bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomical localization of normal parathyroid glands before thyroidectomy through ultrasonography reduces postoperative hypoparathyroidism
Authors: Shou Jin-Duo , He Shui-Ming , Jiang Xian-Feng , Shi Liu-Hong , Xie Lei , Wang Jian-Biao
Published: June 2019

Postoperative hypoparathyroidism due to dysfunction of the parathyroid gland is the most common complication after thyroidectomy. Our objective was to introduce the method of anatomical localization of normal parathyroid glands before thyroidectomy through ultrasonography and to evaluate its efficiency. The study group included 52 patients subjected to anatomical localization of the parathyroid gland prethyroidectomy through ultrasonography. The control group included 52 sex- and age-matched patients without parathyroid gland localization. The proportion of parathyroid glands preserved in situ and postoperative hypoparathyroidism rates in the 2 groups were compared. The rates of normal parathyroid glands identified according to ultrasonography for left superior, left inferior, right superior, and right inferior glands were 78.8%, 90.4%, 57.7%, and 82.7%, respectively. The rate of parathyroid gland excised inadvertently was significantly decreased (P = .038) in the study group as compared with the control group. The rates of parathyroid gland preservation in situ were significantly improved in the left superior (P = .001), left inferior (P = .002), and right inferior glands (P = .005). Furthermore, the incidence of transient hypoparathyroidism decreased significantly (P = .028). Our study indicated that normal parathyroid glands were identified by ultrasonography, and the anatomical localization improved the rate of parathyroid gland preservation in situ and decreased the incidence of transient hypoparathyroidism.
Urinary retention as a postoperative complication associated with functional decline in elderly female patients with femoral neck and trochanteric fractures
Authors: Higashikawa Toshihiro , Shigemoto Kenji , Goshima Kenichi , Usuda Daisuke , Okuro Masashi , Moriyama Manabu , Inujima Hiromi , Hangyou Masahiro , Usuda Kimiko , Morimoto Shigeto , Matsumoto Tadami , Takashima Shigeki , Kanda Tsugiyasu , Sawaguchi Takeshi
Published: June 2019

Urinary retention (UR) has been recognized as one of the most common postoperative complications after hip surgery in elderly. The objective of the present study was to evaluate risk for postoperative complications of UR in elderly female patients with femoral neck fractures.

We recruited 221 female patients (age 85.3 ± 7.0 years) with a history of hip surgery carried out at Toyama Municipal Hospital. UR occurred in 34 out of 221 cases (15.4%). Multiple logistic regression analysis was conducted to investigate the risk factors for UR, including age, body mass index (BMI), serum albumin, cognitive impairment, and activities of daily living (ADL).

The results showed significant association of UR with cognitive impairment (P = .005, odds ratio [OR] 4.11, 95% confidence interval [CI] 1.53–11.03), and ADL (P = .029, OR 2.61, 95% CI 1.11–6.18), under adjustment with age and BMI.

This study demonstrated that cognitive function and ADL were the important risk factors for UR, suggested that the postoperative management of UR is important with taking account of neurofunctional assistance and nursing care in daily living, especially in elderly female patients receiving surgery of femoral neck and trochanteric fractures.
Comparison of the efficacy and safety of phloroglucinol and magnesium sulfate in the treatment of threatened abortion
Authors: Yuan Shaofei , Gao Fengli , Xin Zhong , Guo Haijun , Shi Suqin , Shi Lei , Yang Xia , Guan Jingzhi
Published: June 2019

Background:

To compare the clinical efficacy and safety of phloroglucinol (PHL) and magnesium sulfate (MS) in the treatment of threatened abortion through systematic review.

Methods:

Foreign databases, such as the Cochrane Library, PubMed and EMBASE, and Chinese databases, including the China Biology Medicine disc (SinoMed), China National Knowledge Infrastructure (CNKI), Chongqing VIP (VIP) and WanFang Data, were searched. Published randomized controlled trials (RCTs) documents obtained from these databases were included if they were associated with the research objective. The search timeframe was from the beginning of the establishment of each database to May 2018. Document selection, data abstraction and document quality evaluation were independently performed by 2 investigators. A combined analysis of the data was performed for those documents that fulfilled the study requirements; Rev Man 5.3 and Stata 12.0 software were used to compare and analyze the 2 drugs in terms of the total effective rate (TER), rate of adverse events, time required to relieve uterine contractions, onset time, time of complete relief of uterine contraction symptoms, medication duration and length of hospital stay.

Results:

A total of 21 RCT trials were included in the present research, according to the inclusion criteria. However, the quality of the included studies was low. The meta-analysis suggested that the TER and drug onset time of PHL were higher than those for MS, while the rate of adverse events, the time required to relieve uterine contractions, time to complete relief of uterine contraction symptoms, drug continuous treatment time and length of hospital stay were shorter than those for MS.

Conclusion:

The clinical efficacy of PHL is better than that of MS, and PHL obviously results in fewer adverse reactions than MS. However, due to poor quality of evidence, high quality, multi-center RCTs with large samples are required for further verification.
Pattern identification of lung cancer patients based on body constitution questionnaires (BCQ) and glycoproteomics for precision medicine
Authors: Cho Wonryeon , Kim Ji Hye , Jeong Miseon , Kim Myeong-Sun , Lee Jinwook , Son Hyoungwoo , Cheon Chunhoo , Park Sunju , Ko Seong-Gyu
Published: June 2019

Background:

The patient's pattern identification has been used for personalized medicine in traditional Korean medicine (TKM) and aims for patient-specific therapy by Korean medical doctors. The pattern identification in this trial will be diagnosed from body constitution questionnaire (BCQ) with a more objective diagnosis of it but this method still needs a more concrete scientific basis. Glycoproteins are well-known to be associated with diseases (especially cancers) so glycoproteomics can be applied to differentiate pattern identification types of lung cancer patients. Thus, for the first time proteomics approach will be applied to the pattern identification by comparing BCQ assessment in order to establish a scientific basis with clinical proteomics for precision medicine.

Methods:

This observational trial will at first diagnose the pattern identification types of lung cancer patients with BCQ assessment and then elucidate their relationships with proteomics. Blood samples will be collected before surgery along with clinical information of participants. The patients’ pattern identification in TKM will be diagnosed from BCQ assessment. Then, lung cancer patients will be divided and pooled into 3 lung cancer entire (LCE) groups according to their pattern identification types (Xu, Stasis, or Gentleness). Three lung cancer representative (LCR) groups will be selected and pooled from each LCE group by selecting those with the same control factors. The 3 LCE groups and the 3 LCR groups from lung cancer patients will be independently analyzed through the glycoproteomics approach based on the patients’ pattern identification. Glycoproteins from the 6 groups will be identified through proteomics approach and then categorized for analysis.

Discussion:

This study intends to diagnose pattern identification of patients in TKM with BCQ assessment and proteomics approach. The identification of the glycoproteins in each group will lead to the scientific foundation of personalized medicine in TKM according to patients’ pattern identification for lung cancer therapy. We intend to

(1) diagnose the pattern identification types of lung cancer patients with BCQ under the framework of TKM;

(2) evaluate BCQ assessment with glycoproteomics approach for precision medicine.

Trial registration:

ClinicalTrials.gov NCT03384680. Registered 27 December 2017. Retrospectively registered.
Acupoint catgut embedding for patients with chronic urticaria
Authors: Shi Yunzhou , Hou Tinghui , Zheng Qianhua , Liu Ying , Yang Ting , Li Ying
Published: June 2019

Background:

The purpose of this paper is to evaluate the effectiveness and safety of acupoint catgut embedding in the treatment of chronic urticaria (CU).

Methods:

We will electronically search PubMed, Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and Wan-Fang Database from their inception to March 2019. In addition, we will manually retrieve other resources including the reference lists of identified publications, conference articles, and gray literature. The clinical randomized controlled trials or quasi-randomized controlled trials related to acupoint catgut embedding for the treatment of CU will be included in the study. The language is limited to Chinese and English. Research selection, data extraction, and research quality assessment will be independently completed by 2 researchers. Data were synthesized by using a fixed effect model or random effect model depend on the heterogeneity test. The total effective rate was the primary outcomes. Skin disease quality of life index scores, adverse events, and recurrence rates will also be assessed as secondary outcomes. RevMan V.5.3 statistical software will be used for meta-analysis. If it is not appropriate for a meta-analysis, then a descriptive analysis will be conducted. Data synthesis will use the risk ratio and the standardized or weighted average difference of continuous data to represent the results.

Results:

This study will provide a high-quality synthesis to assess the effectiveness and safety of acupoint catgut embedding for patients with CU.

Conclusion:

This systematic review will provide evidence to judge whether acupoint catgut embedding is an effective intervention for patients with CU.

Systematic review registration:

PROSPERO, CRD42019129459.
Association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk in Chinese people
Authors: Zhong Rui , Chen Qingling , Zhang Xinyue , Li Mengmeng , Zhang Xin , Lin Weihong
Published: June 2019

Background:

The association between Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms and lung cancer risk in Chinese people has been widely explored; however, the results remain controversial. Thus, we conducted a meta-analysis to investigate the association between MTHFR gene polymorphisms and susceptibility to lung cancer in Chinese people.

Objective:

We performed an updated meta-analysis to investigate the association between MTHFR gene polymorphisms and susceptibility to lung cancer in Chinese people.

Methods:

PubMed, EMBASE, WANFANG database, and CNKI were searched to collect eligible articles. The associations of MTHFR gene polymorphism with lung cancer risk were evaluated by calculating the pooled odds ratios (ORs) and the 95% confidence interval (CI). The dominant, recessive, heterozygous, homozygous, and allelic genetic models were used to calculate the combined ORs.

Results:

A total of 16 eligible studies were identified in the present meta-analysis. Evidence from the pooled results indicated a significant association between the MTHFR C677T polymorphism and lung cancer susceptibility in Chinese people under the dominant, recessive, homozygous and allelic genetic models (T vs C: OR = 1.252, 95% CI, 1.090–1.437; TT vs CC: OR = 1.741, 95% CI, 1.252–2.420. (TT + CT) vs CC: OR = 1.227, 95% CI, 1.030–1.426. TT vs (CT + CC): OR = 1.606, 95% CI, 1.207–2.137).

Conclusion:

The present updated meta-analysis demonstrated that the MTHFR C677T polymorphism was significantly associated with susceptibility to lung cancer in Chinese people. Additional case-control studies with large sample sizes are needed to validate our findings.
Postpartum deep vein thrombosis resolved by catheter-directed thrombolysis
Authors: Chen Po-Wei , Liu Ping-Yen
Published: June 2019

Rationale:

Postpartum deep vein thrombosis is a unique condition in diagnosis and treatment. Rivaroxaban, a novel oral anticoagulant, is indicated for acute deep vein thrombosis, but limited data have been reported for postpartum women. Catheter-directed thrombolysis is a common procedure for treating acute deep vein thrombosis, but it is rarely used for postpartum patients, especially after more than 3 months.

Patient concerns:

A 31-year-old Asian woman suffered from progressive erythematous swelling and local heat of the left lower limb after twin delivery.

Diagnoses:

Venous duplex ultrasound examination showed thrombus formation in the left femoral vein and popliteal vein with reduced compressibility. After standard treatment of novel oral anticoagulant therapy for 4 months, we observed only partial improvement of the symptoms, and the condition deteriorated after her ordinary activities.

Interventions:

Venography was performed and a large amount of thrombus lining from left femoral vein to left iliac vein was noted with total occluded left common iliac vein. After catheter-directed thrombolysis and balloon dilatation, better flow was regained and her symptoms improved completely after procedure.

Outcomes:

During a 1-year follow-up without medication, the patient did not complain about leg swelling, exercise aggravation, or any other post-thrombotic symptoms.

Lessons:

Pregnancy seems to be a transient provoking factor for deep vein thrombosis, but it is sometimes refractory even during the postpartum period.

Follow-up imaging studies should be encouraged to confirm the vessel condition, particularly for applying down-titration or discontinuation strategies of medication.

Catheter-directed thrombolysis could be considered as an alternative method for postpartum iliofemoral deep vein thrombosis. Postpartum women usually have favorable functional status and lower bleeding risk.

Rivaroxaban is a favorable choice for deep vein thrombosis, but its use in postpartum women is still controversial, and evidence of its effectiveness is not available. Thus, endovascular intervention can be a relatively safe therapy, in addition to anticoagulation therapy for premenopausal patients with recurrent deep vein thrombosis.
Congenital pulmonary airway malformation mimicking lung cancer
Authors: Zhao Ying , Zhang Yongxiang , Leng Qi , Li Zhenwu , Pang Peng , Qi Xiaoli
Published: June 2019

Rationale:

Congenital pulmonary airway malformation (CPAM) is a rare developmental deformity of the lower respiratory tract. The disease occurs more in newborns. However, on rare occasions, CPAM can be found in adults. Radiologic features of CPAM include cystic or solid mass pattern. In an elderly patient, CPAM can be easily misdiagnosed as lung cancer.

Patient concerns:

A 66-year old woman was admitted with complaints of chronic cough, expectoration. Her past history was unremarkable with no history of tuberculosis or smoking. Physical examination was normal. Computerized tomography of the chest showed an irregular cystic lesion in right lower lobe.

Diagnosis:

Histopathological results confirmed the diagnosis of CPAM.

Intervention:

The right pulmonary wedge resection was performed via thoracoscopic surgery.

Outcomes:

On follow up 1 year later, the patient is asymptomatic.

Lessons:

CPAM is rare in adults, and imaging cannot accurately distinguish CPAM from thin-walled cystic lung cancer. Hence, histopathology is mandatory to confirm the diagnosis.
Prognostic value of preoperative albumin to globulin ratio in elderly patients with rectal cancer
Authors: Xu Yixin , Xu Xuezhong , Xi Cheng , Ye Nianyuan , Wang Yibo
Published: June 2019

To identify the value of predictors of poor prognosis of elderly patients with rectal cancer who underwent surgery, we investigated the relations between albumin to globulin ratio (AGR) and clinicopathological findings.

We conducted a retrospective cohort study of clinicopathological characteristics (general status, pathological features of tumors, preoperative laboratory data, disease free, and overall survival) for elderly patients with stage I-III rectal cancer. The AGR is calculated as albumin/(total protein − albumin).

According to the optimal cut-off point of AGR (1.43), the enrolled patients were divided into low AGR (n = 83) and high AGR (n = 136) groups. Meanwhile, age, hemoglobin, tumor size, and differentiation degree were the independent risk factors of low preoperative AGR value. Compared to patients with high AGR, those with low AGR were related to worse disease-free survival (DFS) (P = .0008) and overall survival (OS) (P = .0003). Moreover, in multivariate analysis, low AGR and poor TNM stage were the independent predictor of poor DFS and OS. Finally, the nomograms illustrated the effect of prognostic factors on DFS and OS.

Preoperative AGR has a significant prognostic value and was identified as an independent predictor of DFS and OS in elderly rectal cancer patients.
Coccidioidomycosis in solid organ transplant recipients
Authors: Nanayakkara Deepa D. , Blodget Emily
Published: June 2019

Purpose of review

The purpose of the review is an update of diagnosis and treatment of coccidioidomycosis infection in solid organ transplant (SOT) patients. Endemic fungal infections continue to be a cause of serious morbidity and mortality in transplant recipients.

Recent findings

In transplant patients there are recommendations regarding screening in areas that are endemic for coccidioidomycosis. This screening involves serologic testing and chest imaging. In endemic areas pretransplant seropositivity varies from 1.4 to 5.6%. In immunocompromised patients with elevated complement fixation titers, evaluation of cerebrospinal fluid is recommended even in the absence of symptoms. Although coccidioidomycosis can be a self-limited disease in immunocompotent patients, all SOT patients should be treated regardless of severity. This may include intravenous amphotericin B in severe cases and fluconazole therapy in milder episodes. In those SOT recipients with evidence of prior coccidioidomycosis, lifelong secondary prophylaxis with fluconazole given risk of recurrent disease.

Coccidioidomycosis continues to be a cause of serious morbidity and mortality in transplant recipients but with proper screening and treatment can be successfully managed.
Metanephric Adenoma–Epithelial Wilms Tumor Overlap Lesions
Authors: Wobker Sara E. , Matoso Andres , Pratilas Christine A. , Mangray Shamlal , Zheng Gang , Lin Ming-Tseh , Debeljak Marija , Epstein Jonathan I. , Argani Pedram
Published: June 2019

Metanephric adenoma (MA) has historically been considered to represent a differentiated form of epithelial Wilms tumor (WT), based in part upon cases that morphologically overlap these 2 neoplasms. More recently, BRAF V600E mutations have been demonstrated in the majority of MAs but not in unselected or even epithelial-predominant WTs, suggesting 2 genetically distinct entities. However, no prior study has examined BRAF status in neoplasms with overlapping histologic features of epithelial WT and MA. We studied a cohort of 11 such overlapping lesions, 2 of which we considered morphologically to be otherwise typical MAs with unusually prominent mitotic activity and 9 of which we classified as epithelial WTs with areas resembling MA. Both mitotically active MAs demonstrated the BRAF V600E mutation. While the majority (5/9) of epithelial WTs with areas resembling MA were negative for BRAF V600E mutation, 4 such cases were positive. Two BRAF V600E mutation-positive WTs occurred in children. One case in a 6-year-old male was morphologically similar to the BRAF V600E mutation-positive adult cases and subsequently metastasized to the lungs; remarkably, the metastases then completely resolved on Braf targeted therapy. A second occurred in a 3-year-old girl whose posttherapy nephrectomy specimen’s tumor was encapsulated and mitotically active like a typical WT, but also had more differentiated areas resembling MA. Immunohistochemistry for Braf V600E paralleled the molecular findings, demonstrating immunoreactivity in both the WT and MA-like areas of all 4 of these neoplasms. In summary, we demonstrate that BRAF V600E mutations are not entirely restricted to typical MA, as they may be seen in MAs showing mitotic activity along with a subset of epithelial-predominant WTs in adults and children that have foci which overlap morphologically with MA.
Estrogen Receptor-positive Ductal Carcinoma In Situ Frequently Overexpresses HER2 Protein Without Gene Amplification
Authors: Horimoto Yoshiya , Terao Takako , Tsutsumi Yuko , Tanabe Masahiko , Mogushi Kaoru , Hlaing May Thinzar , Sasaki Ritsuko , Saeki Harumi , Okazaki Misato , Sonoue Hiroshi , Arakawa Atsushi , Saito Mitsue
Published: June 2019

Overexpression of human epidermal growth factor receptor 2 (HER2) protein is well known to be more frequent in ductal carcinoma in situ (DCIS) than in invasive ductal carcinoma (IDC). However, the reasons for this difference are poorly understood. On the basis of the high frequency of estrogen receptor-positive (ER+) and HER2-positive (HER2+) DCIS, we hypothesized that this tumor type overexpresses HER2 protein without gene amplification and retrospectively investigated the HER2/neu gene status of 71 ER(+)HER2(+) DCIS, surgically removed during the 2007 to 2017 period, employing fluorescence in situ hybridization (FISH). To compare HER2 protein expressions between in situ and invasive components of individual tumors, 86 pT1mi/1a IDC with predominantly in situ disease were also examined. Furthermore, for comparison of FISH status between in situ and coexisting invasive components, another patient cohort, 78 FISH-positive IDC cases, were employed. To elucidate biological differences among DCIS with various combinations of ER and HER2 protein expressions, we also analyzed public microarray data of mRNA. HER2 gene amplification was observed in 35% of ER(+) and HER2 protein-overexpressing specimens, significantly lower than the 94% in ER-negative (ER−) and HER2 protein-overexpressing specimens (P<0.001). HER2 protein expression was decreased in the invasive component as compared with coexisting in situ portions in 40% of individual tumors, whereas the FISH status of these 2 components was well preserved. Moreover, ER(+) and HER2 protein-overexpressing DCIS showed significantly higher hypoxia-inducible factor-1α protein expression than the ER(+) and HER2 protein-nonoverexpressing tumors (P=0.016). We revealed that ER(+) and HER2 protein-overexpressing DCIS, especially ER-high tumors, frequently overexpress HER2 protein without gene amplification. Our data may provide novel insights for understanding the biology of DCIS.
Combined Orthodontic-Surgical Sequential Treatment of Cleidocranial Dysplasia
Authors: Chen Ling , Sun Zhaowei , Zhang Yidian , Lin Jun , Li Zhiyong
Published: June 2019

Cleidocranial dysplasia (CCD) is a rare hereditary disorder characterized by skeletal malformations and dental abnormalities. Mutations of the transcription factor RUNX2 are responsible for the pathogenesis of CCD. We present a case of a 10-year-old boy with CCD, presenting with hypoplastic clavicles, delayed closure of the fontanelles, retarded exfoliation of the deciduous teeth, retarded eruption of the permanent teeth, and multiple impacted supernumerary teeth. Based on the clinical and radiographic examination results showing abnormalities of the bones and teeth, a diagnosis was reached easily, but it was difficult to achieve a complete curative effect. We carried out a highly organized schedule of treatment, including extraction of the deciduous and supernumerary teeth, partial resection of alveolar bone, distraction of impacted teeth, and orthodontic surgery. After 7-year follow-up, the patient has achieved acceptable occlusion and midfacial appearance. The main objectives of this study were to present the diagnosis and treatment of CCD and to emphasize the benefits of combined orthodontic-surgical sequential treatment.
The Management and Prognosis of Facial and Scalp Angiosarcoma
Authors: Alqumber Nedhal A. , Choi Jong-Woo , Kang Min-kyu
Published: June 2019

Background

Angiosarcomas are extremely aggressive malignant tumors that arise from vascular endothelial cells. The risk factors, etiology, prognostic factors, and optimal management strategies for angiosarcomas are as yet unknown.

Methods

We retrospectively analyzed data from 15 patients who were treated in Asan Medical Center, Seoul, Republic of Korea, in the past 12 years, to assess the effect of different treatment modalities and reconstructive methods on the locoregional recurrence, metastasis, and overall survival.

Results

A total of 15 patients were identified (median age at diagnosis, 72 years; range, 61–82 years). Median tumor size was 6 cm. Median follow-up was 287 days. The median overall survival was 14.96 months; a total of 13 (87%) patients had died by the end of the study.

The median locoregional recurrence, metastasis, and overall survival were 7.3, 6.5, and 16.7 months, respectively. On univariate analysis, the use of adjuvant therapy after surgery (vs surgery without adjuvant therapy) was associated with delayed median time to detection of recurrence (7.9 months vs 3.1 months, respectively; P = 0.825), delayed median time to metastasis (8.7 months vs 3.1 months, respectively; P = 0.191), and better median overall survival (7.3 months vs 3.1 months, respectively; P = 0.078).

The use of flap versus skin graft as a reconstructive method was associated with delayed median recurrence (8.75 vs 7.32 months, respectively; P = 0.274) and earlier median metastasis (3.75 vs 6.53 months, respectively; P = 0.365), but the same median overall survival of 16.7 months (P value: 0.945) and tumor smaller or bigger than 5 cm show earlier median time to detection of recurrence (4.17-7.32 months; P = 0.41), earlier median time to metastasis (3.75-6.53 months; P = 0.651), but better median overall survival of 18.21 versus 16.7 months, respectively (P = 0.111).

Conclusions

Multimodal treatment that combines surgery with adjuvant therapy is the best management strategy that influences survival positively in patients with angiosarcoma. The study shows that the reconstructive method does not affect the prognosis in these patients. So it is better to choose the simplest suitable resection and reconstructive method with the least complications and to avoid unnecessary procedures.
Ocins database: a database of bug-busters from Bifidobacterium, Lactobacillus, and Enterococcus
Authors: Choyam Shilja , PSN Suresh , Pandey Rahul , Kammara Rajagopal
Published: June 2019

The ocins are antimicrobial polypeptides produced by probiotic microbes, such as

Lactobacillus

,

Enterococcus

,

Streptococcus

,

Leuconostoc

and

Bifidobacterium

. They are produced in response to stress and for the self-defense of the bacterium. It is indispensable to understand their mechanistic characteristics, structures, and functions, if the food industry is to reduce contamination levels and produce germfree foods. Databases of the ocins that are readily accessible to the food industry are scarce, but urgently required. Therefore, we established a very useful, unique, and a simple ocin database, which not merely provides information about ocins, but also directs their utilisation in the food industry. The database includes information about each ocin, its amino acid sequence, molecular weight, and isoelectric point. The database also possesses all the currently known ocin (probiotic origin only) sequences and structures, target organisms, and relevant to food industries (aqua culture, dairy and meat industries), which is hard to obtain in other databases. The database is free for public and accessed at http://ocins.cftri.com/ocins/.
Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype
Authors: Trevis Krysta J , Brown Natasha J , Green Cherie , Lockhart Paul , Hickey Peter , Fanjul-Fernández Miriam , Bromhead Catherine , Desai Tarishi , Vick Tanya , Gillies Greta , Mountford Hayley , Fitzpatrick Elizabeth , Gordon Lavinia , Hewson Peter , Anderson Vicki , Delatycki Martin B , Scheffer Ingrid E , Wilson Sarah J
Published: June 2019

Families comprising many individuals with Autism Spectrum Disorder (ASD) may carry a dominant predisposing mutation. Our aim was to use rigorous phenotyping of the ‘Broader Autism Phenotype’ (BAP) in large multiplex ASD families to identify endophenotypes of the BAP for future genetic studies. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 109 individuals, including two large multiplex families (Family A: 30; Family B: 34) and an independent sample of small families (n=45). Our protocol identified four psychological endophenotypes of the BAP that were evident in both samples, and showed high sensitivity (97%) and specificity (82%) for individuals classified with the BAP. The patterns of inheritance of these endophenotypes varied in the two large families, supporting their utility for identifying genes in autism.
Cannabinoid Receptor 2 (CB2) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes
Authors: Saroz Yurii , Kho Dan T. , Glass Michelle , Graham Euan Scott , Grimsey Natasha Lillia
Published: June 2019

Cannabinoid receptor 2 (CB2) is a promising therapeutic target for immunological modulation. There is, however, a deficit of knowledge regarding CB2signaling and function in human primary immunocompetent cells. We applied an experimental paradigm which closely models thein situstate of human primary leukocytes (PBMC; peripheral blood mononuclear cells) to characterize activation of a number of signaling pathways in response to a CB2-selective ligand (HU308). We observed a “lag” phase of unchanged cAMP concentration prior to development of classically-expected Gαi-mediated inhibition of cAMP synthesis. Application of G protein inhibitors revealed that this apparent lag was a result of counteraction of Gαieffects by concurrent Gαsactivation. Monitoring downstream signaling events, activation of p38 was mediated by Gαiwhereas ERK1/2 and Akt phosphorylation were mediated by Gαi-coupled βγ. Activation of CREB integrated multiple components; Gαsand βγ mediated ∼85% of the response, while ∼15% was attributed to Gαi. Responses to HU308 had an important functional outcome – secretion of interleukins 6 (IL-6) and 10 (IL-10). IL-2, IL-4, IL-12, IL-13, IL-17A, MIP-1α, and TNF-α were unaffected. IL-6/IL-10 induction had a similar G protein coupling profile to CREB activation. All response potencies were consistent with that expected for HU308 acting via CB2. Additionally, signaling and functional effects were completely blocked by a CB2-selective inverse agonist, giving additional evidence for CB2involvement. This work expands the current paradigm regarding cannabinoid immunomodulation and reinforces the potential utility of CB2ligands as immunomodulatory therapeutics.

Significance statement

Cannabinoid receptor 2 (CB2) is a G protein-coupled receptor which plays a complex role in immunomodulation and is a promising target in a range of disorders with immune system involvement. However, to date the majority of the studies in this field have been performed on cell lines, rodent models, or stimulated primary cells. Here we provide a detailed account of CB2-mediated signaling in primary human immune cells under conditions which closely mimic theirin vivostate. We reveal a complex signaling system involving an unprecedented CB2 signaling pathway and leading to immunomodulatory functional outcomes. This work provides not only a critical foundation impacting CB2-targeted drug discovery, but reveals important wider considerations for GPCR signaling studies and model validity.

Table of Contents Summary Figure
Effects of arm weight support on neuromuscular activation during reaching in chronic stroke patients
Authors: Runnalls Keith D , Ortega-Auriol Pablo , McMorland Angus J C , Anson Greg , Byblow Winston D
Published: June 2019

To better understand how arm weight support (WS) can be used to alleviate upper limb impairment after stroke, we investigated the effects of WS on muscle activity, muscle synergy expression, and corticomotor excitability (CME) in 13 chronic stroke patients and 6 age-similar healthy controls. For patients, lesion location and corticospinal tract integrity were assessed using magnetic resonance imaging. Upper limb impairment was assessed using the Fugl-Meyer upper extremity assessment with patients categorised as either mild or moderate-severe. Three levels of WS were examined: low=0, medium=50 and high=100 % of full support. Surface EMG was recorded from 8 upper limb muscles, and muscle synergies were decomposed using non-negative matrix factorisation from data obtained during reaching movements to an array of 14 targets using the paretic or dominant arm. Interactions between impairment level and WS were found for the number of targets hit, and EMG measures. Overall, greater WS resulted in lower EMG levels, although the degree of modulation between WS levels was less for patients with moderate-severe compared to mild impairment. Healthy controls expressed more synergies than patients with moderate-severe impairment. Healthy controls and patients with mild impairment showed more synergies with high compared to low weight support. Transcranial magnetic stimulation was used to elicit motor-evoked potentials (MEPs) to which stimulus-response curves were fitted as a measure of corticomotor excitability (CME). The effect of WS on CME varied between muscles and across impairment level. These preliminary findings demonstrate that WS has direct and indirect effects on muscle activity, synergies, and CME and warrants further study in order to reduce upper limb impairment after stroke.
Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function
Authors: Ramani Manimaran , Miller Kiara , Kumar Ranjit , Kadasamy Jegen , McMahon Lori , Ballinger Scott , Ambalavanan Namasivayam
Published: June 2019

Preterm infants requiring prolonged oxygen therapy often develop cognitive dysfunction later life. Previously, we reported that 14-week-old young adult mice exposed to hyperoxia as newborns had spatial memory deficits and hippocampal shrinkage. We hypothesized that the underlying mechanism was the induction of hippocampal mitochondrial dysfunction by neonatal hyperoxia. C57BL/6j mouse pups were exposed to 85% oxygen or air from P2 - P14. Hippocampal proteomic analysis was performed in young adult mice (14 weeks). Mitochondrial bioenergetics were measured in neonatal (P14) and young adult mice. We found that hyperoxia exposure reduced mitochondrial ATP-linked oxygen consumption and increased state 4 respiration linked proton leak in both neonatal and young adult mice. Following hyperoxia exposure, complex I function was decreased at P14 but increased in young adult mice. Proteomic analysis revealed that neonatal hyperoxia exposure decreased complex I NDUFB8 and NDUFB11 and complex IV 7B subunits, but increased complex III subunit 9 in young adult mice. In conclusion, neonatal hyperoxia permanently impairs hippocampal mitochondrial function and alters complex I function. These changes may account for memory deficits seen in preterm survivors following prolonged oxygen supplementation and may potentially be a contributing mechanism in other oxidative stress associated cognitive disorders.
Mast cells are mediators of fibrosis and effector cell recruitment in dermal chronic graft-versus-host disease
Authors: Strattan Ethan , Palaniyandi Senthilnathan , Kumari Reena , Du Jing , Hakim Natalya , Huang Timothy , Kesler Melissa V. , Jennings C. Darrell , Sturgill Jamie L. , Hildebrandt Gerhard C.
Published: June 2019

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is often used to treat acute leukemia or defects of hematopoiesis. Its widespread use is hampered by graft-versus-host disease (GVHD), which has high morbidity and mortality in both acute and chronic subtypes. Chronic GVHD (cGVHD) occurs most frequently in skin and often is characterized by pathogenic fibrosis. Mast cells (MCs) are known to be involved in the pathogenesis of other fibrotic diseases. In a murine model of cGVHD after allo-HSCT, C57BL/6J recipients of allogeneic LP/J donor cells develop sclerodermatous dermal cGVHD which is significantly decreased in mast cell-deficient B6.Cg-KitW-sh/HNihrJaeBsmGlliJ recipients. MCs survive conditioning and are associated with fibrosis, chemokine production, and recruitment of GVHD effector cells to the skin. Chemokine production by MCs is blocked by drugs used to treat cGVHD. The importance of MCs in skin cGVHD is mirrored by increased MCs in the skin of patients with dermal cGVHD. We show for the first time a role for MCs in skin cGVHD that may be targetable for preventive and therapeutic intervention in this disease.
Telophase correction refines division orientation in stratified epithelia
Authors: Lough Kendall J. , Byrd Kevin M. , Descovich Carlos P. , Spitzer Danielle C. , Bergman Abby J. , Beaudoin Gerard M. , Reichardt Louis F. , Williams Scott E.
Published: June 2019

During organogenesis, precise control of spindle orientation ensures a proper balance of proliferation and differentiation. In the developing murine epidermis, planar and perpendicular divisions yield symmetric and asymmetric fate outcomes, respectively. Classically, division axis specification involves centrosome migration and spindle rotation, events that occur early in mitosis. Here, we identify a previously uncharacterized orientation mechanism that occurs during telophase, correcting erroneous oblique orientations that unexpectedly persist into anaphase. The directionality of reorientation—towards either planar or perpendicular—correlates with the maintenance or loss of basal contact by the apical daughter. While the conserved scaffolding protein Pins/LGN is believed to function primarily through initial spindle positioning, we now show it also functions actively during telophase to reorient oblique divisions toward perpendicular. The ability to undergo telophase correction is also critically dependent upon an LGN-independent pathway involving the tension-sensitive adherens junction proteins vinculin, a-catenin and afadin, and correction directionality is influenced by local cell density. Failure of this reorientation mechanism impacts tissue architecture, as excessive oblique divisions induce precocious differentiation. The division orientation plasticity provided by telophase correction may provide a means for progenitors to dynamically respond to extrinsic cues provided by neighboring cells in order to adapt to local tissue needs.
A TetR-family protein activates transcription from a new promoter motif associated with essential genes for autotrophic growth in acetogens
Authors: de Souza Pinto Lemgruber Renato , Valgepea Kaspar , Garcia Ricardo Axayacatl Gonzalez , de Bakker Christopher , Palfreyman Robin William , Tappel Ryan , Köpke Michael , Simpson Séan Dennis , Nielsen Lars Keld , Marcellin Esteban
Published: June 2019

Acetogens can fix carbon (CO or CO2) into acetyl-CoA via the Wood-Ljungdahl pathway (WLP) that also makes them attractive cell factories for the production of fuels and chemicals from waste feedstocks. Although most biochemical details of the WLP are well understood and systems-level characterisation of acetogen metabolism has recently improved, key transcriptional features such as promoter motifs and transcriptional regulators are still unknown in acetogens. Here, we use differential RNA-sequencing to identify a previously undescribed promoter motif associated with essential genes for autotrophic growth of the model-acetogen Clostridium autoethanogenum. RNA polymerase was shown to bind to the new promoter motif using a DNA-binding protein assay and proteomics enabled the discovery of four candidates to potentially function directly in control of transcription of the WLP and other key genes of C1 fixation metabolism. Next, in vivo experiments showed that a TetR-family transcriptional regulator (CAETHG_0459) and the housekeeping sigma factor (σA) activate expression of a reporter protein (GFP) in-frame with the new promoter motif from a fusion vector in E. coli. Lastly, a protein-protein interaction assay with the RNA polymerase (RNAP) shows that CAETHG_0459 directly binds to the RNAP. Together, the data presented here advance the fundamental understanding of transcriptional regulation of C1 fixation in acetogens and provide a strategy for improving the performance of gas-fermenting bacteria by genetic engineering.
A Refined Open State of the Glycine Receptor Obtained Via Molecular Dynamics Simulations
Authors: Dämgen Marc A. , Biggin Philip C.
Published: June 2019

Fast neurotransmission is mediated by pentameric ligand-gated ion channels. Glycine receptors are chloride-selective members of this receptor family that mediate inhibitory synaptic transmission and are implicated in neurological disorders including autism and hyperekplexia. They have been structurally characterized by both X-ray crystallography and cryo electron microscopy studies, with the latter giving rise to what was proposed as a possible open state. However, recent work has questioned the physiological relevance of this open state structure, since it rapidly collapses in molecular dynamics simulations. Here, we show that the collapse can be avoided by a careful equilibration protocol that reconciles the more problematic regions of the original electron-density map and gives a stable open state that shows frequent selective chloride permeation. The protocol developed in this work provides a means to refine open-like structures of the whole pentameric ligand-gated ion channel superfamily and reconciles the previous issues with the cryo-EM structure.
Activity subspaces in medial prefrontal cortex distinguish states of the world
Authors: Maggi Silvia , Humphries Mark D.
Published: June 2019

Medial prefrontal cortex (mPfC) activity represents information about the state of the world, including present behaviour, such as decisions, and the immediate past, such as short-term memory. Unknown is whether information about different states of the world are represented in the same mPfC neural population and, if so, how they are kept distinct. To address this, we analyse here mPfC population activity of rats learning rules in a Y-maze, with self-initiated choice trials to an arm-end followed by a self-paced return during the inter-trial interval (ITI). We find that trial and ITI population activity from the same population fall into different low-dimensional subspaces. These subspaces encode different states of the world: multiple features of the task can be decoded from both trial and ITI activity, but the decoding axes for the same feature are roughly orthogonal between the two task phases, and the decodings are predominantly of features of the present during the trial but features of the preceding trial during the ITI. These subspace distinctions are carried forward into sleep, where population activity is preferentially reactivated in post-training sleep, but differently for activity from the trial and ITI subspaces. Our results suggest that the problem of interference when representing different states of the world is solved in mPfC by population activity occupying different subspaces for the world states, which can be independently decoded by downstream targets and independently addressed by upstream inputs.

Significance statement

Activity in the medial prefrontal cortex plays a roles in representing the current and past states of the world. We show that during a maze task the activity of a single population in medial prefrontal cortex represents at least two different states of the world. These representations were sequential and sufficiently distinct that a downstream population could separately read out either state from that activity. Moreover, the activity representing different states is differently reactivated in sleep. Different world states can thus be represented in the same medial prefrontal cortex population, but in such a way that prevents potentially catastrophic interference between them.
The tapeworm interactome: inferring confidence scored protein-protein interactions from the proteome of Hymenolepis microstoma
Authors: James Katherine , Olson Peter D.
Published: June 2019

Reference genome and transcriptome assemblies of helminths have reached a level of completion whereby secondary analyses that rely on accurate gene estimation or syntenic relationships can be now conducted with a high level of confidence. Recent public release of the v.3 assembly of the mouse bile-duct tapeworm, Hymenolepis microstoma, provides chromosome-level characterisation of the genome and a stabilised set of protein coding gene models underpinned by both bioinformatic and empirical data. However, interactome data have not been produced. Conserved protein-protein interactions in other organisms, termed interologs, can be used to transfer interactions between species, allowing systems-level analysis in non-model organisms. Here, we describe a probabilistic, integrated network of interologs for the H. microstoma proteome, based on conserved protein interactions found in eukaryote model species. Almost a third of the 10,139 gene models in the v.3 assembly could be assigned interaction data and assessment of the resulting network indicates that topologically-important proteins are related to essential cellular pathways, and that the network clusters into biologically meaningful components. Moreover, network parameters are similar to those of single-species interaction networks that we constructed in the same way for S. cerevisiae, C. elegans and H. sapiens, demonstrating that information-rich, system-level analyses can be conducted even on species separated by a large phylogenetic distance from the major model organisms from which most protein interaction evidence is based. Using the interolog network, we then focused on sub-networks of interactions assigned to discrete suites of genes of interest, including signalling components and transcription factors, germline ‘multipotency’ genes, and differentially-expressed genes between larval and adult worms. These analyses not only showed an expected bias toward highly-conserved proteins, such as components of intracellular signal transduction, but in some cases predicted interactions with transcription factors that aid in identifying their target genes. With the completion of key helminth genomes, such systems level analyses can provide an important predictive framework to guide basic and applied research on helminths and will become increasingly informative as protein-protein interaction data accumulate.