J. , Chapman Jens R.
Published: March 2019

Study Design.

Survey analysis among spine surgeons.

Objective.

To identify current consensus and discrepancies in managing adverse intraoperative events among spine surgeons.

Summary of Background Data.

Major intraoperative events are not commonly the subject of formal medical training, in part due to the relative paucity of their occurrence and in part due to an insufficient evidence base. Given the clinical impact of appropriate complication management, it is important to identify where surgeons may be able to improve decision making when choosing interventions.

Methods.

A survey was created including five hypothetical unpredicted scenarios affecting different organ systems to assess the respondents’ preferred reactions. The five clinical vignettes that were selected by the researchers involved: 1) loss of spinal signals in neuro-monitoring, 2) prone position cardiac arrest, 3) prone position hypoxia during thoracic corpectomy and instrumentation, 4) supine cervical vertebral artery injury, and 5) sudden onset hypotension in major prone position reconstructive spine surgery. Twenty-eight surveys (Spine Fellows n = 11; Spine surgeon Faculty n = 17) were completed and returned to the investigators. Results were sorted and ranked according to the frequency each action was identified as a top five choice.

Results.

Following formal statistical evaluation loss of signals in neuro-monitoring had the statistically significantly most uniform response while the scenario involving cardiac compromise had the most heterogeneous. Many “best” responses had near or complete consensus while some “distractor” possibilities that could harm a patient were also selected by the respondents.

Conclusion.

The heterogeneity of responses in the face of “disaster scenario” intraoperative events shows there is room for more thorough and directed education of spine surgeons during training. As surgical teaching moves toward increased use of patient simulation and situational learning, these vignettes hopefully serve to provide direction for training future spine surgeons on how best to approach difficult situations.

Level of Evidence: 4
Pedicle Stress Injury in Children and Adolescents With Low Back Pain
Authors: Ekin Elif Evrim , Altunrende Muhittin Emre
Published: March 2019

Study Design.

A cross-sectional, retrospective cohort study.

Objective.

To examine the prevalence of the pedicle stress injury, spondylolysis in children and adolescents with low back pain. And secondly, to test the hypothesis that these pathologies are associated with lumbar lordosis angle.

Summary of Background Data.

The prevalence of the pedicle stress injury has not been investigated in children with low back pain. In recent studies, lumbar lordosis angle was associated with spondylolysis, on the other hand the pedicle stress injury was not investigated yet.

Methods.

In this retrospective study, 789 consecutive lumbar magnetic resonance imaging under 18 years of age were reviewed between January 2015 and July 2018. Seven hundred magnetic resonances imaging among them were included in the study (mean age: 14.87 ± 2.41 yrs; range: 4–17). Prevalence of spondylolysis, spondylolisthesis, pedicle stress injury, pedicle deformation, disc degeneration, and increased lordosis was investigated and compared in terms of sex. The relationship between increased lordosis and other pathologies was evaluated with risk ratio. Nominal variables were evaluated between the two groups using chi-square, Mann–Whitney U test.

Results.

Prevalence of pedicle stress injury (12.7%), spondylolysis (8.7%), spondylolisthesis (4.1%), pedicle deformation (3.1%), disc degeneration (24%), increase in lordosis (17.4%) was found. Spondylolysis and pedicle injury were more frequent in males (P = 0.025, P < 0.001, respectively). Increased lordosis was more frequent in females (P < 0.001). Pedicle stress injury was frequently observed between 13 to 17 years and often an isolated lesion (69.6%). Spondylolysis, spondylolisthesis, pedicle deformity were more frequent in increased lordosis (P < 0.001), whereas pedicle injury frequency was not found to be different (P = 0.997).

Conclusion.

Pedicle stress injury is a common cause of back pain under 18 years of age, more common in males, and often an isolated lesion. No relationship was found between pedicle stress injury and increased lordosis, unlike other pathologies.

Level of Evidence: 3
Case Studies in Thyroid Dysfunction and Pregnancy
Authors: SULLIVAN SCOTT A. , CUFF RYAN D. , GOODIER CHRISTOPHER G. , CHAPMAN ALISON K. , CHITTIMOJU SANJITA B. , STERRETT MARY
Published: March 2019

This chapter represents a selection of 8 clinical scenarios that may commonly be encountered. They help summarize some of the literature and teaching points of the previous chapters. They are not meant to represent every possible presentation of thyroid disease, but rather to present common symptoms and findings that may aid a clinician in making a diagnosis or in selecting initial treatment.
Parathyroid Diseases
Authors: SULLIVAN SCOTT A.
Published: March 2019

Although uncommon in pregnancy, parathyroid dysfunction may produce significant perinatal and maternal morbidity and mortality. The prevalence of hyperparathyroidism is 0.5%. The most common cause of primary hyperparathyroidism in pregnancy is a single parathyroid adenoma, which is present in nearly 80% of cases. Surgery is the only definitive treatment for primary hyperparathyroidism, with a cure rate that is excellent. The most common etiology of hypoparathyroidism is damage to the parathyroid glands after surgery, with an incidence of 0.2%. Treatment of hypoparathyroidism is usually a high-calcium diet with vitamin D supplementation. Vitamin D deficiency is common, associated with perinatal morbidity and easily corrected.
Smartphone Disc Photography Versus Standard Stereoscopic Disc Photography as a Teaching Tool
Authors: Pujari Amar , Selvan Harathy , Goel Siddhi , Ayyadurai Nikitha , Dada Tanuj
Published: March 2019

Optic disc photographic assessment was performed using an unmodified iPhone Xs Max. A video recording of the disc and peripapillary area was obtained in 5 patients. Good quality screenshots were acquired from the video, and, from them, a single best quality image was selected. This was compared with their respective standard optic disc stereo photograph. A glaucomatologist blinded to the type of image acquisition studied these images and concluded that both images could help well in the identification of glaucomatous optic disc features; however, the stereo photograph had better clarity than the iPhone static image. Nevertheless, the iPhone offered the advantage of real-time video assessment of the disc and peripapillary area and could serve as a practical and handy tool for telemedicine and teaching purposes.
Interleukin 6 decreases nociceptor expression of the potassium channel KV1.4 in a rat model of hand–arm vibration syndrome
Authors: Alvarez Pedro , Bogen Oliver , Levine Jon D.
Published: March 2019

Chronic muscle pain is a prominent symptom of the hand–arm vibration syndrome (HAVS), an occupational disease induced by exposure to vibrating power tools, but the underlying mechanism remains unknown. We evaluated the hypothesis that vibration induces an interleukin 6 (IL-6)-mediated downregulation of the potassium voltage-gated channel subfamily A member 4 (KV1.4) in nociceptors leading to muscle pain. Adult male rats were submitted to a protocol of mechanical vibration of the right hind limb. Twenty-four hours after vibration, muscle hyperalgesia was observed, concomitant to increased levels of IL-6 in the gastrocnemius muscle and decreased expression of KV1.4 in the dorsal root ganglia. Local injection of neutralizing antibodies against IL-6 attenuated the muscle hyperalgesia induced by vibration, whereas antisense knockdown of this channel in the dorsal root ganglia mimicked the muscle hyperalgesia observed in the model of HAVS. Finally, knockdown of the IL-6 receptor signaling subunit glycoprotein 130 (gp130) attenuated both vibration-induced muscle hyperalgesia and downregulation of KV1.4. These results support the hypothesis that IL-6 plays a central role in the induction of muscle pain in HAVS. This likely occurs through intracellular signaling downstream to the IL-6 receptor subunit gp130, which decreases the expression of KV1.4 in nociceptors.
Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response
Authors: Recla Jill M. , Bubier Jason A. , Gatti Daniel M. , Ryan Jennifer L. , Long Katie H. , Robledo Raymond F. , Glidden Nicole C. , Hou Guoqiang , Churchill Gary A. , Maser Richard S. , Zhang Zhong-wei , Young Erin E. , Chesler Elissa J. , Bult Carol J.
Published: March 2019

Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.
Effect of Sertraline, Dosulepin, and Venlafaxine on Non-BDNF Neurotrophins in Patients With Depression
Authors: Mishra Biswa Ranjan , Maiti Rituparna , Nath Santanu , Sahoo Pallabi , Jena Monalisa , Mishra Archana
Published: March 2019

Background

The neurotrophic hypothesis of depression has been mostly studied with a focus on brain-derived neurotrophic factor (BDNF) leading to lack of data on non-BDNF neurotrophins (NTs). The aim of this study was to evaluate the effect of antidepressant drugs on changes in serum nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4).

Methods

A prospective cohort study was conducted on 105 patients with depression who were subgrouped to the group 1 (mild and moderate depression without somatic syndrome treated with sertraline), group 2 (mild and moderate depression with somatic syndrome treated with dosulepin), and group 3 (severe depression without psychotic symptoms treated with venlafaxine). At baseline, the severity of depression (Montgomery-Asberg Depression Rating Scale [MADRS]), serum NGF, NT-3, and NT-4 were estimated. Thirty-five healthy volunteers were recruited as controls for a baseline comparison of NTs. All patients were followed up after 6 weeks to evaluate the changes in NT levels and correlate it with the change in MADRS scores.

Results

At baseline, NT levels were significantly lower in patients with depression in comparison with healthy control. In group 1, serum NGF, NT-3, and NT-4 level were found to increase significantly after treatment, whereas changes in groups 2 and 3 were statistically not significant. Montgomery-Asberg Depression Rating Scale score and serum NGF at baseline had an inverse relation (r = −0.648), whereas the change in MADRS score in sertraline group had a positive correlation (r = 0.86) with the change of serum NGF.

Conclusions

Monotherapy with sertraline increased the level of non-BDNF NTs; however, treatment with dosulepin and venlafaxine did not produce any significant changes in patients with depression.
Effect of Red Yeast Rice on Cognitive Functioning in Schizophrenia
Authors: Bruno Antonio , Pandolfo Gianluca , Crucitti Manuela , Troili Giulia Maria , Battaglia Fortunato , Zoccali Rocco Antonio , Muscatello Maria Rosaria Anna
Published: March 2019

Background

Cognitive deficits (CDs) in schizophrenia affect poor outcome and real-world community functioning. Because redox imbalance has been implicated, among other factors, in the pathophysiology of CDs, antioxidant compounds may have a beneficial effect in their treatment. Red yeast rice (RYR), besides its lipid-lowering effect, exhibit antioxidant and anti-inflammatory.

Methods

Thirty-five schizophrenia outpatients (age range, 18–60 years) on stable antipsychotic treatment and assessed by neuropsychological (Wisconsin Card Sorting Test [WCST], Verbal Fluency, and Stroop task) and psychodiagnostic instruments (Brief Psychiatric Rating Scale) received RYR at daily dosage of 200 mg/d (total monacolin K/capsule content, 11.88 mg) for 12 weeks.

Results

Red yeast rice supplementation significantly improved WCST “perseverative errors” (P = 0.015), “total errors” (P = 0.017, P = 0.001), and phonemic fluency test (P = 0.008); a trend for improvement on other WCST variables (“nonperseverative errors,” “perseverative responses,” and “categories”) was observed. Effect sizes, according to Cohen's suggestions, were small in all explored cognitive dimensions. There were no significant change in clinical symptoms and no subject-reported adverse effects.

Conclusions

Despite several limitations (open design, lack of a control group, short period of observation, small sample size, mode of controlling patients' compliance, the lack of assessment of patients' functional improvement), results suggest that RYR supplementation may be a potentially promising strategy for addressing CDs in schizophrenia; further randomized, placebo-controlled studies are needed to better evaluate the potential role of RYR for the treatment of CDs in schizophrenia.
Longitudinally Measured Changes in Somnolence Severity With a Visual Analog Scale in a Randomized Lithium Versus Quetiapine-IR Study in Bipolar Disorder
Authors: Gao Keming , Su Meilei , Ganocy Stephen J. , Goto Toyomi , Yuan Chengmei , Fang Fang , Conroy Carla , Brownrigg Brittany , Serrano Mary Beth , Calabrese Joseph R.
Published: March 2019

Objective

The aim of this study was to use a visual analog scale (VAS) longitudinally measuring somnolence severity in patients with bipolar disorder.

Methods

A data set of patients with bipolar spectrum disorders who were randomized to lithium or quetiapine-IR for 16 weeks was used. The somnolence severity was measured with a VAS from 0 to 100 (VAS based), and somnolence frequency was recorded according to incident report (incidence based) at each visit. The rates of VAS-based and incidence-based somnolence and changes in somnolence severity from baseline to the end of study were compared between the lithium and quetiapine groups. Longitudinal changes in somnolence severity were analyzed with linear regression analysis.

Results

Of 42 patients randomized, only 3 scored 0 on the VAS at baseline. The rates of incidence-based and VAS-based somnolence were similar in the lithium and quetiapine-IR groups. The VAS change scores from baseline to each visit varied in both groups with significant decreases at weeks 6 and 12 in the quetiapine-IR group only. The decrease at week 6 in the quetiapine-IR group was significantly different from that in the lithium group. Patterns of changes in somnolence severity were inconsistent in both groups. A significant interaction between time course and the decrease in VAS scores was observed in the quetiapine-IR group, but not in the lithium group.

Conclusions

Baseline somnolence was highly prevalent in patients with bipolar disorder. The change in somnolence severity was different between lithium-treated and quetiapine-treated patients. Quantifying somnolence longitudinally is important in clinical trials and practice.
Proprotein convertase subtilisin/kexin type 9 and lipid metabolism
Authors: Spolitu Stefano , Dai Wen , Zadroga John A. , Ozcan Lale
Published: March 2019

Purpose of review

The purpose of this review is to highlight the recent findings of one of the most promising therapeutic targets in LDL cholesterol (LDL-C) management, proprotein convertase subtilisin/kexin type 9 (PCSK9).

Recent findings

Endoplasmic reticulum cargo receptor, surfeit locus protein 4 interacts with PCSK9 and regulates its exit from endoplasmic reticulum and its secretion. Once secreted, PCSK9 binds to heparin sulfate proteoglycans on the hepatocyte surface and this binding is required for PCSK9–LDL receptor (LDLR) complex formation and LDLR degradation. Posttranscriptionally, recent work has shown that PCSK9 gets degraded in lysosomes by activation of the glucagon receptor signaling, providing more data on the hormonal regulation of PCSK9. Finally, human studies with PCSK9 inhibitors offered more evidence on their benefits and safe use.

Recent work on the regulation of PCSK9 has enhanced our understanding of its biology, which may provide important information for future PCSK9-based therapies.
A Biotin Tagging Immunoelectron Microscopy for Paraffin-embedded Sections
Authors: Nishida Haruto , Kashima Kenji , Yano Shinji , Daa Tsutomu , Arakane Motoki , Oyama Yuzo , Kusaba Takahiro , Kadowaki Hiroko , Yokoyama Shigeo
Published: March 2019

We herein introduce a novel method of biotin tagging immunoelectron microscopy for formalin-fixed, paraffin-embedded sections. This method was developed to utilize the antigenicity of biotin on epoxy-embedded ultrathin sections that could readily be recovered by a previously established antigen retrieval method as most monoclonal antibodies failed to recognize their targets by immunoelectron microscopy following antigen retrieval. The biotin tagging method was composed of preembedding immunostaining, epoxy-embedding and sectioning, and postembedding immunostaining steps. The preembedding step utilized the streptavidin-biotin-peroxidase complex method for immunohistochemistry to tag every antigen with a biotin in 3-μm thick paraffin-embedded sections. Next, fixation and processing for transmission electron microscopy (TEM) were performed on sections on glass slides, and ultrathin sections were prepared in epoxy-embedded blocks. In the postembedding step, antigen retrieval was followed by serial incubations with an antibiotin monoclonal antibody and anti-mouse IgG-labeled gold particles. The results obtained using antibodies against a variety of intracellular targets were satisfactory; positive gold particles were observed corresponding to targeted intracellular structures. This study demonstrated that the biotin tagging method was a convenient approach for successful labeling of paraffin-embedded sections for TEM using monoclonal antibodies, although it has relatively poor subcellular labeling quality.
Ethics in the PED
Authors: Dreisinger Naomi , Moore David
Published: March 2019

Death is an uncommon event in the pediatric emergency department. The sudden end of a young life is always an undesirable event. Staff and family members are never prepared. Although staff in the emergency department can become routinized to caring for acutely ill and dying patients, family members may become shocked by this novel and terrible experience. Whether the patient is old or young, previously sick or healthy, it is important to stop and consider how hard it must be for the assembled family. As frontline clinicians, we all deeply care about the outcome of our patients and their families, yet for them to feel they have been understood and well cared for, it is recognized that clinicians must attend to health care conversations on a deeper and more relational level. Consideration that these events happen and reinforcing that it is difficult for all involved ensure staff that their challenges are recognized.
The changing course of multiple sclerosis: rising incidence, change in geographic distribution, disease course, and prognosis
Authors: Magyari Melinda , Sorensen Per Soelberg
Published: March 2019

Purpose of review

This review provides a brief update of new research findings on the changing epidemiology, disease course, and prognosis of multiple sclerosis (MS).

Recent findings

Evidence not only continues to support the female predominance in incidence and prevalence of the disease but also supports an increase in incidence of MS in geographic areas that were previously considered to be low incidence for the disease.

An increased interest in population-based registries and databases will provide more valid epidemiological measures and observational studies conducted in well-defined study populations. Such studies are crucial for an accurate description of both changing prognosis of MS and differential characteristics of the various MS phenotypes.
Title: Intergenerational effects of early adversity on survival in wild baboons
Authors: Zipple Matthew N. , Archie Elizabeth A. , Tung Jenny , Altmann Jeanne , Alberts Susan C.
Published: March 2019

In humans and nonhuman animals, early life adversity can affect an individual’s health, survival, and fertility for many years after the adverse experience. However, whether early life adversity also imposes intergenerational effects on the exposed individual’s offspring is not well understood. Here, we fill this gap by leveraging prospective, longitudinal data on a wild, long-lived primate. We find that juveniles whose mothers experienced early life adversity exhibit high mortality before age 4, and this effect is independent of the juvenile’s own experience of early adversity. Furthermore, our results point towards a strong role for classic parental effects in driving these effects: mothers that experienced early life adversity displayed reduced viability in adulthood, which in turn led to reductions in offspring survival. Importantly, these mothers’ juvenile offspring often preceded them in death by 1 to 2 years, indicating that, for high adversity mothers, the quality of maternal care declines near the end of life. While we cannot exclude direct effects of a parent’s environment on offspring quality (e.g., transgenerational epigenetic changes), our results are most consistent with a classic parental effect, in which the environment experienced by a parent affects its future phenotype and therefore its offspring’s phenotype. Together, our findings demonstrate that adversity experienced by individuals in one generation can have strong effects on the survival of offspring in the next generation, even if those offspring did not themselves experience early adversity.
Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression
Authors: Courtney David G. , Chalem Andrea , Bogerd Hal P. , Law Brittany A. , Kennedy Edward M. , Holley Christopher L. , Cullen Bryan R.
Published: March 2019

While it has been known for several years that viral RNAs are subject to the addition of several distinct covalent modifications to individual nucleotides, collectively referred to as epitranscriptomic modifications, the effect of these editing events on viral gene expression has been controversial. Here, we report the purification of murine leukemia virus (MLV) genomic RNA to homogeneity and show that this viral RNA contains levels ofN6-methyladenosine (m6A), 5-methylcytosine (m5C) and 2’O-methylated (Nm) ribonucleotides that are an order of magnitude higher than detected on bulk cellular mRNAs. Mapping of m6A and m5C residues on MLV transcripts identified multiple discrete editing sites and allowed the construction of MLV variants bearing silent mutations that removed a subset of these sites. Analysis of the replication potential of these mutants revealed a modest but significant attenuation in viral replication in 3T3 cells in culture. Consistent with a positive role for m6A and m5C in viral replication, we also demonstrate that overexpression of the key m6A reader protein YTHDF2 enhances MLV replication, while downregulation of the m5C writer NSUN2 inhibits MLV replication.

Importance

The data presented in this manuscript demonstrate that MLV RNAs bear an exceptionally high level of the epitranscriptomic modifications m6A, m5C and Nm, thus suggesting that these each facilitate some aspect of the viral replication cycle. Consistent with this hypothesis, we demonstrate that mutational removal of a subset of these m6A or m5C modifications from MLV transcripts inhibits MLV replication incisand a similar result was also observed upon manipulation of the level of expression of key cellular epitranscriptomic cofactors intrans. Together, these results argue that the addition of several different epitranscriptomic modifications to viral transcripts stimulates viral gene expression and suggest that MLV has therefore evolved to maximize the level of these modifications that are added to viral RNAs.
Driving the scalability of DNA-based information storage systems
Authors: Tomek Kyle J. , Volkel Kevin , Simpson Alexander , Hass Austin G. , Indermaur Elaine W. , Tuck James , Keung Albert J.
Published: March 2019

The extreme density of DNA presents a compelling advantage over current storage media; however, in order to reach practical capacities, new approaches for organizing and accessing information are needed. Here we use chemical handles to selectively extract unique files from a complex database of DNA mimicking 5 TB of data and design and implement a nested file address system that increases the theoretical maximum capacity of DNA storage systems by five orders of magnitude. These advancements enable the development and future scaling of DNA-based data storage systems with reasonable modern capacities and file access capabilities.
TET2 regulates the neuroinflammatory response in microglia
Authors: Carrillo-Jimenez Alejandro , Deniz Özgen , Niklison-Chirou Maria Victoria , Ruiz Rocio , Bezerra-Salomão Karina , Stratoulias Vassilis , Amouroux Rachel , Yip Ping Kei , Vilalta Anna , Cheray Mathilde , Scott-Egerton Alexander Michael , Rivas Eloy , Tayara Khadija , García-Domínguez Irene , Garcia-Revilla Juan , Fernandez-Martin Juan Carlos , Espinosa-Oliva Ana Maria , Shen Xianli , StGeorge-Hyslop Peter , Brown Guy Charles , Hajkova Petra , Joseph Bertrand , Venero Jose L. , Branco Miguel Ramos , Burguillos Miguel Angel
Published: March 2019

Epigenetic mechanisms regulate distinct aspects of the inflammatory response in various immune cell types. Despite the central role for microglia, the resident macrophages of the brain, in neuroinflammation and neurodegeneration little is known about their epigenetic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes that lead to early metabolic alterations, as well as a later inflammatory response independently of its 5mC oxidation activity at the affected genes. We further show that TET2 regulates the proinflammatory response in microglia induced by intraperitoneal injection of LPSin vivo. We observed that microglia associated to amyloid β plaques, recently defined as disease-associated microglia, expressed TET2 in brain tissue from individuals with Alzheimer’s disease (AD) and in 5×FAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response, and suggest TET2 as a potential target to combat neurodegenerative brain disorders.
Construction and analysis of an interologous protein-protein interaction network ofCamellia sinensisleaf (TeaLIPIN) from RNA-Seq datasets
Authors: Singh Gagandeep , Singh Vikram , Singh Vikram
Published: March 2019

Worldwide, tea (Camellia sinensis) is the most consumed beverage primarily due to the taste, flavour and aroma of its newly formed leaves; and has been used as an important ingredient in several traditional medicinal systems because of its antioxidant properties. For this medicinally and commercially important plant, design principles of gene-regulatory and protein-protein interaction networks at sub-cellular level are largely un-characterized mainly because neither its reference assembly nor annotated genome is available though plenty of its transcriptomes have been studied. In this work, we report a tea leaf interologous PPI network (TeaLIPIN) consisting of 11,208 nodes and 1,97,820 interactions. A reference transcriptome assembly was first developed from all the 44 samples of 6 publicly available leaf transcriptomes (1,567,288,290 raw reads). By inferring the high-confidence interactions among potential proteins coded by these transcripts using known experimental information about PPIs in 14 plants, an interologous PPI network was constructed and its modular architecture was explored. Comparing this PPI network with 10,000 realisations of corresponding random networks (Erdős-Rényi models) and examining over three network centrality metrics, we predict 2,931 bottleneck proteins (havingp-values<0.01). 270 of these are deduced to have transcription factor domains by developing the HMM models of known plant TFs. Final transcripts were also mapped to the draft tea genome in order to search the probable loci of their origin. We believe that the proposed novel methodology can easily be adopted to develop and explore the PPI interactomes in other plant species by making use of the available transcriptomic data.
The mRNA-bound proteome ofLeishmania mexicana: novel genetic insight into an ancient parasite
Authors: de Pablos Luis M. , Ferreira Tiago R. , Dowle Adam A. , Forrester Sarah , Parry Ewan , Newling Katherine , Walrad Pegine B.
Published: March 2019

Leishmaniaparasite infections, termed the leishmaniases, cause significant global infectious disease burden. The lifecycle of the parasite embodies three main stages that require precise coordination of gene regulation to survive environmental shifts between sandfly and mammalian hosts. Constitutive transcription in kinetoplastid parasites means that gene regulation is overwhelmingly reliant on post-transcriptional mechanisms, yet strikingly fewLeishmania trans-regulators are known. Utilizing optimised crosslinking and deep, quantified mass spectrometry, we present a comprehensive analysis of 1,400 mRNA binding proteins (mRBPs) and whole cell proteomes from the three mainLeishmanialifecycle stages. Supporting the validity, while the crosslinked RBPome is magnitudes more enriched the protein identities of the crosslinked and non-crosslinked RBPomes were nearly identical. Moreover, multiple candidate RBPs were endogenously tagged and found to associate with discrete mRNA target pools in a stage-specific manner. Results indicate that inL.mexicanaparasites, mRNA levels are not a strong predictor of the whole cell expression or RNA binding potential of encoded proteins. Evidence includes a low correlation between transcript and corresponding protein expression and stage-specific variation in protein expression versus RNA binding potential. Unsurprisingly, RNA binding protein enrichment correlates strongly with relative replication efficiency of the specific lifecycle stage. Our study is the first to quantitatively define and compare the mRBPome of multiple stages in kinetoplastid parasites. It provides novel, in-depth insight into thetrans-regulatory mRNA:Protein (mRNP) complexes that driveLeishmaniaparasite lifecycle progression.
Precuneus stimulation alters the neural dynamics of autobiographical memory retrieval
Authors: Hebscher Melissa , Ibrahim Christine , Gilboa Asaf
Published: March 2019

Autobiographical memory (AM) unfolds over time, but little is known about the dynamics of its retrieval. Space-based models of memory implicate the hippocampus, retrosplenial cortex, and precuneus in early memory computations. Here we used inhibitory continuous theta burst stimulation (cTBS) to determine the causal role of the precuneus in the temporal dynamics of AM retrieval. Compared to vertex, precuneus stimulation altered evoked neural activity during early memory construction, as early as 400 ms after cue presentation, as well as during later memory elaboration. We further identified a parietal late positive component during memory elaboration, the amplitude of which was associated with spatial perspective during recollection. Precuneus stimulation disrupted this association, suggesting that this region plays a crucial role in the neural representation of spatial perspective during AM. These findings help clarify the neural correlates of early memory retrieval and demonstrate a causal role for the precuneus in the temporal dynamics of AM retrieval.
Patterning of the vertebrate head in time and space by BMP signalling
Authors: Zhu Kongju , Spaink Herman P. , Durston Antony J.
Published: March 2019

How head patterning is regulated in vertebrates is yet to be understood. In this study, we show that frog embryos injected with Noggin at different blastula and gastrula stages had their head development sequentially arrested at different positions. When timed BMP inhibition was applied to BMP-overexpressing embryos, the expression of five genes:xcg-1(a marker of the cement gland, which is the front-most structure in the frog embryo),six3(a forebrain marker),otx2(a forebrain and mid-brain marker),gbx2(an anterior hindbrain marker) andhoxd1(a posterior hindbrain marker) were sequentially fixed. These results suggest that timed interactions between BMP and anti-BMP are involved in patterning the vertebrate head progressively in time and space. Since the above genes are not expressed sequentially, there may be a BMP dependent gene sequence during head patterning that can be arrested by BMP inhibition and regulate the specification of positional values in the head.
Rate-limiting transport of positive charges through the Sec-machinery is integral to the mechanism of protein transport
Authors: Allen William J. , Corey Robin A. , Watkins Daniel W. , Oliveira A. Sofia F. , Hards Kiel , Cook Gregory M. , Collinson Ian
Published: March 2019

Transport of proteins across and into membranes is a fundamental biological process with the vast majority being conducted by the ubiquitous Sec machinery. In bacteria, this is usually achieved when the SecY-complex engages the cytosolic ATPase SecA (secretion) or translating ribosomes (insertion). Great strides have been made towards understanding the mechanism of protein translocation. Yet, important questions remain – notably, the nature of the individual steps that constitute transport, and how the proton-motive force (PMF) across the plasma membrane contributes. Here, we apply a recently developed high-resolution protein transport assay to explore these questions. We find that pre-protein transport is limited primarily by the diffusion of arginine residues across the membrane, particularly in the context of bulky hydrophobic sequences. This specific effect of arginine, caused by its positive charge, is mitigated for lysine which can be deprotonated and transported across the membrane in its neutral form. These observations have interesting implications for the mechanism of protein secretion, suggesting a simple mechanism by which PMF can aid transport, and enabling a ‘proton ratchet’, wherein re-protonation of exiting lysine residues prevents channel re-entry, biasing transport in the outward direction.
A gene based approach to test genetic association based on an Optimally Weighted Combination of Multiple Traits
Authors: Zhang Jianjun , Sha Qiuying , Liu Guanfu , Wang Xuexia
Published: March 2019

There is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases for which multiple correlated traits are often measured. Joint analysis of multiple traits could increase statistical power by aggregating multiple weak effects. Existing methods for multiple trait association tests usually study each of the multiple traits separately and then combine the univariate test statistics or combine p-values of the univariate tests for identifying disease associated genetic variants. However, ignoring correlation between phenotypes may cause power loss. Additionally, the genetic variants in one gene (including common and rare variants) are often viewed as a whole that affects the underlying disease since the basic functional unit of inheritance is a gene rather than a genetic variant. Thus, results from gene level association test can be more readily integrated with downstream functional and pathogenic investigation, whereas many existing methods for multiple trait association tests only focus on testing a single common variant rather than a gene. In this article, we propose a statistical method by Testing an Optimally Weighted Combination of Multiple traits (TOW-CM) to test the association between multiple traits and multiple variants in a genomic region (a gene or pathway). We investigate the performance of the proposed method through extensive simulation studies. Our simulation studies show that the proposed method has correct type I error rates and is either the most powerful test or comparable with the most powerful tests. In addition, we illustrate the usefulness of TOW-CM by analyzing a whole-genome genotyping data from a COPDGene study.
Class I and II aminoacyl-tRNA synthetase tRNA groove discrimination created the first synthetase•tRNA cognate pairs and was therefore essential to the origin of genetic coding
Authors: Carter Charles W. , Wills Peter R.
Published: March 2019

The genetic code likely arose when a bidirectional gene began to produce ancestral aminoacyl-tRNA synthetases (aaRS) capable of distinguishing between two distinct sets of amino acids. The synthetase Class division therefore necessarily implies a mechanism by which the two ancestral synthetases could also discriminate between two different kinds of tRNA substrates. We used regression methods to uncover the possible patterns of base sequences capable of such discrimination and find that they appear to be related to thermodynamic differences in the relative stabilities of a hairpin necessary for recognition of tRNA substrates by Class I aaRS. The thermodynamic differences appear to be exploited by secondary structural differences between models for the ancestral aaRS called synthetase Urzymes and reinforced by packing of aromatic amino acid side chains against the nonpolar face of the ribose of A76 if and only if the tRNA CCA sequence forms a hairpin. The patterns of bases 1, 2 and 73 and stabilization of the hairpin by structural complementarity with Class I, but not Class II aaRS Urzymes appears to be necessary and sufficient to have enabled the generation of the first two aaRS•tRNA cognate pairs, and the launch of a rudimentary binary genetic coding related recognizably to contemporary cognate pairs. As a consequence, it seems likely that non-random aminoacylation of tRNAs preceded the advent of the tRNA anticodon stem-loop. Consistent with this suggestion, coding rules in the acceptor-stem bases also reveal a palimpsest of the codon•anticodon interaction, as previously proposed.
Lipidome profiles of postnatal day 2 vaginal swabs reflect fat composition of gilt’s postnatal diet
Authors: Harlow KaLynn , Ferreira Christina R. , Sobreira Tiago J.P. , Casey Theresa , Stewart Kara
Published: March 2019

We hypothesized that postnatal development of the vagina is impacted by early nutritional environment. Our objective was to determine if lipid profiles of vaginal swabs were different between gilts suckled by sow or fed milk replacer the first 48 h postpartum, with and without a lard-based fat supplement. Gilts (>1.3 kg) were selected at birth across 8 litters and assigned to treatments: colostrum suckled (S, n=8); S plus fat supplement (SF, n=5); bottle-fed milk replacer (B, n=8); or B plus fat supplement (BF, n=7). At 48 h postnatal, vaginal swabs were taken with a cytology brush, immersed in ultrapure water to burst cells, and lipids extracted for analysis using multiple reaction monitoring (MRM)-profiling. Lipids extracted from serum collected at 48 h from gilts and milk collected from sows at 24 h were also analyzed with MRM-profiling. Receiver operating characteristic curve analysis found 18 lipids highly distinguished [area-under-the-curve (AUC) > 0.9] between S and B gilts, including phosphatidylethanolamine with 34 carbon and four unsaturations in the fatty acyl residues [PE(34:4)]. Twelve lipids from vaginal swabs highly correlated (r> 0.6;p< 0.01) with nutrition source. Lipids more abundant in milk replacer drove association. For example, mean intensity of PE (34:4) was 149-fold higher in milk replacer than colostrum, with 1.6- and 2.12-fold higher levels in serum and vaginal swab samples (p< 0.001), respectively, of B versus S gilts. Findings support that vaginal swabs can be used to noninvasively study effects of perinatal nutrition on tissue composition.

Summary sentence

Vaginal swab lipidome profiles at 48 h reflect the fat composition of neonatal diet during first two days postnatal.
Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis
Authors: Kupz Andreas , Pai Saparna , Giacomin Paul R. , Whan Jennifer A. , Walker Robert A. , Hammoudi Pierre-Mehdi , Smith Nicholas C. , Miller Catherine M.
Published: March 2019

Toxoplasmic encephalitis is an AIDS-defining condition in HIV+individuals. The decline of IFN-γ-producing CD4+T cells in AIDS is a major contributing factor in reactivation of quiescentToxoplasma gondiito an actively replicating stage of infection. Hence, it is important to identify CD4-independent mechanisms to control acuteT. gondiiinfection. Here we have investigated the targeted expansion and regulation of IFN-γ production by CD8+T cells, DN T cells and NK cells in response toT. gondiiinfection using IL-2 complex (IL2C) pre-treatment in an acutein vivomouse model. Our results show that expansion of CD8+T cells, DN T cells and NK cell by S4B6 IL2C treatment increases survival rates of mice infected withT. gondiiand this increased survival is dependent on both IL-12- and IL-18-driven IFN-γ production. Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic cell types but independent fromT. gondii-derived dense granule (GRA) proteins. Our results provide evidence for a protective role of IL2C-mediated expansion of CD8+T cells, DN T cells and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute toxoplasmosis.

Author Summary

A third of the world’s population is chronically infected with the parasiteToxoplasma gondii. In most cases the infection is asymptomatic, but in individuals suffering from AIDS, reactivation of brain and muscle cysts containingT. gondiiis a significant cause of death. The gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing factor in reactivation ofT. gondiiinfection and the development of acute disease. In this study, we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease and premature death via increased availability of interferon gamma-producing immune cells. We also demonstrate that the upstream signaling molecule interleukin-18 is required for the protective immune response by non-CD4 cells and show that the sensing of active parasite invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell expansion may be a promising therapy in toxoplasmosis and suggests that the development of novel intervention strategies targeting danger recognition pathways may be useful against toxoplasmosis, particularly in the context of AIDS.
Is there more room to improve? The lifespan trajectory of procedural learning and its relationship to the between- and within-group differences in average response times
Authors: Juhasz Dora , Nemeth Dezso , Janacsek Karolina
Published: March 2019

Characterizing the developmental trajectories of cognitive functions such as learning, memory and decision making across the lifespan faces fundamental challenges. Cognitive functions typically encompass several processes that can be differentially affected by age. Methodological issues also arise when comparisons are made across age groups that differ in basic performance measures, such as in average response times (RTs). Here we focus on procedural learning – a fundamental cognitive function that underlies the acquisition of cognitive, social, and motor skills – and demonstrate how disentangling subprocesses of learning and controlling for differences in average RTs can reveal different developmental trajectories across the human lifespan. Two hundred-seventy participants aged between 7 and 85 years performed a probabilistic sequence learning task that enabled us to separately measure two processes of procedural learning, namely general skill learning and statistical learning. Using raw RT measures, in between-group comparisons, we found a U-shaped trajectory with children and older adults exhibiting greater general skill learning compared to adolescents and younger adults. However, when we controlled for differences in average RTs (either by using ratio scores or focusing on a subsample of participants with similar average speed), only children (but not older adults) demonstrated superior general skill learning consistently across analyses. Testing the relationship between average RTs and general skill learning within age groups shed light on further age-related differences, suggesting that general skill learning measures are more affected by average speed in some age groups. Consistent with previous studies of learning probabilistic regularities, statistical learning showed a gradual decline across the lifespan, and learning performance seemed to be independent of average speed, regardless of the age group. Overall, our results suggest that children are superior learners in various aspects of procedural learning, including both general skill and statistical learning. Our study also highlights the importance to test, and control for, the effect of average speed on other RT measures of cognitive functions, which can fundamentally affect the interpretation of group differences in developmental, aging and clinical psychology and neuroscience studies.
Crystallographic and spectroscopic characterization of 4-nitro-2-(trifluoromethyl)benzoic acid and 4-nitro-3-(trifluoromethyl)benzoic acid
Authors: Diehl III George L. , Je Lisa , Tanski Joseph M.
Published: March 2019

The title compounds, both C8H4F3NO4, represent two isomers of nitro trifluoromethyl benzoic acid. The compounds each contain a nitro functionality para to the carboxylic acid group, with the trifluoromethyl substituent ortho to the acid group in the 2-isomer and ortho to the nitro group in the 3-isomer. The regiochemistry with respect to the trifluoromethyl group results in steric interactions that rotate the carboxylic acid group or the nitro group out of the aromatic plane in the 2- and 3-isomer, respectively. Each molecule engages in intermolecular hydrogen bonding, forming head-to-tail dimers with graph-set notation R
2
2(8) and donor–acceptor hydrogen-bonding distances of 2.7042 (14) Å in the 2-isomer and 2.6337 (16) in the 3-isomer. Recrystallization attempts did not yield untwinned crystals.