bluuebunny/crossref_metadata_2025 huggingface dataset:
Viability of Mesenchymal Stem Cells in an Ex Vivo Circulation System
Authors: Cho Hwa Jin , Hong Hyun , Kim Do Wan , Lee Kyo Seon , Han Hwa Seon , Kim Geum Hee , Choi Kyung Soon , Kim Yong Sook , KAYUMOV MUKHAMMAD , Ki Katrina K. , Suen Jacky , Fraser John , Jeong In Seok
Published: June 2019

Extracorporeal membrane oxygenation (ECMO) is a well-known therapy for refractory cardiac and respiratory failure. Stem cell therapy has been investigated as an adjunctive treatment for use during ECMO, but little is known about the viability of stem cells during ECMO support. We evaluated the viability and activity of mesenchymal stem cells (MSCs) in ex vivo circulation (EVC) conditions. The experimental groups were divided into two subgroups: EVC with oxygenator (OXY group) and EVC without oxygenator (Non-OXY group). Mesenchymal stem cells (1.0 × 107) were injected into the EVC system. Cell counting, a lactate dehydrogenase (LDH) cytotoxicity assay, and the mitochondrial functions of viable MSCs were analyzed. The post-EVC oxygen consumption rate (OCR) was significantly lower than the pre-EVC OCR, regardless of whether the oxygenator was used. The LDH levels were significantly higher in the OXY group than in the Non-OXY group. The cellular loss was mainly due to lysis of the cells whereas the loss of cellular activity was attributed to the nonphysiologic condition itself, as well as the oxygenator. We concluded that direct infusion of MSCs during ECMO support did not serve as adjunctive therapy. Further studies are needed to improve the viability in an ECMO setting.
Left Ventricular Assist Device Outflow Graft Pseudoaneurysm Treated with Covered Balloon Expandable Stent
Authors: Pya Yuriy , Mussayev Abdurashid , Alimbayev Serik , Medressova Assel , Bekbossynov Serik , Andossova Saltanat , Khissamutdinov Nail , Jetybayeva Saltanat , la Fleur Philip
Published: June 2019

Left ventricular assist device (LVAD) outflow graft injury is a very rare complication after LVAD implantation and is usually treated surgically. This is a case report of successful stenting of the damaged outflow graft 2.5 years after LVAD implantation, followed by successful heart transplantation.
Efficacy of risk stratification protocols and clinical, physical, and biochemical parameters to previse signals and symptoms during cardiovascular rehabilitation programs
Authors: Vanzella Laís Manata , Takahashi Carolina , Ribeiro Felipe , Lima Isabelle Maina , Silva Anne Kastelianne França da , Christófaro Diego Giulliano Destro , Vanderlei Luiz Carlos Marques
Published: June 2019

Introduction

Despite the benefits, cardiovascular rehabilitation programs (CRPs) have been related to the appearance of signals and symptoms. Risk stratification protocols are commonly used to identify risks during the physical exercise; however, studies that investigate their efficacy to previse signals and symptoms are inconclusive. Furthermore, clinical, physical, and biochemical parameters have been used as risk markers for the appearance of adverse events, and to investigate their efficacy to previse signals and symptoms during the CRP sessions that could better guide the strategies adopted on these programs.

Objectives

The aim of this study was to evaluate the correlations between risk stratification protocols and clinical, physical, and biochemical parameters with the appearance of signals/symptoms during CRP, as well as to evaluate if modifications on clinical, physical, and biochemical parameters could influence in the appearance of signals/symptoms during CRP.

Materials and methods

The study was prospectively registered at ClinicalTrials.gov (NCT03446742). Forty-four patient participants of a CRP will be evaluated. First, their risk stratification is going to be performed by 2 evaluators and their clinical, physical, and biochemical parameters are going to be measured. Then, the patients are going to be followed during 24 sessions during their CRP routines in order to identify appearance of their signals/symptoms. So, the patients are going to perform their cardiovascular rehabilitation routines for 6 months and then, their clinical, physical, and biochemical parameters are going to be measured again and they are going to be followed during 24 sessions during their CRP routines in order to identify the appearance of their signals/symptoms.
The prescription patterns of traditional Chinese medicine for women with polycystic ovary syndrome in Taiwan
Authors: Lin Mei-Jiun , Chen Hsiao-Wei , Liu Pi-Hua , Cheng Wei-Jen , Kuo Shun-Li , Kao Ming-Chen
Published: June 2019

Polycystic ovary syndrome (PCOS) is a common endocrine disease of reproductive-age women, accounting for about 9% to 18% of all women in this age group. Hyperandrogenemia, oligomenorrhea, or amenorrhea or anovulation, and polycystic ovary morphology are the 3 main criteria used to diagnose PCOS currently. Substantial scientific evidence and consensus on treating Taiwanese PCOS was lacking. The aim of this study is to investigate the characteristics and utilization of traditional Chinese medicine (TCM) among Taiwanese women with PCOS.

The data used in this study were derived from the Longitudinal Health Insurance Database (LHID 2000 and LHID 2005). Demographic characteristics, TCM usage, the frequency, as well as average daily dose of Chinese herbal formulas and the single herbs prescribed for patients with PCOS, were analyzed. Chinese herbal formulas and the single herbs prescribed for PCOS women during 1999 to 2013 were extracted to build up Chinese Herbal Medicine prescription database.

In our study, 66.43% (n = 8205) women sought TCM treatment because of PCOS for infertility or menstrual disorders. The most commonly prescribed Chinese herbal formula was Jia-wei-xiao-yao-san (Supplemented Free Wanderer Powder). The most commonly prescribed single herb was Yi-mu-cao (Leonuri herba). Among top 20 Chinese herbal formulas, Si-wu-tang has the largest average daily dosage (9.60 g).

Our study identified the characteristics and prescription patterns of TCM for patients with PCOS in Taiwan. We may need do further longitudinal research for TCM and its long-term response for improvement of pregnancy rate and reduction of metabolic disease rate.
Peri-cardiac surgery coagulation management in a severe hemophilia A patient
Authors: Xu Hongfei , Henry Davies , Li Chengcheng , Zhao Haige , Yang Yanyan
Published: June 2019

Rationale:

Hemophilia A (HA) is an X-linked recessive disorder caused by clotting factor VIII (FVIII) deficiency. There is limited data on the use of replacement therapy in cardiac surgery. Since no international guideline for anticoagulation in such patient exists, careful thought should be taken to design an individualized anticoagulation strategy.

Patient concerns:

We report a 54-year-old male with severe HA with FVIII activity of 0.8% when he was first diagnosed, who underwent successful mitral valve repair and coronary artery bypass graft with FVIII replacement perioperatively.

Diagnoses:

Transthoracic echocardiography and coronary angiography confirmed the HA patient with the diagnosis of severe mitral valve regurgitation and left anterior descending artery stenosis.

Interventions:

Before surgery, a bolus of 1000 IU FVIII was injected, which obtained an FVIII of 80%. After induction, a 3750 IU bolus of FVIII was injected and subsequent FVIII level reached 135%. Mitral valve repair and coronary artery bypass graft with FVIII replacement were performed. After the surgery, a repeat FVIII activity level was 50.6%. The 400 mL of autologous blood and 700 mL of cardiopulmonary bypass (CPB) machine blood was returned to the patient as well as 4 units of fresh frozen plasma with an additional bolus of 1000 IU FVIII. 100 mg aspirin per day alone was given after surgery.

Outcomes:

The patient recovered uneventfully and 1-year follow-up showed no complications.

Lessons:

The anticoagulant or antiplatelet regimen of HA patient following surgery should be individualized based on the evaluation of the risk factors for bleeding and thrombosis and the lowest FVIII activity ever recorded after FVIII replacement therapy.
Primary Ewing's sarcoma of the vertebral body
Authors: Zhao Duo-Yi , Zhang Wei-Lin , Cui Yan , Ma Cheng-Bin , Ni Sheng-Hui , Zhang Zhi-Yu
Published: June 2019

Rational:

The occurrence of Ewing's sarcoma in the vertebral body of elderly women is extremely rare, and the case of Ewing's sarcoma in the spine with secondary surgical repair after wrong diagnosis and treatment has not been reported. We report a case involving primary Ewing's sarcoma of the vertebral body in an elderly female. Owing to its rarity and controversial issues, we report a case report to discuss its clinical features, treatments, radiological, and histological characteristics.

Patient concerns:

The elderly female patient came to see us with the manifestation of total paralysis of both lower limbs. The patient with a vertebral compression fracture as the primary manifestation was misdiagnosed in another hospital. The patient underwent inappropriate surgical treatment and was transferred to our hospital for diagnosis and second-stage surgery.

Diagnoses:

The postoperative pathological examination and immunohistochemical examination in our hospital confirmed: Ewing's sarcoma; Surgical history at other hospitals suggests: after Bone cement injection.

Interventions:

The patient underwent a T6 and T8 laminectomy and T5/6-T9 pedicle screw fixation.

Outcomes:

Reexamination 1 month after the surgery showed that the tumor had been partially resected, the spinal cord compression was relieved, the tumor did not grow further, and the patient's lower limb physical ability, tactile sense, algesia and temperature sense recovered slightly.

Lessons:

For patients with ewing's tumor in the spinal canal with symptoms of spinal cord compression, even if the patients with poor results after a unadvisable operation, it is still necessary to be actively in spinal cord compression by surgery. The differential diagnosis of Ewing's sarcoma and compression fractures is very important. For patients with vertebral tumors, special attention should be taken during vertebroplasty for bone cement leakage caused by excessive bone cement injection and increased local pressure. And some experience with imaging and laboratory findings.
Minimally invasive triangular osteosynthesis for highly unstable sacral fractures
Authors: Kanezaki Shozo , Miyazaki Masashi , Notani Naoki , Ishihara Toshinubu , Sakamoto Tomonori , Sone Takashi , Kataoka Masashi , Tsumura Hiroshi
Published: June 2019

Triangular osteosynthesis involves unilateral L5 iliac posterior instrumentation combined with an iliosacral screw fixation. The aim of this study was to describe this procedure and report the preliminary clinical results in patients with unstable sacral fractures treated with minimally invasive triangular osteosynthesis (MITO). Between 2012 and 2017, 10 patients (6 men and 3 women, mean age, 50 ± 23 years) with sacral fractures were treated with MITO and were followed up for a mean of 15.0 ± 8.5 months in our institution. Classification of sacral fracture, operative time, intraoperative bleeding, timing of full weight bearing, bone union, complications, and clinical outcomes were investigated. Two cases were classified as Denis zone 1, 2 cases as zone 2, and 6 as zone 3. Four patients had Roy-Camille type 1 fracture and 2 patients had type 2. All patients underwent MITO, which involved bilateral lumbopelvic fixation and a uni/bilateral iliosacral screw with stab incisions for percutaneous fixation or central longitudinal incision. The operative time was a mean of 182 ± 64 minutes, and the amount of intraoperative bleeding was a mean of 63 ± 74 g. Full-weight bearing was initiated at a mean of 8.2 ± 2.4 weeks. Eight fractures healed; 1 patient had pulmonary embolism and 1 had implant loosening. Based on Majeed score, 8 patients had “excellent” clinical outcomes, 1 patient had a “good” clinical outcome, and the other had a “fair” clinical outcome. MITO could be less invasive on the soft tissues and be a reliable procedure for bony union. It might provide sufficient stability to accelerate the commencement of post-operative rehabilitation, even in patients with highly unstable sacral fractures.
A nomogram for predicting survival in patients with nodular melanoma
Authors: Yang Jin , Pan Zhenyu , Zhao Fanfan , Feng Xiaojie , Liu Qingqing , Li Yuanjie , Lyu Jun
Published: June 2019

The use of traditional American Joint Committee on Cancer (AJCC) staging alone has limitations in predicting patient survival with nodular melanoma (NM). We aimed to establish a comprehensive prognostic nomogram and compare its prognostic value with the AJCC staging system.

A nomogram was constructed to predict the 3-year and 5-year survival rates of NM patients by Cox regression. Several common model-validation parameters were used to evaluate the performance of our survival model.

The multivariate analyses demonstrated that the age at diagnosis; being divorced, separated, or widowed; AJCC stages II, III, and IV; a regional SEER stage and the lymph-node density (LND) were risk factors for survival. The concordance index, the area under the time-dependent receiver operating characteristic curve, and calibration plots indicated that the nomogram performed well, while the net reclassification improvement and the integrated discrimination improvement showed that the nomogram performed better than the AJCC staging system. Finally, the decision curve analyses curves of the nomogram yielded net benefits that were higher than when using AJCC staging system with either the training or the validation cohort.

The prognostic value of the nomogram is better than that of the AJCC staging system alone. In addition, we found that LND is an important risk factor for the survival of NM patients. The nomogram developed in this study may be a valuable tool for clinical practice when advising patients about their survival risk over the next 3 to 5 years.
Pancreatic schwannoma mimicking pancreatic cystadenoma
Authors: Wang Shunda , Xing Cheng , Wu Huanwen , Dai Menghua , Zhao Yupei
Published: June 2019

Introduction:

Schwannomas, also known as neurilemmoma, are benign neoplasms that originating from Schwann cells in peripheral nerve sheaths. The head, neck, and extremities are the most common sites; however, pancreatic schwannomas are rare neoplasms. Accurate preoperative diagnosis of these tumors is very tough because of pancreatic schwannomas usually mimicking other cystic tumors. Here we present a case of pancreatic schwannoma misdiagnosed as pancreatic cystadenoma.

Patient concerns:

We presented a rare case of a 55-year-old female admitted to our hospital for abdominal distension. The physical examination and results of laboratory testing reveal no abnormalities.

Diagnosis:

A computed tomography (CT) scan detected a hypodense 2.4 cm × 2.6 cm mass with a clear margin at the neck of the pancreas. Pancreatic cystadenoma was strongly suspected.

Interventions:

The patient underwent robotic distal pancreatectomy with splenectomy. The gross specimen showed a pale and solid mass with a capsule.

Outcomes:

Histological examination of the surgical specimen demonstrated a pancreatic schwannoma. Immunohistochemistry results were as follows: S-100 (+), CD117 (−), SMA (−), and Desmin (−). She was discharged on postoperative day 6 and no recurrence of the tumor happened during the 12-month follow-up.

Conclusion:

Precise preoperative diagnosis of pancreatic schwannomas is very difficult despite the application of multiple imaging modalities. Surgery is the most effective treatment for this rare disease and the final diagnosis usually relies on pathology. Following complete tumor removal, patients with pancreatic schwannomas generally have a good prognosis.
Performance of the Psychotic Depression Assessment Scale as a Predictor of ECT Outcome
Authors: van Diermen Linda , Versyck Pieter , van den Ameele Seline , Madani Yamina , Vermeulen Tom , Fransen Erik , Sabbe Bernard G. C. , van der Mast Roos C. , Birkenhäger Tom K. , Schrijvers Didier
Published: June 2019

Objectives

The presence of psychotic symptoms is an important predictor of responsiveness to electroconvulsive therapy (ECT). This study investigates whether a continuous severity measure, the Psychotic Depression Assessment Scale (PDAS), is a more accurate predictor.

Methods

Depression severity was assessed before and after the ECT course using the Montgomery-Asberg Depression Rating Scale (MADRS) in 31 patients with psychotic depression and 34 depressed patients without psychotic symptoms. Logistic regression models for MADRS response and remission were fitted, with either the PDAS total score or the dichotomous predictors “absence/presence of psychotic symptoms” as the independent variables. Age, episode duration, and treatment resistance were added as covariates.

Results

Both the asserted presence of psychotic symptoms and a higher PDAS total score reflected MADRS response (areas under the curve, 0.83 and 0.85, respectively), with MADRS remission also being predicted by the presence of psychotic symptoms and higher PDAS scores (areas under the curves, 0.86 and 0.84, respectively). Age was a contributor to these prediction models, with response and remission rates being highest in the older patients. Psychotic Depression Assessment Scale scores decreased significantly during ECT: at end point, 81.5% of the patients showed significant response and 63.9% had achieved remission.

Conclusions

The PDAS indeed accurately predicts response to and remission after ECT in (psychotic) depression and most pronouncedly so in older patients but seems to have no clear advantage over simply verifying the presence of psychotic symptoms. This could be the consequence of a ceiling effect, as ECT was extremely effective in patients with psychotic depression.

ClinicalTrials.gov: Identifier: NCT02562846.
Pseudogene associated recurrent gene fusion in prostate cancer
Authors: Chakravarthi Balabhadrapatruni VSK , Dedigama-Arachchige Pavithra , Carskadon Shannon , Sundaram Shanker Kalyana , Li Jia , Wu Kuan-Han Hank , Chandrashekar Darshan Shimoga , Peabody James , Stricker Hans , Hwang Clara , Chitale Dhananjay , Williamson Sean , Gupta Nilesh , Navone Nora M , Rogers Craig , Menon Mani , Varambally Sooryanarayana , Palanisamy Nallasivam
Published: June 2019

Analysis of next generation transcriptome sequencing data of prostate cancer identified a novel gene fusion formed by the fusion of a protein coding gene (KLK4) with a non-coding pseudogene (KLKP1) and expression of its cognate protein. Screening of 659 prostate cancer TMA showed about 32% of positive cases predominantly expressed in higher Gleason grade tumors. Concomitant expression with ERG but not with SPINK1 and other ETS fusion positive tumors. Fusion gene expression potentially regulated by AR and ERG. Antibody specific to the KLK4-KLKP1 fusion protein was validated by immunohistochemistry and western blot methods. Oncogenic properties were validated by in vitro and in vivo functional studies. Clinical data analysis shows significant association with prostate cancer in young men and overall survival analysis indicate favorable prognosis. Non-invasive detection in urine samples has been confirmed. Taken together, we present a novel biomarker for routine screening of high Gleason grade prostate cancer at diagnosis.

SIGNIFICANCE

We discovered and validated a novel prostate cancer (PCa) specific fusion gene involving a protein coding (KLK4) and a pseudogene (KLKP1) and its cognate protein. The unique feature of this fusion gene is the conversion of the noncoding pseudogene into a protein coding gene and its unique expression only in about 30% of high Gleason grade PCa. Expression of this gene is found to be concomitant in ERG fusion positive prostate cancer but mutually exclusive with SPINK1, ETV1, ETV4 and ETV5 positive tumors. Like other ETS family gene fusions, KLK4-KLKP1 can be detected in the urine samples of patients with prostate cancer enabling non-invasive detection of high Gleason grade prostate cancer. Given the unique feature of this fusion oncogenic potential, high Gleason grade specific expression and noninvasive detection, this novel gene fusion has a potential to be used as a biomarker for early detection of high-grade prostate cancer and a therapeutic target.
N1-methyladenine safeguards against aberrant RNA-protein association during proteostasis stress
Authors: Alriquet Marion , Calloni Giulia , Martínez-Limón Adrían , Ponti Riccardo Delli , Hanspach Gerd , Hengesbach Martin , Tartaglia Gian G. , Vabulas R. Martin
Published: June 2019

Post-transcriptional modifications of nucleotide bases can effect several aspects of mRNA function. For example, the recent work has established the role of m6A in the coordinated regulation of transcriptome turnover and translation during cellular differentiation and tumorigenesis. The levels of m1A in mRNAs reach up to 10% of those of m6A, yet the functional consequences of this modification are much less clear. Here we show that N1-methyladenine protects mRNAs against aberrant interactions during heat shock and amyloidogenesis in mammalian cells. The m1A methylation motif correlated with the enhanced sequestration of transcripts in stress granules (SG). The cognate methyltransferase TRMT6/61A accumulated and m1A was enriched in SG. Downregulation of the catalytic subunit TRMT61A enhanced amyloidogenesis in the cytosol and increased bystander protein and RNA co-aggregation with Aβ aggregates. Faulty granulation of mutant RNAs has been implicated in pathogenesis of protein aggregation disorders. Our results demonstrate that also normal mRNAs succumb to co-aggregation with proteins if RNA dynamics during stress is disturbed due to the insufficient N1-adenine methylation.
Midkine-a is required for cell cycle progression of Müller glia during neuronal regeneration
Authors: Nagashima Mikiko , D’Cruz Travis S. , Hesse Doneen , Sifuentes Christopher J. , Raymond Pamela A. , Hitchcock Peter F.
Published: June 2019

In zebrafish, Müller glia function as intrinsic retinal stem cells that can regenerate ablated neurons. Understanding the mechanisms governing neuronal stem cells may provide clues to regenerate neurons in mammals. We report that in Müller glia the cytokine/growth factor, Midkine-a, functions as a core autocrine regulator of the cell cycle. Utilizing midkine-a mutants, we determined that Midkine-a regulates elements of an Id2a-retinoblastoma network in reprogrammed Müller glia that controls the expression of cell cycle genes and is required for transition from G1 to S phases of the cell cycle. In mutants, Müller glia that fail to divide undergo reactive gliosis, a pathological hallmark of Müller glia in mammals. Finally, we show that activation of the Midkine-a receptor, ALK, is required for Müller glia proliferation. These data provide mechanistic insights into Müller glia stem cells in the vertebrate retina and suggest avenues for eliciting neuronal regeneration in mammals.
Gli2 is necessary for migration of ventral Neural Stem Cells to demyelinated lesions
Authors: Radecki Daniel Z. , Messling Heather , Haggerty-Skeans James R. , Samanta Jayshree , Salzer James L.
Published: June 2019

Enhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells in the sub-ventricular zone are marked by Gli1 expression and do not generate oligodendrocytes. However, in response to demyelination they migrate to lesions and differentiate into oligodendrocytes. Inhibition of Gli1 further increases their contribution to remyelination. Gli1 and Gli2 are both transcriptional effectors of the Sonic Hedgehog pathway with highly conserved domains but the role of Gli2 in remyelination by ventral neural stem cells is not clear. Here we show that while genetic ablation of Gli1 in the ventral neural stem cells increases remyelination, loss of Gli2 in these cells decreases their migration to the white matter lesion and reduces their differentiation into mature oligodendrocytes. These studies indicate Gli1 and Gli2 have distinct, non-redundant functions in NSCs, including that Gli2 is essential for the enhanced remyelination mediated by Gli1 inhibition. They highlight the importance of designing specific Gli1 inhibitors that do not inhibit Gli2 as a strategy for therapies targeting the Shh pathway.

Graphical Abstract
Shiny-SoSV: A web-based performance calculator for somatic structural variant detection
Authors: Gong Tingting , Hayes Vanessa M , Chan Eva KF
Published: June 2019

Somatic structural variants are an important contributor to cancer development and evolution. Accurate detection of these complex variants from whole genome sequencing data is influenced by a multitude of parameters. However, there are currently no tools for guiding study design nor are there applications that could predict the performance of somatic structural variant detection. To address this gap, we developed Shiny-SoSV, a user-friendly web-based calculator for determining the impact of common variables on the sensitivity and precision of somatic structural variant detection, including choice of variant detection tool, sequencing depth of coverage, variant allele fraction, and variant breakpoint resolution. Using simulation studies, we determined singular and combinatoric effects of these variables, modelled the results using a generalised additive model, allowing structural variant detection performance to be predicted for any combination of predictors. Shiny-SoSV provides an interactive and visual platform for users to easily compare individual and combined impact of different parameters. It predicts the performance of a proposed study design, on somatic structural variant detection, prior to the commencement of benchwork. Shiny-SoSV is freely available at https://hcpcg.shinyapps.io/Shiny-SoSV with accompanying user’s guide and example use-cases.
An improved pig reference genome sequence to enable pig genetics and genomics research
Authors: Warr Amanda , Affara Nabeel , Aken Bronwen , Beiki H. , Bickhart Derek M. , Billis Konstantinos , Chow William , Eory Lel , Finlayson Heather A. , Flicek Paul , Girón Carlos G. , Griffin Darren K. , Hall Richard , Hannum Greg , Hourlier Thibaut , Howe Kerstin , Hume David A. , Izuogu Osagie , Kim Kristi , Koren Sergey , Liu Haibou , Manchanda Nancy , Martin Fergal J. , Nonneman Dan J. , O’Connor Rebecca E. , Phillippy Adam M. , Rohrer Gary A. , Rosen Benjamin D. , Rund Laurie A. , Sargent Carole A. , Schook Lawrence B. , Schroeder Steven G. , Schwartz Ariel S. , Skinner Ben M. , Talbot Richard , Tseng Elizabeth , Tuggle Christopher K. , Watson Mick , Smith Timothy P. L. , Archibald Alan L.
Published: June 2019

The domestic pig (Sus scrofa) is important both as a food source and as a biomedical model with high anatomical and immunological similarity to humans. The draft reference genome (Sscrofa10.2) of a purebred Duroc female pig established using older clone-based sequencing methods was incomplete and unresolved redundancies, short range order and orientation errors and associated misassembled genes limited its utility. We present two annotated highly contiguous chromosome-level genome assemblies created with more recent long read technologies and a whole genome shotgun strategy, one for the same Duroc female (Sscrofa11.1) and one for an outbred, composite breed male (USMARCv1.0). Both assemblies are of substantially higher (>90-fold) continuity and accuracy than Sscrofa10.2. These highly contiguous assemblies plus annotation of a further 11 short read assemblies provide an unprecedented view of the genetic make-up of this important agricultural and biomedical model species. We propose that the improved Duroc assembly (Sscrofa11.1) become the reference genome for genomic research in pigs.
Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits
Authors: Thion Morgane Sonia , Mosser Coralie-Anne , Férézou Isabelle , Grisel Pauline , Baptista Sofia , Low Donovan , Ginhoux Florent , Garel Sonia , Audinat Etienne
Published: June 2019

The etiology of neurodevelopmental disorders is linked to defects in Parvalbumin (PV)-expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia, have a two-step impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a novel framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.
Matrix metalloproteinase 1 modulates invasive behavior of tracheal branches during ingression intoDrosophilaflight muscles
Authors: Sauerwald Julia , Backer Wilko , Matzat Till , Schnorrer Frank , Luschnig Stefan
Published: June 2019

Tubular networks like the vasculature extend branches throughout the bodies of animals, but how developing vessels interact with and invade tissues is not well understood. We investigated the underlying mechanisms using the developing tracheal tube network ofDrosophilaindirect flight muscles (IFMs) as a model. Live imaging revealed that tracheal sprouts invade IFMs directionally with growth-cone-like structures at branch tips. Ramification inside IFMs proceeds until tracheal branches fill the myotube. However, individual tracheal cells occupy largely separate territories, possibly mediated by cell-cell repulsion. Matrix metalloproteinase 1 (MMP1) is required in tracheal cells for normal invasion speed and for the dynamic organization of growth-cone-like branch tips. MMP1 remodels the Collagen IV-containing matrix around branch tips and promotes degradation of Branchless FGF in cultured cells. Thus, tracheal-derived MMP1 may play dual roles in sustaining branch invasion by modulating ECM properties as well as by shaping the distribution of the FGF chemoattractant.
Affective Touch Dimensions: From Sensitivity to Metacognition
Authors: von Mohr Mariana , Kirsch Louise P. , Loh Joey K. , Fotopoulou Aikaterini
Published: June 2019

Touch can give rise to different sensations including sensory, emotional and social aspects. Tactile pleasure typically associated with caress-like skin stroking of slow velocities (1-10 cm/s) has been hypothesised to relate to an unmyelinated, slow-conducting C-tactile afferent system (CT system), developed to distinguish affective touch from the ‘‘noise’’ of other tactile information on hairy skin (the so-called ‘social touch hypothesis’). However, to date, there is no psychometric examination of the discriminative and metacognitive processes that contribute to accurate awareness of pleasant touch stimuli. Over two studies (total N= 194), we combined for the first time CT stimulation with signal detection theory and metacognitive measurements to assess the social touch hypothesis on the role of the CT system in affective touch discrimination. Participants’ ability to accurately discriminate pleasantness of tactile stimuli of different velocities, as well as their response bias, was assessed using a force-choice task (high versus low pleasantness response) on two different skin sites: forearm (CT-skin) and palm (non-CT skin). We also examined whether such detection accuracy was related to the confidence in their decision (metacognitive sensitivity). Consistently with the social touch hypothesis, we found higher sensitivity d’ on the forearm versus the palm, indicating that people are better at discriminating between stimuli of high and low tactile pleasantness on a skin site that contains CT afferents. Strikingly, we also found more negative response bias on the forearm versus the palm, indicating a tendency to experience all stimuli on CT-skin as ‘high-pleasant’, with such effects depending on order, likely to be explained by prior touch exposure. Finally, we found that people have greater confidence in their ability to discriminate between affective touch stimuli on CT innervated skin than on non-CT skin, possibly relating to the domain specificity of CT touch hence suggesting a domain-specific, metacognitive hypothesis that can be explored in future studies as an extension of the social touch hypothesis.

Highlights

Touch mediated by C-tactile (CT) afferents on hairy skin elicits pleasant sensations

We combine for the first time CT stimulation with signal detection theory

Better accuracy to detect pleasantness of tactile stimuli at CT optimal speeds on CT skin

Higher confidence in ability to accurately distinguish affective touch on CT skin
Coevolution-based prediction of protein-protein interactions in polyketide biosynthetic assembly lines
Authors: Wang Yan , Marrero Miguel Correa , Medema Marnix H. , van Dijk Aalt D.J.
Published: June 2019

Polyketide synthases are multimodular enzymes that generate diverse molecules of great pharmaceutical importance, including a range of clinically used antimicrobials and antitumor agents. Many polyketides are synthesized by type I polyketide synthases (PKSs), which are organized in assembly lines, in which multiple enzymes line up in a specific order. This order is defined by specific protein-protein interactions. The unique modular structure and catalyzing mechanism of these assembly lines makes their products predictable and also spurred combinatorial biosynthesis studies to produce novel polyketides using synthetic biology. However, predicting the interactions of PKSs, and thereby inferring the order of their assembly line, is still challenging, especially for cases in which this order is not reflected by the ordering of the PKS-encoding genes in the genome. Here, we introduce PKSpop, which uses a coevolution-based protein-protein interaction prediction algorithm to infer protein order in PKS assembly lines. Our method accurately predicts protein orders (80% accuracy). Additionally, we identify new residue pairs that are key in determining interaction specificity, and show that coevolution of N- and C-terminal docking domains of PKSs is significantly more predictive for protein-protein interactions than coevolution between ketosynthase and acyl carrier protein domains.
Evaluation of Open Hollow Hydroxyapatite Microsphere on Bone Regeneration in Rat Calvarial Defects
Authors: Shen Youqu , Rahaman Mohamed , Liu Yongxian , Huang Yue-Wern
Published: June 2019

Hollow hydroxyapatite (HA) microspheres showed the ability to facilitate bone regeneration in rats with non-healing calvarial defects. However, new bone formation in the rat calvarial defect implanted with the closed HA microspheres was limited. The objective of this work is to evaluate size-, time, and structure-dependent bone regeneration between open and closed HA microspheres in an osseous model. Open HA microspheres were obtained by sectioning closed HA microspheres. The open HA microsphere had dense convex surface and rough and porous concave surface. For both size ranges (ϕ106-150 μm vs. ϕ212-250 μm), the open HA microsphere were more effective in facilitating bone regeneration than the closed HA microspheres in rat calvarial defects. Bone regeneration in the open HA microspheres (49 ± 7% for ϕ106-150 μm; 40 ± 8% for ϕ212-250 μm) were higher than the closed HA microsphere (26 ± 8% for ϕ106-150 μm; 30 ± 9% for ϕ212-250 μm) at 12 weeks. Furthermore, the open HA microspheres of smaller size showed a significant increase in bone regeneration than the open HA microspheres of larger size at both 6 weeks and 12 weeks. The difference in bone regeneration between these microspheres could be due to their differences in microstructures, namely curvature, concavity, porosity, surface roughness, and total surface area available for cells to attached to.
Insulin-like growth factor 1 receptor signaling in tenocytes is required for adult tendon growth
Authors: Disser Nathaniel P , Sugg Kristoffer B , Talarek Jeffrey R , Sarver Dylan C , Rourke Brennan J , Mendias Christopher L
Published: June 2019

Tenocytes serve to synthesize and maintain collagen fibrils and other matrix proteins in tendon. The underlying biological mechanisms of postnatal tendon growth and repair are not well understood. Insulin-like growth factor 1 (IGF1) plays an important role in the growth and remodeling of numerous tissues, but less is known about IGF1 in tendon. We hypothesized that IGF1 signaling is required for proper tendon growth in response to mechanical loading through regulation of collagen synthesis and cell proliferation. We conditionally deleted the IGF1 receptor (IGF1R) in scleraxis (Scx) expressing tenocytes, and compared to control Scx:IGF1R+ mice, Scx:IGF1RΔ mice demonstrated reduced tenocyte proliferation and smaller tendons in response to mechanical loading. Additionally, we identified that both the PI3K/Akt and ERK pathways are activated downstream of IGF1 and interact in a coordinated manner to regulate cell proliferation and protein synthesis. These studies indicate that IGF1 signaling is required for proper postnatal tendon growth.
An Optimized Screen Reduces the Number of GA Transporters and provides Insights into NPF Substrate Determinants
Authors: Wulff Nikolai , Ernst Heidi Asschenfeldt , Jørgensen Morten Egevang , Lambertz Sophie , Maierhofer Tobias , Belew Zeinu Mussa , Crocoll Christoph , Motawia Mohammed Saddik , Geiger Dietmar , Jørgensen Flemming Steen , Mirza Osman , Nour-Eldin Hussam Hassan
Published: June 2019

Based on recent in vitro data, a relatively large number of the plant Nitrate transporter 1/Peptide transporter Family (NPF) proteins has been suggested to function as gibberellic acid (GA) transporters. Most GA transporting NPF proteins also appear to transport other structurally unrelated phytohormones or metabolites. Several of the GAs used in previous in vitro assays are membrane permeable weak organic acids whose movement across membranes are influenced by the pH-sensitive ion-trap mechanism. Moreover, a large proportion of in vitro GA transport activities have been demonstrated indirectly via long-term yeast-based GA-dependent growth assays that are limited to detecting transport of bioactive GAs. Thus, there is a need for an optimized transport assay for identifying and characterizing GA transport. Here, we develop an improved transport assay in Xenopus laevis oocytes wherein we directly measure movement of six different GAs across oocyte membranes over short time. We show that membrane permeability of GAs in oocytes can be predicted based on number of oxygen atoms and that several GAs do not diffuse over membranes regardless of changes in pH values. In addition, we show that small changes in internal cellular pH can result in strongly altered distribution of membrane permeable phytohormones. This prompts caution when interpreting heterologous transport activities. We use our transport assay to screen all Arabidopsis thaliana NPF proteins for transport activity towards six GAs (two membrane permeable and four non-permeable). The results presented here, significantly reduce the number of bona fide NPF GA transporters in Arabidopsis and narrow the activity to fewer subclades within the family. Furthermore, to gain first insight into the molecular determinants of substrate specificities towards organic molecules transported in the NPF, we charted all surface exposed amino acid residues in the substrate-binding cavity and correlated them to GA transport. This analysis identified distinct residues within the substrate-binding cavity that are shared between GA transporting NPF proteins; the potential roles of these residues in determining substrate specificity are discussed.
Rare earth element (REE)-dependent growth of Pseudomonas putida KT2440 depends on the ABC-transporter PedA1A2BC and is influenced by iron availability
Authors: Wehrmann Matthias , Berthelot Charlotte , Billard Patrick , Klebensberger Janosch
Published: June 2019

In the soil-dwelling organism Pseudomonas putida KT2440, the rare earth element (REE)-utilizing and pyrroloquinoline quinone (PQQ)-dependent ethanol dehydrogenase PedH is part of a periplasmic oxidation system that is vital for growth on various alcoholic volatiles. Expression of PedH and its Ca2+-dependent counterpart PedE is inversely regulated in response to lanthanide (Ln3+) bioavailability, a mechanism termed the REE-switch. In the present study, we demonstrate that copper, zinc, and in particular, iron availability influences this regulation in a pyoverdine-independent manner by increasing the minimal Ln3+ concentration required for the REE-switch to occur by several orders of magnitude. A combined genetic- and physiological approach reveals that an ABC-type transporter system encoded by the gene cluster pedA1A2BC is essential for efficient growth with low (nanomolar) Ln3+ concentrations. In the absence of pedA1A2BC, a ~100-fold higher La3+ concentration is needed for PedH-dependent growth but not for the ability to repress growth based on PedE activity. From these results, we conclude that cytoplasmic uptake of lanthanides through PedA1A2BC is essential to facilitate REE-dependent growth under environmental conditions with poor REE bioavailability. Our data further suggest that the La3+/Fe3+ ratio impacts the REE-switch through the mismetallation of putative La3+-binding proteins, such as the sensor histidine kinase PedS2, in the presence of high iron concentrations. As such, this study provides an example for the complexity of bacteria-metal interactions and highlights the importance of medium compositions when studying physiological traits in vitro in particular in regards to REE-dependent phenomena.
Immune, Autonomic, and Endocrine Dysregulation in Autism and Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorders Versus Unaffected Controls
Authors: Casanova Emily L. , Sharp Julia L. , Edelson Stephen M. , Kelly Desmond P. , Sokhadze Estate M. , Casanova Manuel F.
Published: June 2019

Background

A growing body of literature suggests etiological overlap between Ehlers-Danlos syndrome (EDS)/hypermobility spectrum disorders (HSD) and some cases of autism, although this relationship is poorly delineated. In addition, immune, autonomic, and endocrine dysregulation are reported in both conditions and may be relevant to their respective etiologies.

Aims

To study symptom overlap in these two comorbid spectrum conditions.

Methods and Procedures

We surveyed 702 adults aged 25+ years on a variety of EDS/HSD-related health topics, comparing individuals with EDS/HSD, autism, and unaffected controls.

Outcomes and Results

The autism group reported similar though less severe symptomology as the EDS/HSD group, especially in areas of immune/autonomic/endocrine dysregulation, connective tissue abnormalities (i.e., skin, bruising/bleeding), and chronic pain. EDS/HSD mothers with autistic children reported more immune symptoms than EDS/HSD mothers without, suggesting the maternal immune system could play a heritable role in these conditions (p = 0.0119).

Conclusions and Implications

These data suggest that EDS/HSD and autism share aspects of immune/autonomic/endocrine dysregulation, pain, and some tissue fragility, which is typically more severe in the former. This overlap, as well as documented comorbidity, suggests some forms of autism may be hereditary connective tissue disorders (HCTD).
Differential scanning fluorimetric analysis of the amino-acid binding to taste receptor using a model receptor protein, the ligand-binding domain of fish T1r2a/T1r3
Authors: Yoshida Takashi , Yasui Norihisa , Kusakabe Yuko , Ito Chiaki , Akamatsu Miki , Yamashita Atsuko
Published: June 2019

Taste receptor type 1 (T1r) is responsible for the perception of essential nutrients, such as sugars and amino acids, and evoking sweet and umami (savory) taste sensations. T1r receptors recognize many of the taste substances at their extracellular ligand-binding domains (LBDs). In order to detect a wide array of taste substances in the environment, T1r receptors often possess broad ligand specificities. However, the entire ranges of chemical spaces and their binding characteristics to any T1rLBDs have not been extensively analyzed. In this study, we exploited the differential scanning fluorimetry (DSF) to medaka T1r2a/T1r3LBD, a current sole T1rLBD heterodimer amenable for recombinant preparation, and analyzed their thermal stabilization by adding various amino acids. The assay showed that the agonist amino acids induced thermal stabilization and shifted the melting temperatures (Tm) of the protein. An agreement between the DSF results and the previous biophysical assay was observed, suggesting that DSF can detect ligand binding at the orthosteric-binding site in T1r2a/T1r3LBD. The assay further demonstrated that most of the tested L-amino acids, but no D-amino acid, inducedTmshifts of T1r2a/T1r3LBD, indicating the broad L-amino acid specificities of the proteins probably with several different manners of recognition. TheTmshifts by each amino acid also showed a fair correlation with the responses exhibited by the full-length receptor, verifying the broad amino-acid binding profiles at the orthosteric site in LBD observed by DSF.
Study of the AMP-activated protein kinase role in energy metabolism changes during the postmortem aging of yak longissimus lumborum
Authors: Yang Yayuan , Han Ling , Yu Qunli , Gao Yongfang , Song Rende
Published: June 2019

To explore the postmortem physiological mechanism of muscle, activity of adenosine monophosphate activated protein kinase (AMPK) as well as its role in energy metabolism of postmortem yaks were studied. In this experiment, we injected 5-amino-1-beta-d-furanonyl imidazole-4-formamide (AICAR), a specific activator of AMPK, and the specific AMPK inhibitor STO-609, to observe the changes in glycolysis, energy metabolism, AMPK activity and AMPK gene expression (PRKA1 and PRKA2) in postmortem yaks during maturation. The results showed that AICAR could increase the expression of the PRKKA1 and PRKAA2 genes, activate AMPK and increase its activity. The effects of AICAR include a lower concentration of ATP, an increase in AMP production, an acceleration of glycolysis, an increase in the lactic acid concentration, and a decrease in the pH value. In contrast, STO-609 had the opposite effect. Under hypoxic adaptation, the activity of the meat AMPK increased, which accelerated glycolysis and metabolism, and more effectively regulated energy production.