bluuebunny/crossref_metadata_2025 huggingface dataset:
Biogenesis of respiratory cytochromes in bacteria
Authors: Thöny-Meyer L
Published: June 2021

Biogenesis of respiratory cytochromes is defined as consisting of the posttranslational processes that are necessary to assemble apoprotein, heme, and sometimes additional cofactors into mature enzyme complexes with electron transfer functions. Different biochemical reactions take place during maturation: (i) targeting of the apoprotein to or through the cytoplasmic membrane to its subcellular destination; (ii) proteolytic processing of precursor forms; (iii) assembly of subunits in the membrane and oligomerization; (iv) translocation and/or modification of heme and covalent or noncovalent binding to the protein moiety; (v) transport, processing, and incorporation of other cofactors; and (vi) folding and stabilization of the protein. These steps are discussed for the maturation of different oxidoreductase complexes, and they are arranged in a linear pathway to best account for experimental findings from studies concerning cytochrome biogenesis. The example of the best-studied case, i.e., maturation of cytochrome c, appears to consist of a pathway that requires at least nine specific genes and more general cellular functions such as protein secretion or the control of the redox state in the periplasm. Covalent attachment of heme appears to be enzyme catalyzed and takes place in the periplasm after translocation of the precursor through the membrane. The genetic characterization and the putative biochemical functions of cytochrome c-specific maturation proteins suggest that they may be organized in a membrane-bound maturase complex. Formation of the multisubunit cytochrome bc, complex and several terminal oxidases of the bo3, bd, aa3, and cbb3 types is discussed in detail, and models for linear maturation pathways are proposed wherever possible.
Mating types and sexual development in filamentous ascomycetes
Authors: Coppin E , Debuchy R , Arnaise S , Picard M
Published: June 2021

The progress made in the molecular characterization of the mating types in several filamentous ascomycetes has allowed us to better understand their role in sexual development and has brought to light interesting biological problems. The mating types of Neurospora crassa, Podospora anserina, and Cochliobolus heterostrophus consist of unrelated and unique sequences containing one or several genes with multiple functions, related to sexuality or not, such as vegetative incompatibility in N. crassa. The presence of putative DNA binding domains in the proteins encoded by the mating-type (mat) genes suggests that they may be transcriptional factors. The mat genes play a role in cell-cell recognition at fertilization, probably by activating the genes responsible for the hormonal signal whose occurrence was previously demonstrated by physiological experiments. They also control recognition between nuclei at a later stage, when reproductive nuclei of each mating type which have divided in the common cytoplasm pair within the ascogenous hyphae. How self is distinguished from nonself at the nuclear level is not known. The finding that homothallic species, able to mate in the absence of a partner, contain both mating types in the same haploid genome has raised more issues than it has resolved. The instability of the mating type, in particular in Sclerotinia trifolorium and Botrytinia fuckeliana, is also unexplained. This diversity of mating systems, still more apparent if the yeasts and the basidiomycetes are taken into account, clearly shows that no single species can serve as a universal mating-type model.
Prediction of outcome from MRI and general movements assessment after hypoxic-ischaemic encephalopathy in low-income and middle-income countries: data from a randomised controlled trial
Authors: Aker Karoline , Thomas Niranjan , Adde Lars , Koshy Beena , Martinez-Biarge Miriam , Nakken Ingeborg , Padankatti Caroline S , Støen Ragnhild
Published: June 2021

Objective

To evaluate the accuracy of neonatal MRI and general movements assessment (GMA) in predicting neurodevelopmental outcomes in infants with hypoxic-ischaemic encephalopathy (HIE).

Design

Secondary analyses of a randomised controlled trial (RCT).

Setting

Tertiary neonatal intensive care unit in India.

Methods

Fifty infants with HIE were included in an RCT of therapeutic hypothermia (25 cooled and 25 non-cooled). All infants underwent brain MRI at day 5, GMA at 10–15 weeks and outcome assessments including Bayley Scales of Infant and Toddler Development, third edition, at 18 months. Associations between patterns of brain injury, presence/absence of fidgety movements (FMs) and outcomes were assessed.

Results

Seventeen of 47 (36%) had adverse outcome (5 (21%) cooled vs 12 (52%) non-cooled, p=0.025). Eight infants died (four before an MRI, another three before GMA). Two developed severe cerebral palsy and seven had Bayley-III motor/cognitive composite score <85. Twelve (26%) had moderately/severely abnormal MRI and nine (23%) had absent FMs. The positive predictive value (95% CI) of an adverse outcome was 89% (53% to 98%) for moderate/severe basal ganglia and thalami (BGT) injury, 83% (56% to 95%) for absent/equivocal signal in the posterior limb of the internal capsule (PLIC) and 67% (38% to 87%) for absent FMs. Negative predictive values (95% CI) were 85% (74% to 92%) for normal/mild BGT injury, 90% (78% to 96%) for normal PLIC and 86% (74% to 93%) for present FMs.

Conclusion(s)

Neonatal MRI and GMA predicted outcomes with high accuracy in infants with HIE. The GMA is a feasible low-cost method which can be used alone or complementary to MRI in low-resource settings to prognosticate and direct follow-up.

Trial registration number

CTRI/2013/05/003693.
Neurodevelopmental outcome of patients with congenital gastrointestinal malformations: a systematic review and meta-analysis
Authors: Roorda Daniëlle , Königs Marsh , Eeftinck Schattenkerk Laurens , van der Steeg Lideke , van Heurn Ernest , Oosterlaan Jaap
Published: June 2021

Aim

Children with congenital gastrointestinal malformations may be at risk of neurodevelopmental impairment due to challenges to the developing brain, including perioperative haemodynamic changes, exposure to anaesthetics and postoperative inflammatory influences. This study aggregates existing evidence on neurodevelopmental outcome in these patients using meta-analysis.

Method

PubMed, Embase and Web of Science were searched for peer-reviewed articles published until October 2019. Out of the 5316 unique articles that were identified, 47 studies met the inclusion criteria and were included. Standardised mean differences (Cohen’s d) between cognitive, motor and language outcome of patients with congenital gastrointestinal malformations and normative data (39 studies) or the studies’ control group (8 studies) were aggregated across studies using random-effects meta-analysis. The value of (clinical) moderators was studied using meta-regression and diagnostic subgroups were compared.

Results

The 47 included studies encompassed 62 cohorts, representing 2312 patients. Children with congenital gastrointestinal malformations had small-sized cognitive impairment (d=−0.435, p<0.001; 95% CI −0.567 to −0.302), medium-sized motor impairment (d=−0.610, p<0.001; 95% CI −0.769 to −0.451) and medium-sized language impairment (d=−0.670, p<0.001; 95% CI −0.914 to −0.425). Patients with short bowel syndrome had worse motor outcome. Neurodevelopmental outcome was related to the number of surgeries and length of total hospital stay, while no relations were observed with gestational age, birth weight, age and sex.

Interpretation

This study shows that children with congenital gastrointestinal malformations exhibit impairments in neurodevelopmental outcome, highlighting the need for routine screening of neurodevelopment during follow-up.
Managing high frequency users of an electronic consultation system in primary care: a quality improvement project
Authors: Leung Katherine , Qureshi Saffan
Published: June 2021

The COVID-19 pandemic prompted a rapid change in primary care provision. There was a significant shift from face-to-face appointments to remote methods such as electronic consultation (e-consultation). Patients from a primary care provider in London were actively encouraged to use an online consultation platform called ‘Dr iQ’. A group of high frequency users of Dr iQ emerged and clinicians were concerned their health needs were not being met through the platform. High frequency attendance in a traditional general practice setting is associated with increased time and healthcare costs.

This project evaluated the number of high frequency users (identified as 10 or more consultations a month) of Dr iQ in one busy inner city practice over a 5-month period. We aimed to decrease the subsequent monthly usage frequency of all Dr iQ high frequency users from 10 or more consultations to less than 10 consultations. Our interventions included a semi-structured telephone interview, discussion among the multidisciplinary team, and regular scheduled telephone or face-to-face appointments. Following two Plan–Do-Study–Act cycles, all 12 high frequency users showed a decrease in the number of consultations submitted to Dr iQ to less than 10 consultations a month.

This project proposes a method of case managing high frequency users of e-consultation. The majority of high frequency users had unmet health needs and felt a lack of continuity of care on Dr iQ. They often had complex physical and mental health problems. As remote consulting technology continues to develop, more research is required to understand the epidemiology and aetiology of e-consultation high frequency use in order to improve patient outcomes.
Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity
Authors: Legscha Kevin Jan , Antunes Ferreira Edite , Chamoun Antonios , Lang Alexander , Awwad Mohamed Hemaid Sayed , Ton Gigi Nu Hoang Quy , Galetzka Danuta , Guezguez Borhane , Hundemer Michael , Bourdon Jean-Christophe , Munder Markus , Theobald Matthias , Echchannaoui Hakim
Published: June 2021

Background

Tumor microenvironment-associated T cell senescence is a key limiting factor for durable effective cancer immunotherapy. A few studies have demonstrated the critical role of the tumor suppressor TP53-derived p53 isoforms in cellular senescence process of non-immune cells. However, their role in lymphocytes, in particular tumor-antigen (TA) specific T cells remain largely unexplored.

Methods

Human T cells from peripheral blood were retrovirally engineered to coexpress a TA-specific T cell receptor and the Δ133p53α-isoform, and characterized for their cellular phenotype, metabolic profile and effector functions.

Results

Phenotypic analysis of Δ133p53α-modified T cells revealed a marked reduction of the T-cell inhibitory molecules (ie, CD160 and TIGIT), a lower frequency of senescent-like CD57+and CD160+CD8+T cell populations, and an increased number of less differentiated CD28+T cells. Consistently, we demonstrated changes in the cellular metabolic program toward a quiescent T cell state. On a functional level, Δ133p53α-expressing T cells acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumor-specific killing in vitro and in mouse tumor model. Finally, we demonstrated the capacity of Δ133p53α to restore the antitumor response of senescent T cells isolated from multiple myeloma patients.

Conclusion

This study uncovered a broad effect of Δ133p53α isoform in regulating T lymphocyte function. Enhancing fitness and effector functions of senescent T cells by modulation of p53 isoforms could be exploited for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.
Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2
Authors: Pellizzari Giulia , Martinez Olivier , Crescioli Silvia , Page Robert , Di Meo Ashley , Mele Silvia , Chiaruttini Giulia , Hoinka Jan , Batruch Ihor , Prassas Ioannis , Grandits Melanie , López-Abente Jacobo , Bugallo-Blanco Eva , Ward Malcolm , Bax Heather J , French Elise , Cheung Anthony , Lombardi Sara , Figini Mariangela , Lacy Katie E , Diamandis Eleftherios P , Josephs Debra H , Spicer James , Papa Sophie , Karagiannis Sophia N
Published: June 2021

Background

Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies.

Methods

Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy.

Results

We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γ and interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected.

Conclusions

These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.
Protein citrullination as a source of cancer neoantigens
Authors: Katayama Hiroyuki , Kobayashi Makoto , Irajizad Ehsan , Sevillano Alejandro M , Patel Nikul , Mao Xiangying , Rusling Leona , Vykoukal Jody , Cai Yining , Hsiao Fuchung , Yu Chuan-Yih , Long James , Liu Jinsong , Esteva Franscisco , Fahrmann Johannes , Hanash Sam
Published: June 2021

Background

Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.

Methods

Protein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.

Results

Proteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).

Conclusions

An immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.
Hypothetical flavour ban and intention to vape among vape shop customers: the role of flavour preference and e-cigarette dependence
Authors: Huh Jimi , Yu Sheila , Galimov Artur , Meza Leah R , Galstyan Ellen , Medel Donna , Unger Jennifer B , Baezconde-Garbanati Lourdes , Sussman Steve
Published: June 2021

Introduction

E-cigarette users typically initiate vaping with flavoured e-liquids. People who vape flavours tend to underestimate the harm of vaping. We examined the inter-relationship between flavour preference, vaping for cessation purposes, e-cigarette dependence, e-cigarette harm perception and purchase/use intention, given a hypothetical flavour ban. We hypothesised that non-tobacco flavour preference and vaping for cessation would be negatively associated with harm perception of e-cigarettes and intention to continue vaping if a flavour ban occurred and that these effects would be mediated by e-cigarette dependence.

Methods

From July 2019 to March 2020, we conducted intercept interviews with 276 customers at 44 vape shops in California. The predictor variables were flavour preference and vaping for cessation. The outcome variables were harm perception of e-cigarettes and intention to purchase/use, given a hypothetical flavour ban. Multilevel structural equation modelling tested whether e-cigarette dependence mediates the effects of flavour preference on hypothetical continued vaping and purchase.

Results

Those who preferred flavours showed significantly lower intention to purchase e-liquids (β=−0.28, p<0.001) and to continue vaping (β=−0.17, p=0.001), given a hypothetical flavour ban. Those who vaped for smoking cessation indicated greater intention to purchase e-liquid (β=0.10, p=0.016) and to continue vaping (β=0.17, p=0.001), given a hypothetical flavour ban. E-cigarette dependence significantly mediated these effects (ps<0.04).

Discussion

Flavour preference was negatively related to intention to continue to vape within a hypothetical flavour ban. Our results also highlight the importance of e-cigarette dependence and use of e-cigarettes as smoking cessation methods. Implications for future flavour bans are discussed.
Analysis of the illicit tobacco market in Georgia in response to fiscal and non-fiscal tobacco control measures
Authors: Little Megan , Ross Hana , Bakhturidze George , Kachkachishvili Iago
Published: June 2021

Background

Georgian illicit cigarette consumption was 1.5% in 2017. In 2018, a new tobacco control law took effect followed by a substantial cigarette excise tax increase in 2019. Research shows these policies reduce tobacco consumption, but the tobacco industry argues they increase illicit trade. There is limited evidence on this, particularly from developing countries.

Methods

A panel household survey in Georgia obtained data over three waves: 2017 baseline, 2018 after the tobacco control law took effect and 2019 after taxes increased. A sample of 1578 smokers (and quitters in later waves) from five regions reported their tobacco use and were asked to present a cigarette pack in their possession. These were examined for tax stamps and health warnings to establish legality.

Findings

There was no evidence of an increase in illicit cigarette consumption in Tbilisi, Kutaisi, Akhaltsikhe or Gori in any wave. In Zugdidi, near the Russian-occupied Abkhazia, illicit cigarette consumption was increasing even prior to the tax increase, reaching 30.9% by wave 3. A country-wide shift occurred from manufactured cigarettes to roll-your-own tobacco (whose tax remained unchanged) between waves 2 and 3.

Conclusion

No evidence of a country-wide increase in illicit cigarette trade was found after non-fiscal tobacco measures took effect and cigarette taxes increased. Relatively high illicit cigarette consumption in Zugdidi highlights the role of disputed territories and border administration in illicit cigarette supply. Substitution towards roll-your-own tobacco after manufactured cigarette taxes increased demonstrates the importance of equalising taxes on tobacco products to maximise public health benefits.
Fungal endophytes increase biomass production in pale swallow-wort (Vincetoxicum rossicum (Kleopow) Barbar.)
Authors: Dickinson Richard B. , Bourchier Robert S. , Fulthorpe Roberta R. , Shen Shu Yi , Jones Ian M. , Smith Sandy M.
Published: June 2021

Pale swallow-wort, Vincetoxicum rossicum (Kleopow) Barbar., is an invasive weed in the lower Great Lakes Basin of North America. We investigated the relationship between V. rossicum productivity and several environmental variables across 54 established V. rossicum populations in southern Ontario. Variables included climate measurements, soil characteristics (pH, texture, and nutrient status), habitat type, plant community, and the diversity of root-associated fungi. Vincetoxicum rossicum roots were collected at all 54 sites, and associated fungi were compared using terminal restriction fragment length polymorphism. Aboveground biomass of V. rossicum was measured at 23 sites with similar light regimes, allowing comparison between populations. Results suggested that abiotic soil variables, and habitat type have little effect on V. rossicum productivity. Aboveground biomass production was significantly correlated with precipitation, and the presence of fungal pathogens and dark septate endophytes. Annual precipitation and soil clay content were also positively correlated with the abundance of soil pathogens. Accumulation of these microbes may negatively affect co-occurring native plants and associated fungal partners. The presence of these fungal species in soil could be used as an indicator of site susceptibility to invasion by V. rossicum and assist in the development of management plans for this exotic vine.
A management-scale investigation of consistent individual differences in behaviour and trapping bias in sea lamprey (Petromyzon marinus)
Authors: Holub Rachel , Bravener Gale , McLaughlin Robert
Published: June 2021

The sea lamprey (Petromyzon marinus) is invasive in the Laurentian Great Lakes. Trapping in large rivers could suppress sea lamprey recruitment by removing migrating adults prior to spawning. Currently, the proportion of sea lamprey trapped (efficiency) is too low for control purposes, possibly because trapping is biased toward certain behavioural types. We tested if individual differences in time to enter a novel environment (risk-taking) and proportion of time moving (activity) under standardized laboratory conditions were correlated with time to encounter and enter a trap in the field. 638 sea lamprey were tagged, assessed for risk-taking and activity in sequential trials, and released in the river to be trapped. In the laboratory, individuals differed consistently in risk-taking and activity behaviours, and more active individuals entered a simulated trap sooner than less active individuals. In the field, however, the times to first trap encounter, and capture in a trap, were not correlated with risk-taking or activity. Our study provides a novel demonstration of how patterns from small-scale behavioural studies may not extend to management-scale applications.
Application of Blockchain-Based Sports Health Data Collection System in the Development of Sports Industry
Authors: Yu Song
Published: June 2021

In recent years, with the continuous development of blockchain technology and the prosperity of digital currency, various industries have carried out extensive practice around the application of blockchain technology, such as my country’s sports industry. Through the measurement and collection of athletes’ health and exercise information, the athlete’s exercise volume and exercise level can be quantitatively evaluated. Blockchain technology provides a new opportunity for the development of the sports industry. The characteristics of the decentralization, security, credibility, and traceability of the data collection system are highly compatible with the development of the sports industry. In order to develop and expand the sports industry and scientifically evaluate the physical fitness of athletes, this research focuses on the blockchain-based sports health data collection system in the sports industry. This article adopts the accuracy index and the formula of data return and conducts demand analysis, accuracy, and recall analysis of the health data collection system. The research conclusion of this paper is that when using sensors to collect sports health data, the data collection of sensors located on the arm is more accurate, with an accuracy rate of over 90%, and the collection effect of multinode sensors is higher than that of single-node sensors. The collection of sports health data is beneficial to the training of athletes and the development of the sports industry to meet the growing demand for sports health. Our country’s sports industry will also develop with the application of blockchain.
Experimental Study of Stress-Seepage Coupling Properties of Sandstone under Different Loading Paths
Authors: Chen Xi , Wang Wei , Cao Yajun , Zhu Qizhi , Xu Weiya , Ruan Huaining
Published: June 2021

The study on hydromechanical coupling properties of rocks is of great importance for rock engineering. It is closely related to the stability analysis of structures in rocks under seepage condition. In this study, a series of conventional triaxial tests under drained condition and hydrostatic compression tests under drained or undrained condition on sandstones were conducted. Moreover, complex cyclic loading and unloading tests were also carried out. Based on the experimental results, the following conclusions were obtained. For conventional triaxial tests, the elastic modulus, peak strength, crack initiation stress, and expansion stress increase with increased confining pressure. Pore pressure weakened the effect of the confining pressure under drained condition, which led to a decline in rock mechanical properties. It appeared that cohesion was more sensitive to pore pressure than to the internal friction angle. For complex loading and unloading cyclic tests, in deviatoric stress loading and unloading cycles, elastic modulus increased obviously in first loading stage and increased slowly in next stages. In confining pressure loading and unloading cycles, the Biot coefficient decreased first and then increased, which indicates that damage has a great impact on the Biot coefficient.
The Potential Role of Chemerin, Lipocalin 2, and Apelin in the Diagnosis and Pathophysiology of Gestational Diabetes Mellitus
Authors: Mierzyński Radzisław , Poniedziałek-Czajkowska Elżbieta , Dłuski Dominik , Kamiński Maciej , Mierzyńska Agnieszka , Leszczyńska-Gorzelak Bożena
Published: June 2021

The exact role of adipokines in the pathogenesis of gestational diabetes mellitus (GDM) still remains not fully clear, and multiple studies have analyzed their potential contribution to the pathophysiology of this pregnancy complication. This study is aimed at evaluating serum chemerin, lipocalin 2, and apelin concentrations in GDM and healthy pregnant patients, assessing the correlation between these adipokines, and suggesting the potential role of these cytokines in the diagnosis and pathophysiology of GDM. The study comprised 237 pregnant women: 153 with GDM and 84 with physiological pregnancy. Serum concentrations of chemerin, lipocalin 2, and apelin were obtained at 24–29 weeks of gestation. The mean concentrations of chemerin and lipocalin 2 were significantly higher in the GDM group. The concentration of apelin was slightly higher in the GDM group, but not statistically significant. The strong positive correlation between chemerin and lipocalin 2 concentrations was noticed in both groups. Our data suggest that maternal chemerin and lipocalin 2 may play a significant role in the pathophysiology of GDM. We imply that these adipokines could potentially be established as novel biomarkers for the early identification of GDM. However, more studies are needed to analyze the effect of these adipokines on glucose metabolism during early pregnancy.
Central Pain in Parkinson’s Disease: Behavioral and Cognitive Characteristics
Authors: Vila-Chã N. , Cavaco S. , Mendes A. , Gonçalves A. , Moreira I. , Fernandes J. , Damásio J. , Azevedo L. F. , Castro-Lopes J. M.
Published: June 2021

Introduction. Pain is a major nonmotor symptom of Parkinson’s disease (PD), and central parkinsonian pain is the core feature of the putative Park pain subtype of PD. This study aimed to explore the cognitive and behavioral profile of PD patients with central parkinsonian pain. Material and Methods. A structured interview was used to identify and characterize pain in a cohort of 260 consecutive PD patients. The Ford classification of pain was applied. The Dementia Rating Scale-2 (DRS-2) and the Impulse Control Disorders in Parkinson’s Disease Short Form (QUIP-S) were administered, and patients’ smoking habits were recorded. The Unified Parkinson’s Disease Rating Scale (UPDRS) was used to assess motor and nonmotor symptoms in off and on conditions. Results. One hundred and eighty-eight patients (68%) reported pain; and in 41 (22%) of them, the pain was classified as central parkinsonian pain. PD patients with central parkinsonian pain had better cognitive performance in DRS-2 Initiation/Perseveration and Conceptualization subscales but reported more other compulsive behaviors (e.g., hobbyism, punding, and walkabout) and had more current smoking habits than those without pain or with non-central parkinsonian pain. Multiple logistic regression analyses revealed that the DRS-2 Conceptualization subscale, other compulsive behaviors, and smoking habits remained statistically associated with central parkinsonian pain even when other significant covariates were considered. Only patients with pain, regardless of type, had a gambling disorder. Discussion. The study results provide further evidence that pain revealed that patients with central parkinsonian pain are more likely to present compulsive or addictive behaviors, despite having more preserved cognitive performance. Patients with central parkinsonian pain appear to have a distinct phenotype of PD.
Vitamin E TPGS 1000 Induces Apoptosis in the K562 Cell Line: Implications for Chronic Myeloid Leukemia
Authors: Calvo-Alvarez Jazmin , Jimenez-Del-Rio Marlene , Velez-Pardo Carlos
Published: June 2021

Chronic myeloid leukemia (CML) is a hematologic malignancy derived from the myeloid lineage molecularly characterized by t(9;22)(q34;q11) resulting in BCR‐ABL1 gene fusion, which is known as Philadelphia (Ph) chromosome. Although tyrosine kinase inhibitors (TKIs) have restored and maintained the quality of life of patients with CML, an important minority of patients become resistant to first‐and‐second‐generation TKIs and require an alternative treatment. The K562 cell (Ph+, p53‐/‐) line was treated with Vit E TPGS 1000 (20–80 μM) only or with other products of interest (e.g., antioxidant N‐acetylcysteine (NAC), specific JNK and caspase‐3 inhibitor SP600125, and NSCSI, respectively) for 24 h at 37°C. Cells were analyzed by fluorescence microscopy (FM), flow cytometry (FC), and Western blotting (WB) techniques. We show that TPGS induces apoptosis in K562 cells through H2O2 signaling mechanism comprising the activation of a minimal molecular cascade: the kinase JNK>the transcription factor c‐JUN>the activation of BCL‐only BH3 proapoptotic protein PUMA>loss of mitochondrial membrane potential (ΔΨm)>activation of caspase‐3>chromatin condensation>fragmentation of DNA. Additionally, TPGS oxidizes the stress sensor protein DJ‐1‐Cys106‐SH into DJ‐1‐Cys106‐SO3 and arrested the cell cycle in the S phase. Remarkably, NAC, SP600125, and NSCSI blocked TPGS‐induced OS and apoptosis in K562. Since TPGS is safe in mice and humans, it is especially promising for preclinical and clinical CML leukemia research. Our findings support the view that oxidation therapy offers an important opportunity to eliminate CML.
Unique Biomarker Characteristics in Gestational Diabetes Mellitus Identified by LC-MS-Based Metabolic Profiling
Authors: Meng Xingjun , Zhu Bo , Liu Yan , Fang Lei , Yin Binbin , Sun Yanni , Ma Mengni , Huang Yuli , Zhu Yuning , Zhang Yunlong
Published: June 2021

Background. Gestational diabetes mellitus (GDM) is a type of glucose intolerance disorder that first occurs during women’s pregnancy. The main diagnostic method for GDM is based on the midpregnancy oral glucose tolerance test. The rise of metabolomics has expanded the opportunity to better identify early diagnostic biomarkers and explore possible pathogenesis. Methods. We collected blood serum from 34 GDM patients and 34 normal controls for a LC-MS-based metabolomics study. Results. 184 metabolites were increased and 86 metabolites were decreased in the positive ion mode, and 65 metabolites were increased and 71 were decreased in the negative ion mode. Also, it was found that the unsaturated fatty acid metabolism was disordered in GDM. Ten metabolites with the most significant differences were selected for follow-up studies. Since the diagnostic specificity and sensitivity of a single differential metabolite are not definitive, we combined these metabolites to prepare a ROC curve. We found a set of metabolite combination with the highest sensitivity and specificity, which included eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, arachidonic acid, citric acid, α-ketoglutaric acid, and genistein. The area under the curves (AUC) value of those metabolites was 0.984 between the GDM and control group. Conclusions. Our results provide a direction for the mechanism of GDM research and demonstrate the feasibility of developing a diagnostic test that can distinguish between GDM and normal controls clearly. Our findings were helpful to develop novel biomarkers for precision or personalized diagnosis for GDM. In addition, we provide a critical insight into the pathological and biological mechanisms for GDM.
Hepatic Steatosis Index and Chronic Kidney Disease among Middle-Aged Individuals: A Large-Scale Study in Japan
Authors: Ochiai Hirotaka , Shirasawa Takako , Yoshimoto Takahiko , Nagahama Satsue , Sakamoto Ken , Azuma Minami , Kokaze Akatsuki
Published: June 2021

Background. Though nonalcoholic fatty liver disease (NAFLD) is related to chronic kidney disease (CKD), it is unclear whether the hepatic steatosis index (HSI), a screening tool for NAFLD, is related to CKD. The present study investigated the relationship between HSI and CKD among middle-aged individuals in Japan. Methods. Subjects were adults (aged 40–64 years) who received an annual health checkup in Japan between April 2013 and March 2014. Height and weight were measured, and venous blood samples were obtained to determine alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine levels. HSI was calculated by the following formula:

HSI
=
8
×
ALT
/
AST
 
ratio
+
body
 
mass
 
index

(+2, if diabetes; +2, if female). CKD was defined as an estimated glomerular filtration

rate
<
60
 
mL
/
min
/
1.73
 

m

2

and/or urinary protein of ≥ (+). Logistic regression analysis was performed to estimate the odds ratio (OR) and its 95% confidence interval (CI) for CKD. Results. Data of 94,893 adults were analyzed. Compared with men with an

HSI
<
30

, men with

30
≤
HSI
≤
36

(OR: 1.50, 95% CI: 1.40–1.61) and

HSI
>
36

(OR: 2.14, 95% CI: 1.99–2.31) had significantly higher ORs for CKD. Moreover, there was a significant dose-response relationship between HSI and CKD (

P

for

trend
<
0.001

). Even after adjusting for confounders, the significant results persisted. These findings in men were similar to those in women. Conclusions. This study showed that the HSI was associated with CKD among middle-aged adults in Japan. Additionally, a dose-response relationship of HSI to CKD was observed. The present study suggested that it might be useful to monitor the HSI among middle-aged individuals to detect CKD at an early stage.
Minimally Invasive Elective Surgery as a Treatment of Bowel Invagination in a Peutz-Jeghers Syndrome Case
Authors: García Picazo Alberto , López de la Torre Beatriz , Vivas Alfredo , García Francisco J. , Ferrero Eduardo
Published: June 2021

We present a case of a 24-year-old woman with Peutz-Jeghers syndrome, recurrent colic abdominal pain, and lower gastrointestinal bleed for the last 5 years. Colonoscopy showed hamartomas without any dysplasia. In the enteral magnetic resonance imaging, a distal jejunum and ileum invagination, secondary to hamartomas was detected. The patient was referred to the Surgery Department and despite few symptoms, elective surgery was proposed. By laparoscopic surgery approach, the entire bowel was carefully revised, 3 intussusceptions and bowel volvulus were found, 2 in jejunum and 1 in ileum, causing incomplete obstruction and intestinal dilatation, with a diameter of 6 cm. These intussusception areas were marked with a silk filament, after achieving devolvulation and disinvagination. A 5-cm laparotomy was done, to externalize the entire bowel, to explore it manually, to verify the absence of other lesions, and locate silk points. By longitudinal enterotomies on the antimesenteric intestinal border where silk filaments were located, the polyps were removed through their stalk, and the enterotomies were transversely closed. Postoperative evolution was favorable, starting oral tolerance on the fourth day and being discharged from the hospital on the seventh day. Eight months later, the patient was asymptomatic with a better quality of life.
Carcinoembryonic Antigen Elevation in a Patient with SARS-CoV-2 and a History of Colon Cancer
Authors: Alrifai Taha , Sharko Anita , Leslie William T.
Published: June 2021

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic continues to affect millions of people and impact health-care delivery worldwide. New data and insights into the diagnosis and treatment of SARS-CoV-2 are emerging rapidly. Several prognostic biomarkers have been studied in patients with SARS-CoV-2. Among those biomarkers is the carcinoembryonic antigen (CEA). We report the case of a 46-year-old male with a history of colon cancer who was found to have an elevated CEA level during routine surveillance. Further workup confirmed a diagnosis of SARS-CoV-2 infection. The CEA level normalized with the resolution of the infection.
Novel Strategy for Diagnosis of Focal Nodular Hyperplasia Using Gadolinium Ethoxybenzyl Diethylenetriaminepentaacetic Acid: Enhanced Magnetic Resonance Imaging and Magnetic Resonance Elastography
Authors: Takeda Nobutaka , Tsuchiya Atsunori , Natsui Kazuki , Ishii Yui , Arao Yoshihisa , Kimura Naruhiro , Tominaga Kentaro , Takeuchi Suguru , Hayashi Kazunao , Takamura Masaaki , Terai Shuji
Published: June 2021

Focal nodular hyperplasia (FNH) is the second most frequent benign liver tumor, and it is a fiber-rich stiff lesion. Typically, FNH can be diagnosed by imaging without biopsy. However, liver biopsy and diagnostic resection may be required to differentiate atypical FNH from other liver tumors, such as hepatocellular adenoma (HCA). Therefore, improved noninvasive diagnostic methods are needed. We experienced 2 cases where combination of magnetic resonance elastography (MRE) and gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) helped diagnose FNH. A 36-year-old woman and 17-year-old boy with liver tumors measuring 40 mm in diameter each showed hypointense nodule centers, indicating a central scar, surrounded by hyperintense signals during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. To rule out HCA, we performed MRE and liver biopsy. On MRE, the mean stiffness of the mass was 11.6 kPa (mean stiffness of the background liver was 1.7 kPa) and 11.1 kPa (mean stiffness of the background liver was 2.4 kPa) in the first and second patients, respectively. Histological examination of both specimens showed CK7-positive bile-ductular proliferations, abundant fibrous tissue, and few Ki-67-positive cells. Based on these results, we diagnosed these tumors as FNH. Combination of Gd-EOB-DTPA-enhanced MRI and MRE can evaluate the character and stiffness of lesion and help in the diagnosis of FNH.
High Sensitivity of the Circadian Clock in the Hippocampal Dentate Gyrus to Glucocorticoid- and GSK3-Beta-Dependent Signals
Authors: Liška Karolína , Sládek Martin , Houdek Pavel , Shrestha Norzin , Lužná Vendula , Ralph Martin R. , Sumová Alena
Published: June 2021

Aims: Circadian clocks in the hippocampus (HPC) align memory processing with appropriate time of day. Our study was aimed at ascertaining the specificity of glycogen synthase kinase 3-beta (GSK3β)- and glucocorticoid (GC)-dependent pathways in the entrainment of clocks in individual HPC regions, CA1-3, and dentate gyrus (DG). Methods: The role of GCs was addressed in vivo by comparing the effects of adrenalectomy (ADX) and subsequent dexamethasone (DEX) supplementation on clock gene expression profiles (Per1, Per2, Nr1d1, and Bmal1). In vitro the effects of DEX and the GSK3β inhibitor, CHIR-99021, were assessed from recordings of bioluminescence rhythms in HPC organotypic explants of mPER2Luc mice. Results: Circadian rhythms of clock gene expression in all HPC regions were abolished by ADX, and DEX injections to the rats rescued those rhythms in DG. The DEX treatment of the HPC explants significantly lengthened periods of the bioluminescence rhythms in all HPC regions with the most significant effect in DG. In contrast to DEX, CHIR-99021 significantly shortened the period of bioluminescence rhythm. Again, the effect was most significant in DG which lacks the endogenously inactivated (phosphorylated) form of GSK3β. Co-treatment of the explants with CHIR-99021 and DEX produced the CHIR-99021 response. Therefore, the GSK3β-mediated pathway had dominant effect on the clocks. Conclusion: GSK3β- and GC-dependent pathways entrain the clock in individual HPC regions by modulating their periods in an opposite manner. The results provide novel insights into the mechanisms connecting the arousal state-relevant signals with temporal control of HPC-dependent memory and cognitive functions.
Morpho-physiological responses in wheat (Triticum aestivum L) influenced by normal and water stress conditions
Authors: Shar Piar Ali , Shar Akhtar Hussain , Memon Shabana , Soomro Ayaz Ali , Naich Saleem  Ahmed , Rind Nadir Ali , Laghari Asadullah , Rind Khalid Hussain , Meghwar Parkash , Otho Sohail Ahmed
Published: June 2021

Drought is a disaster around the world accumulating salt and ero-sion in lands. Presently, a research was conducted to determine the morpho-physiological response in bread wheat under normal and stress irrigations. This experiment was conducted at the experimental field of Sindh Agriculture University, Tandojam, Hy-derabad, Pakistan, for two consecutive years during the Rabi season of the year 2011-12 and 2012-13. Stress was imposed by withhold-ing irrigations at three different growth stages of the plant, i.e. T1: normal irrigations applied, T2: stress at tillering stage, and T3: stress at the booting stage. The progenies Sarsabz x Khirman and Sarsabz x TD-1 contributed the highest heritability% (81.0% and 85.5%) for osmotic potential (-MPa) at stress at booting stage. For grain yield spike-1(g), the progeny Kiran-95 x Khirman showed maximum her-itability as 84.37 in T3. However, the progeny TD-1 x Imdad proved to be the best combiner progeny indicating highest heritability per-centage (91.0%) among the progenies for grain yield at booting stress.
Resilience of the Internal Mammary Artery to Atherogenesis: Shifting From Risk to Resistance to Address Unmet Needs
Authors: Kraler Simon , Libby Peter , Evans Paul C. , Akhmedov Alexander , Schmiady Martin O. , Reinehr Michael , Camici Giovanni G. , Lüscher Thomas F.
Published: June 2021

Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.
Leveraging Machine Learning and Artificial Intelligence to Improve Peripheral Artery Disease Detection, Treatment, and Outcomes
Authors: Flores Alyssa M. , Demsas Falen , Leeper Nicholas J. , Ross Elsie Gyang
Published: June 2021

Peripheral artery disease is an atherosclerotic disorder which, when present, portends poor patient outcomes. Low diagnosis rates perpetuate poor management, leading to limb loss and excess rates of cardiovascular morbidity and death. Machine learning algorithms and artificially intelligent systems have shown great promise in application to many areas in health care, such as accurately detecting disease, predicting patient outcomes, and automating image interpretation. Although the application of these technologies to peripheral artery disease are in their infancy, their promises are tremendous. In this review, we provide an introduction to important concepts in the fields of machine learning and artificial intelligence, detail the current state of how these technologies have been applied to peripheral artery disease, and discuss potential areas for future care enhancement with advanced analytics.
Genetic Determinants of Peripheral Artery Disease
Authors: Klarin Derek , Tsao Philip S. , Damrauer Scott M.
Published: June 2021

Peripheral artery disease—atherosclerosis of the abdominal aorta and lower extremity vascular bed—is a complex disease with both environmental and genetic determinants. Unmitigated disease is associated with major functional decline and can lead to chronic limb-threatening ischemia, amputation, and increased mortality. Over the last 10 years, major advances have been made in identifying the genetic basis of this common, complex disease. In this review, we provide an overview of the primary types of genetic analyses performed for peripheral artery disease, including heritability and linkage studies, and more recently biobank-based genome-wide association studies. Looking forward, we highlight areas of future study including efforts to identify causal peripheral artery disease genes, rare variant and structural variant analyses using whole-exome and whole-genome sequencing data, and the need to include individuals of diverse genetic ancestries.