bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective evaluation of NGS-based liquid biopsy in untreated late stage non-squamous lung carcinoma in a single institution
Authors: Heeke Simon , Hofman Véronique , Ilié Marius , Allegra Maryline , Lespinet Virginie , Bordone Olivier , Benzaquen Jonathan , Boutros Jacques , Poudenx Michel , Lalvée Salomé , Tanga Virginie , Salacroup Carole , Bonnetaud Christelle , Marquette Charles-Hugo , Hofman Paul
Published: February 2020

Background

NGS from plasma samples in non-squamous cell lung carcinoma (NSCC) can aid in the detection of actionable genomic alterations. However, the absolute clinical value of NGS in liquid biopsy (LB) made at baseline is currently uncertain. We assessed the impact of plasma-based NGS using an in-house test and an outsourced test in comparison to a routine molecular pathology workflow.

Methods

Twenty-four advanced/metastatic treatment-naïve NSCC patients were prospectively included. NGS analyses were conducted both in-house using the Oncomine cfTNA Panel and in an external testing center using the Foundation Liquid assay. NGS analysis and/or specific molecular based assays were conducted in parallel on tissue or cytological samples.

Results

Both LB tests were well correlated. Tissue NGS results were obtained in 67% of patients and demonstrated good correlation with LB assays. Activating EGFR mutations were detected using LB tests in three patients. PD-L1 expression assessed in tissue sections enabled the initiation of pembrolizumab treatment in five patients.

Conclusion

NGS from LB is feasible in routine clinical practice using an in-house or an outsourced test at baseline. However, the impact on therapy selection was limited in this small series of patients and LB was not able to replace tissue-based testing in our hands.
Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative
Authors: Hansmann Sandra , Lainka Elke , Horneff Gerd , Holzinger Dirk , Rieber Nikolaus , Jansson Annette F. , Rösen-Wolff Angela , Erbis Gabi , Prelog Martina , Brunner Juergen , Benseler Susanne M. , Kuemmerle-Deschner Jasmin B.
Published: February 2020

Background

Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies.

Methods

The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice.

Results

The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS.

Conclusions

The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID.
Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice
Authors: Casili Giovanna , Lanza Marika , Filippone Alessia , Campolo Michela , Paterniti Irene , Cuzzocrea Salvatore , Esposito Emanuela
Published: February 2020

Background

Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine.

Methods

Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity.

Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation.

Results

DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated.

Conclusion

These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.
Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling
Authors: Li Lei , Wu Xiang-Hui , Zhao Xiao-Jing , Xu Lu , Pan Cai-Long , Zhang Zhi-Yuan
Published: February 2020

Background

Alzheimer’s disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation.

Methods

The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis.

Results

Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase.

Conclusions

Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.
Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease
Authors: Moreno-Rodriguez Marta , Perez Sylvia E. , Nadeem Muhammad , Malek-Ahmadi Michael , Mufson Elliott J.
Published: February 2020

Background

Chitinase 3-like 1 (CHI3L1), chitinase 3-like 2 (CHI3L2), and neuronal pentraxin II (NPTX2) are inflammatory biomarkers of Alzheimer’s disease (AD). Although studies have demonstrated that cerebrospinal fluid levels of these proteins are changed in AD, no studies have undertaken a detailed examination of alterations in protein levels, cellular expression, and interaction with amyloid in the brain during the progression of AD.

Methods

The study evaluated levels of both CHI3L1 and CHI3L2, NPTX2, ionized calcium-binding adapter molecule 1 (Iba1), complement component 1q (C1q), glial fibrillary acidic protein (GFAP), and CD44, in the frontal cortex of people who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD), and severe AD (sAD) using immunoblot and immunohistochemical techniques.

Results

CHI3L1-immunoreactive (-ir) astrocyte numbers were increased in the frontal cortex and white matter in sAD compared to NCI. On the other hand, increases in GFAP and Iba1-ir cell numbers were observed in MCI compared to NCI but only in white matter. Western blot analyses revealed significantly lower frontal cortex CHI3L2 levels, whereas CD44 levels were increased in sAD. No significant differences for CHI3L1, GFAP, C1q, and NPTX2 protein levels were detected between clinical groups. Strong significant correlations were found between frontal cortex CHI3L1 and Iba1-ir cell numbers in white matter and CHI3L1 and C1q protein levels in the early stages of the disease. C1q and Iba1, CD44 with CHI3L2, and GFAP protein levels were associated during disease progression. CHI3L1 and Iba1 cell numbers in white matter showed a significant associations with episodic memory and perceptual speed.

Conclusions

White matter CHI3L1 inflammatory response is associated with cognitive impairment early in the onset of AD.
Ocean acidification promotes broad transcriptomic responses in marine metazoans: a literature survey
Authors: Strader Marie E. , Wong Juliet M. , Hofmann Gretchen E.
Published: February 2020

For nearly a decade, the metazoan-focused research community has explored the impacts of ocean acidification (OA) on marine animals, noting that changes in ocean chemistry can impact calcification, metabolism, acid-base regulation, stress response and behavior in organisms that hold high ecological and economic value. Because OA interacts with several key physiological processes in marine organisms, transcriptomics has become a widely-used method to characterize whole organism responses on a molecular level as well as inform mechanisms that explain changes in phenotypes observed in response to OA. In the past decade, there has been a notable rise in studies that examine transcriptomic responses to OA in marine metazoans, and here we attempt to summarize key findings across these studies. We find that organisms vary dramatically in their transcriptomic responses to pH although common patterns are often observed, including shifts in acid-base ion regulation, metabolic processes, calcification and stress response mechanisms. We also see a rise in transcriptomic studies examining organismal response to OA in a multi-stressor context, often reporting synergistic effects of OA and temperature. In addition, there is an increase in studies that use transcriptomics to examine the evolutionary potential of organisms to adapt to OA conditions in the future through population and transgenerational experiments. Overall, the literature reveals complex organismal responses to OA, in which some organisms will face more dramatic consequences than others. This will have wide-reaching impacts on ocean communities and ecosystems as a whole.
Exercising with Baxter: preliminary support for assistive social-physical human-robot interaction
Authors: Fitter Naomi T. , Mohan Mayumi , Kuchenbecker Katherine J. , Johnson Michelle J.
Published: February 2020

Background

The worldwide population of older adults will soon exceed the capacity of assisted living facilities. Accordingly, we aim to understand whether appropriately designed robots could help older adults stay active at home.

Methods

Building on related literature as well as guidance from experts in game design, rehabilitation, and physical and occupational therapy, we developed eight human-robot exercise games for the Baxter Research Robot, six of which involve physical human-robot contact. After extensive iteration, these games were tested in an exploratory user study including 20 younger adult and 20 older adult users.

Results

Only socially and physically interactive games fell in the highest ranges for pleasantness, enjoyment, engagement, cognitive challenge, and energy level. Our games successfully spanned three different physical, cognitive, and temporal challenge levels. User trust and confidence in Baxter increased significantly between pre- and post-study assessments. Older adults experienced higher exercise, energy, and engagement levels than younger adults, and women rated the robot more highly than men on several survey questions.

Conclusions

The results indicate that social-physical exercise with a robot is more pleasant, enjoyable, engaging, cognitively challenging, and energetic than similar interactions that lack physical touch. In addition to this main finding, researchers working in similar areas can build on our design practices, our open-source resources, and the age-group and gender differences that we found.
Socioeconomic resources and quality of life in alcohol use disorder patients: the mediating effects of social support and depression
Authors: Lee Soo Bi , Chung Sulki , Seo Jeong Seok , Jung Won Mi , Park Il Ho
Published: February 2020

Background

Quality of life (QoL) has recently attracted increased attention as a major indicator of the recovery from alcohol use disorder (AUD). This study investigated the mediating effects of social support and depression for the relationship between socioeconomic resources and QoL among people with AUD in South Korea.

Methods

Patients across South Korea who had been diagnosed with AUD in the previous year (n = 404) and were registered at hospitals and addiction management centers were surveyed. The participants ranged in age from 19 to 65 years. Structural equation modeling was performed, using stable residence, income, stable employment, social support, depression, and QoL as predictors. Bootstrapping analysis was performed to test for mediating effects.

Results

The socioeconomic resources income (β = .297, p < .001), stable employment (β = .131, p < .01), and stable residence (β = .091, p < .05) showed statistically significant and positive relationships with social support. However, none of these were significantly related to depression. Social support showed a significant and negative relationship with depression (β = −.172, p < .001). Income positively and directly influenced QoL (β = .148, p < .001). All three socioeconomic resources indirectly influenced depression through social support, which, in turn, influenced QoL. This suggests that socioeconomic resources directly influence QoL and indirectly influence it through social support.

Conclusion

These findings suggest that social support has an important role in improving the QoL of people with AUD. Furthermore, socioeconomic resources, such as having a stable residence, employment, and income, are necessary for recovery from alcohol addiction.
Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?
Authors: Tornero C. , Navarro-Compán V. , Tenorio J. A. , García-Carazo S. , Buño A. , Monjo I. , Plasencia-Rodriguez C. , Iturzaeta J. M. , Lapunzina P. , Heath K. E. , Balsa A. , Aguado P.
Published: February 2020

Background

Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase–ALP–measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants.

Results

Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9–30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9–13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively.

Conclusions

In subjects with persistent hypophosphatasaemia –secondary causes excluded– one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.
Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field
Authors: Yanes Tatiane , Young Mary-Anne , Meiser Bettina , James Paul A.
Published: February 2020

Polygenic factors are estimated to account for an additional 18% of the familial relative risk of breast cancer, with those at the highest level of polygenic risk distribution having a least a twofold increased risk of the disease. Polygenic testing promises to revolutionize health services by providing personalized risk assessments to women at high-risk of breast cancer and within population breast screening programs. However, implementation of polygenic testing needs to be considered in light of its current limitations, such as limited risk prediction for women of non-European ancestry. This article aims to provide a comprehensive review of the evidence for polygenic breast cancer risk, including the discovery of variants associated with breast cancer at the genome-wide level of significance and the use of polygenic risk scores to estimate breast cancer risk. We also review the different applications of this technology including testing of women from high-risk breast cancer families with uninformative genetic testing results, as a moderator of monogenic risk, and for population screening programs. Finally, a potential framework for introducing testing for polygenic risk in familial cancer clinics and the potential challenges with implementing this technology in clinical practice are discussed.
Effectiveness of Gyejibongnyeong-Hwan for shoulder pain: study protocol for a randomised, wait-list controlled pilot trial
Authors: Jang Soobin , Sung Hyun Kyung , Ko Mi Mi , Shin Seon Mi , Go Ho-Yeon , Jung Jeeyoun
Published: February 2020

Background

Shoulder pain is an uncomfortable feeling in the muscle around the shoulder. The cause of myalgia is the accumulation of lactic acid in muscles and impaired blood circulation, which is called blood stasis in traditional East Asian medicine. This study aimed to explore the therapeutic effect of Gyejibongnyeong-Hwan (GBH) for shoulder discomfort related to blood stasis before and after treatment.

Methods/design

This study will be a double-centre, randomised, wait-list controlled pilot trial. Participants with shoulder pain and with a visual analogue scale score of 4 or higher out of 10, blood stasis score of 9 or higher, and triglyceride level of ≥150 mg/dl or total cholesterol level of ≥200 mg/dl will be recruited from two university hospitals. A total of 40 participants will be assigned to the immediate and waiting treatment groups. The immediate treatment group will receive GBH for 8 weeks on enrolment while the waiting treatment group will receive GBH for 8–16 weeks after 8 weeks of controlled waiting. The primary outcome is shoulder pain, and the secondary outcomes are the blood stasis score, blood pressure, ankle–brachial pressure index, brachial–ankle pulse wave velocity, body mass index, waist circumference, indexes of oximetry, and levels of blood lipid, blood sugar, resistin, C-reactive protein, serum amyloid P, and D-dimer.

Discussion

The results of this pilot trial will be the bases for a full-scale clinical trial of GBH.

Trial registration

Clinical Research Information Service, KCT0003837. Registered on 23 April 2019. https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=14258
Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
Authors: Kaji Seiji , Maki Takakuni , Ishimoto Tomoyuki , Yamakado Hodaka , Takahashi Ryosuke
Published: February 2020

Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of α-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.
Effects of a blend of Saccharomyces cerevisiae-based direct-fed microbial and fermentation products on plasma carbonyl-metabolome and fecal bacterial community of beef steers
Authors: Adeyemi James A. , Peters Sunday O. , De Donato Marcos , Cervantes Andres Pech , Ogunade Ibukun M.
Published: February 2020

Background

Previous studies have evaluated the metabolic status of animals fed direct-fed microbial (DFM) using enzyme-based assays which are time-consuming and limited to a few metabolites. In addition, little emphasis has been placed on investigating the effects of DFM on hindgut microbiota. We examined the effects of dietary supplementation of a blend of Saccharomyces cerevisiae-based DFM and fermentation products on the plasma concentrations of carbonyl-containing metabolites via a metabolomics approach, and fecal bacterial community, via 16S rRNA gene sequencing, of beef steers during a 42-day receiving period. Forty newly weaned steers were randomly assigned to receive a basal diet with no additive (CON; n = 20) or a basal diet supplemented with 19 g of Commence™ (PROB; n = 20) for a 42-day period. Commence™ (PMI, Arden Hills, MN) is a blend of 6.2 × 1011 cfu/g of S. cerevisiae, 3.5 × 1010 cfu/g of a mixture of Enterococcus lactis, Bacillus subtilis, Enterococcus faecium, and Lactobacillus casei, and the fermentation products of these aforementioned microorganisms and those of Aspergillus oryzae and Aspergillus niger. On d 0 and 40, rectal fecal samples were collected randomly from 10 steers from each treatment group. On d 42, blood was collected for plasma preparation.

Results

A total number of 812 plasma metabolites were detected. Up to 305 metabolites [fold change (FC) ≥ 1.5, FDR ≤ 0.01] including glucose, hippuric acid, and 5-hydroxykynurenamine were increased by PROB supplementation, whereas 199 metabolites (FC ≤ 0.63, FDR ≤ 0.01) including acetoacetate were reduced. Supplementation of PROB increased (P ≤ 0.05) the relative abundance of Prevotellaceae UCG-003, Megasphaera, Dorea, Acetitomaculum, and Blautia. In contrast, the relative abundance of Elusimicrobium, Moheibacter, Stenotrophomonas, Comamonas, and uncultured bacterium belonging to family p-2534-18B5 gut group (phylum Bacteroidetes) were reduced (P ≤ 0.05).

Conclusions

The results of this study demonstrated that supplementation of PROB altered both the plasma carbonyl metabolome towards increased glucose concentration suggesting an improved energy status, and fecal bacterial community, suggesting an increased hindgut fermentation of the beef steers.
Branched chain amino acids alter fatty acid profile in colostrum of sows fed a high fat diet
Authors: Ma Chang , Liu Yajng , Liu Shaoshuai , Lévesque Crystal L. , Zhao Fengqi , Yin Jindong , Dong Bing
Published: February 2020

Background

Branched chain amino acids (BCAAs) are important substrates for milk protein synthesis in the mammary gland, and are tightly related to lipid metabolism. No study has been performed examining the role of BCAAs with high fat diets on milk fat synthesis. This study was designed to investigate the effect of dietary BCAAs on growth performance of piglets, progeny body weight, and milk fat composition in sows fed a high fat diet. Four diets (CON = control diet; HF = high fat diet with 8% soybean oil; HF-MB=HF plus 0.39% BCAAs; HF-HB=HF plus 0.78% BCAAs) were fed to sows from late gestation to weaning.

Results

Compared to HF, BCAAs (HF-MB and HF-HB) increased the litter weight (P < 0.05) and overall litter weight gain (P < 0.05) at weaning and increased colostrum fat content by 27.3–35.8% (P < 0.01). Fatty acid profiles between the two doses of BCAAs were similar. Compared with HF, HF-MB tended to decrease the percentage of C18:3n3 (P = 0.063) and increased the percentage of C18:1n9c (P = 0.03). In addition, BCAAs in HF-MB increased the concentration of total fatty acid by 22.1% in colostrum (P = 0.03) but decreased that in serum at parturition by 53.2% (P = 0.027). The fatty acids in colostrum that increased with BCAAs were C15:0, C17:0, C20:3n6, C20:4n6, C20:5n3 and C22:6n3 (P = 0.00~0.04). Colostrum fatty acids of C20:0, C21:0, C22:0, C16:1, C20:1, C18:1n9c also tended to be increased (0.05 < P < 0.1) with BCAAs. The change in sow serum fatty acid profile due to BCAAs was different from that in colostrum.

Conclusions

BCAAs in high fat diet of sows altered the fatty acid composition in colostrum and enhanced litter growth. Our study indicated that BCAAs supplementation can enhance mammary fatty acid uptake and mammary fat synthesis and that supplemental BCAAs and fat in late gestation and lactation diets for sows can improve reproductive performance.
Computational determination of human PPARG gene: SNPs and prediction of their effect on protein functions of diabetic patients
Authors: Mustafa Howeida Abdullah , Albkrye Afraa Mohamed Suliman , AbdAlla Buthiena Mohamed , Khair Mona AbdelRahman Mohammed , Abdelwahid Nidal , Elnasri Hind Abdelaziz
Published: February 2020

Background

The Peroxisome proliferator‐activated receptor gamma gene (PPARG), encodes a member of the peroxisome‐activated receptor subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) which regulate transcription of various genes. Three subtypes of PPARs are known: PPAR‐alpha, PPAR‐delta and PPAR‐gamma. The protein encoded by this gene is PPAR‐gamma which is a regulator of adipocyte differentiation. PPARG‐gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer.

Aim

This study aimed to perform insilico analysis to predict the effects that can be imposed by SNPs reported in PPARG gene.

Methodology

This gene was investigated in NCBI database (http://www.ncbi.nlm.nih.gov/) during the year 2016 and the SNPs in coding region (exonal SNPs) that are non‐synonymous (ns SNPs) were analyzed by computational softwares. SIFT, Polyphen, I‐Mutant and PHD‐SNP softwares). SIFT was used to filter the deleterious SNPs, Polyphen was used to determine the degree of pathogenicity, I‐Mutant was used to determine the effect of mutation on protein stability while PHD‐SNP software was used to investigate the effect of mutation on protein function. Furthermore, Structural and functional analysis of ns SNPs was also studied using Project HOPE software and modeling was conducted by Chimera.

Results

A total of 34,035 SNPs from NCBI, were found, 21,235 of them were found in Homo sapiens, 134 in coding non synonymous (missense) and 89 were synonymous. Only SNPs present in coding regions were selected for analysis. Out of 12 deleterious SNPs sorted by SIFT, 10 were predicted by Polyphen to be probably damaging with PISC score = 1 and only two were benign. All these 10 double positive SNPs were disease related as predicted by PHD‐SNPs and revealed decreased stability indicated by I‐Mutant.

Conclusion

Based on the findings of this study, it can be concluded that the deleterious ns SNPs (rs72551364 and rs121909244SNPs) of PPARG are important candidates for the cause of different types of human diseases including diabetes mellitus.
The association between internal migration and pulmonary tuberculosis in China, 2005–2015: a spatial analysis
Authors: Liao Wei-Bin , Ju Ke , Gao Ya-Min , Pan Jay
Published: February 2020

Background

Internal migration places individuals at high risk of contracting tuberculosis (TB). However, there is a scarcity of national-level spatial analyses regarding the association between TB and internal migration in China. In our research, we aimed to explore the spatial variation in cases of sputum smear-positive pulmonary TB (SS + PTB) in China; and the associations between SS + PTB, internal migration, socioeconomic factors, and demographic factors in the country between 2005 and 2015.

Methods

Reported cases of SS + PTB were obtained from the national PTB surveillance system database; cases were obtained at the provincial level. Internal migration data were extracted from the national population sampling survey and the census. Spatial autocorrelations were explored using the global Moran’s statistic and local indicators of spatial association. The spatial temporal analysis was performed using Kulldorff’s scan statistic. Fixed effects regression was used to explore the association between SS + PTB and internal migration.

Results

A total of 4 708 563 SS + PTB cases were reported in China between 2005 and 2015, of which 3 376 011 (71.7%) were male and 1 332 552 (28.3%) were female. There was a trend towards decreasing rates of SS + PTB notifications between 2005 and 2015. The result of global spatial autocorrelation indicated that there were significant spatial correlations between SS + PTB rate and internal migration each year (2005–2015). Spatial clustering of SS + PTB cases was mainly located in central and southern China and overlapped with the clusters of emigration. The proportions of emigrants and immigrants were significantly associated with SS + PTB. Per capita GDP and education level were negatively associated with SS + PTB. The internal migration flow maps indicated that migrants preferred neighboring provinces, with most migrating for work or business.

Conclusions

This study found a significant spatial autocorrelation between SS + PTB and internal migration. Both emigration and immigration were statistically associated with SS + PTB, and the association with emigration was stronger than that for immigration. Further, we found that SS + PTB clusters overlapped with emigration clusters, and the internal migration flow maps suggested that migrants from SS + PTB clusters may influence the TB epidemic characteristics of neighboring provinces. These findings can help stakeholders to implement effective PTB control strategies for areas at high risk of PTB and those with high rates of internal migrants.
Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial
Authors: Dietrich Detlef E. , Bode Liv , Spannhuth Carsten W. , Hecker Hartmut , Ludwig Hanns , Emrich Hinderk M.
Published: February 2020

Background

Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine.

Methods

The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC).

Results

Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL).

Conclusions

Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs.

Trial registration

The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do
Causes and consequences of individual variation in animal movement
Authors: Shaw Allison K.
Published: February 2020

Animal movement comes in a variety of ‘types’ including small foraging movements, larger one-way dispersive movements, seasonally-predictable round-trip migratory movements, and erratic nomadic movements. Although most individuals move at some point throughout their lives, movement patterns can vary widely across individuals within the same species: differing within an individual over time (intra-individual), among individuals in the same population (inter-individual), or among populations (inter-population). Yet, studies of movement (theoretical and empirical alike) more often focus on understanding ‘typical’ movement patterns than understanding variation in movement. Here, I synthesize current knowledge of movement variation (drawing parallels across species and movement types), describing the causes (what factors contribute to individual variation), patterns (what movement variation looks like), consequences (why variation matters), maintenance (why variation persists), implications (for management and conservation), and finally gaps (what pieces we are currently missing). By synthesizing across scales of variation, I span across work on plasticity, personality, and geographic variation. Individual movement can be driven by factors that act at the individual, population, community and ecosystem level and have ramifications at each of these levels. Generally the consequences of movement are less well understood than the causes, in part because the effects of movement variation are often nested, with variation manifesting at the population level, which in turn affects communities and ecosystems. Understanding both cause and consequence is particularly important for predicting when variation begets variation in a positive feedback loop, versus when a negative feedback causes variation to be dampened successively. Finally, maintaining standing variation in movement may be important for facilitating species’ ability to respond to future environmental change.
Risk of climate-induced damage in historic parchment
Authors: Krzemień Leszek , Czyżewska Agata , Soboń Magdalena , Kozłowski Roman , Bratasz Łukasz
Published: February 2020

Moisture adsorption and related dimensional change were examined in several samples of historic and contemporary parchment. The tensile behaviour was determined for contemporary parchment and two selected historic materials. The moisture-related data for most parchments are close to the contemporary material while aging and past treatments may lower adsorption of moisture and, in consequence, the dimensional change induced by changes in the moisture content. Contemporary parchment exhibited larger water vapour adsorption and moisture-related response compared to most historic materials and, therefore, can be regarded as the worst-case material in terms of the climate-induced risks to parchment. Tensile parameters of parchment varied significantly with increasing relative humidity (RH). Elasticity modulus declined from on average 1200 to 400 MPa and strain at failure doubled when RH increased from 30 to 85%. Parchment’s critical strain at which permanent deformation occurred decreased dramatically with increasing RH reaching zero at 80%. Irreversible curling produced by variations in RH to which flat parchment specimens were subjected were measured by scanning the specimen surface with the use of a laser triangulation sensor. The degree of curling was expressed quantitatively as standard deviation of local curvatures in the parchment sheet. The study opens a perspective of using the relationship between degree of curling and magnitude of RH variations to derive categories of risk to parchment from indoor climate variations, under the condition that quantitative loss of aesthetical/display value of parchment objects resulting from increased curling is agreed. Historical parchment documents generally demonstrating considerable curling engendered by uncontrolled storage conditions in the past are not vulnerable to further distortion when subjected to variations in RH even of considerable magnitude.
RFA measurements of survival midpalatal orthodontic mini-implants in comparison to initial healing period
Authors: Nienkemper Manuel , Willmann Jan H. , Becker Kathrin , Drescher Dieter
Published: February 2020

Background

In dental implantology, the development of stability over time is a well-investigated topic. In case of orthodontic mini-implants, quantitative data for long-term stability is not available yet. This study aims to clinically investigate the long-term stability of mini-implants inserted in the midsagittal suture of the anterior palate. Moreover, the influence of the length of implants was elucidated. The stability of 2 × 9 and 2 × 11 mm mini-implants after orthodontic treatment (9 mm, 2.84 years ± 1.25 years; 11 mm, 3.17 years ± 0.96 years) was assessed by resonance frequency analysis (RFA). The obtained long-term pieces of data were compared with each other (9 mm vs 11 mm), as well as with the data from the matched early stability groups, to assess the initial and early secondary stability after the insertion from previous clinical trials.

Results

For both lengths, the long-term stability (2 × 9 mm, 25.12 ± 7.11, n = 21; 2 × 11 mm, 24.39 ± 5.82, n = 18) was significantly lower than primary stability (2 × 9 mm, 36.14 ± 6.08, n = 19; 2 × 11 mm, 33.35 ± 3.53, n = 20). The differences within the groups disappeared over the initial healing period: after 4 weeks for the 2 × 9 mm implants and after 2 weeks for the 2 × 11 mm implants. Also, the 2 × 9 mm and 2 × 11 mm implants showed comparable long-term stability values.

Conclusion

The stability of midpalatal mini-implants does not change in the long term after the initial healing period. Moreover, 2 × 9 mm mini-implants seem to be appropriate for orthodontic anchorage, as the stability of 2 × 11 mm implants is not higher. Therefore, owing to lower invasiveness, 2 × 9 mm implants should be preferred.
LncRNA SNHG7/miR-34a-5p/SYVN1 axis plays a vital role in proliferation, apoptosis and autophagy in osteoarthritis
Authors: Tian Feng , Wang Junhu , Zhang Zhanhua , Yang Jie
Published: February 2020

Background

Osteoarthritis (OA) is one of the most common rheumatic diseases of which clinical symptoms includes swelling, synovitis and inflammatory pain, affect patients’ daily life. It was reported that non-coding RNAs play vital roles in OA. However, the regulation mechanism of ncRNA in OA pathogenesis has not been fully elucidated.

Methods

The expression of SNHG7, miR-34a-5p and SYVN1 was detected using qRT-PCR in tissues, serum and cells. The protein expression of SYVN1, PCNA, cleavage-caspase 3, beclin1 and LC3 were measured using western blot. The RNA immunoprecipitation (RIP), RNA pulldown, and luciferase reporter assays were used to verify the relationship between SNHG7, miR-34a-5p and SYVN1. The MTT and flow cytometry assay was performed to detected cell proliferation and cell apoptosis respectively.

Results

In this study, SNHG7 and SYVN1 expression were down-regulated, but miR-34a-5p was up-regulated in OA tissues and IL-1β treated cells compared with normal tissues and chondrocyte. Functional investigation revealed that up-regulated SNHG7 or down-regulated miR-34a-5p could promote cell proliferation and inhibit cell apoptosis and autophagy in OA cells. More than that, RIP, pulldown and luciferase reporter assay was applied to determine that miR-34a-5p was a target miRNA of SNHG7 and SYVN1 was a target mRNA of miR-34-5p. Rescue experiments showed that overexpression of miR-34a reversed high expression of SNHG7-mediated suppression of apoptosis and autophagy as well as promotion of proliferation, while its knockdown inhibited cell apoptosis and autophagy and promoted cell proliferation which could be impaired by silencing SYVN1. In addition, SNHG7 regulated SYVN1 through sponging miR-34a-5p.

Conclusion

SNHG7 sponged miR-34a-5p to affect cell proliferation, apoptosis and autophagy through targeting SYVN1 which provides a novel sight into the pathogenesis of OA.