bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical classification systems and long-term outcome in mid- and late-stage Parkinson’s disease
Authors: Ygland Rödström Emil , Puschmann Andreas
Published: August 2021

Parkinson’s disease shows a heterogeneous course and different clinical subtyping systems have been described. To compare the capabilities of two clinical classification systems, motor-phenotypes, and a simplified clinical motor-nonmotor subtyping system, a cohort was included at mean 7.9 ± 5.3 years of disease duration, classified using both clinical systems, and reexamined and reclassified at the end of an observation period. Time-points were retrospectively extracted for five major disease milestones: death, dementia, Hoehn and Yahr stage 5, nursing home living, and walking aid use. Eighty-nine patients were observed for 8.1 ± 2.7 years after inclusion. Dementia developed in 32.9% of the patients and 36.0–67.4% reached the other milestones. Motor-phenotypes were unable to stratify risks during this period, but the worst compared with the more favorable groups in the motor-nonmotor system conveyed hazard ratios between 2.6 and 63.6 for all milestones. A clear separation of risks for dying, living at the nursing home, and reaching motor end-stage was also shown when using only postural instability and gait disorder symptoms, without weighing them against the severity of the tremor. At reexamination, 29.4% and 64.7% of patients had changed classification groups in the motor-phenotype and motor-nonmotor systems, respectively. The motor-nonmotor system thus stratified risks of reaching crucial outcomes in mid–late Parkinson’s disease far better than the well-studied motor-phenotypes. Removing the tremor aspect of motor-phenotypes clearly improved this system, however. Classifications in both systems became unstable over time. The simplification of the motor-nonmotor system was easily applicable and showed potential as a prognostic marker during a large part of Parkinson’s disease.
The coordination of major events in C4 photosynthesis evolution in the genus Flaveria
Authors: Lyu Ming-Ju Amy , Gowik Udo , Kelly Steve , Covshoff Sarah , Hibberd Julian M. , Sage Rowan F. , Ludwig Martha , Wong Gane Ka-Shu , Westhoff Peter , Zhu Xin-Guang
Published: August 2021

C4 photosynthesis is a remarkable complex trait, elucidations of the evolutionary trajectory of C4 photosynthesis from its ancestral C3 pathway can help us better understand the generic principles of the evolution of complex traits and guide the engineering of C3 crops for higher yields. Here, we used the genus Flaveria that contains C3, C3–C4, C4-like and C4 species as a system to study the evolution of C4 photosynthesis. We first mapped transcript abundance, protein sequence and morphological features onto the phylogenetic tree of the genus Flaveria, and calculated the evolutionary correlation of different features; we then predicted the relative changes of ancestral nodes of those features to illustrate the major events during the evolution of C4 photosynthesis. We found that gene expression and protein sequence showed consistent modification patterns in the phylogenetic tree. High correlation coefficients ranging from 0.46 to 0.9 among gene expression, protein sequence and morphology were observed. The greatest modification of those different features consistently occurred at the transition between C3-C4 species and C4-like species. Our results show highly coordinated changes in gene expression, protein sequence and morphological features, which support evolutionary major events during the evolution of C4 metabolism.
An integrative analysis uncovers a new, pseudo-cryptic species of Amazonian marmoset (Primates: Callitrichidae: Mico) from the arc of deforestation
Authors: Costa-Araújo Rodrigo , Silva- José S. , Boubli Jean P. , Rossi Rogério V. , Canale Gustavo R. , Melo Fabiano R. , Bertuol Fabrício , Silva Felipe E. , Silva Diego A. , Nash Stephen D. , Sampaio Iracilda , Farias Izeni P. , Hrbek Tomas
Published: August 2021

Amazonia has the richest primate fauna in the world. Nonetheless, the diversity and distribution of Amazonian primates remain little known and the scarcity of baseline data challenges their conservation. These challenges are especially acute in the Amazonian arc of deforestation, the 2500 km long southern edge of the Amazonian biome that is rapidly being deforested and converted to agricultural and pastoral landscapes. Amazonian marmosets of the genusMicoare little known endemics of this region and therefore a priority for research and conservation efforts. However, even nascent conservation efforts are hampered by taxonomic uncertainties in this group, such as the existence of a potentially new species from the Juruena–Teles Pires interfluve hidden within theM. emiliaeepithet. Here we test if these marmosets belong to a distinct species using new morphological, phylogenomic, and geographic distribution data analysed within an integrative taxonomic framework. We discovered a new, pseudo-crypticMicospecies hidden within the epithetM. emiliae, here described and named after Horacio Schneider, the pioneer of molecular phylogenetics of Neotropical primates. We also clarify the distribution, evolutionary and morphological relationships of four otherMicospecies, bridging Linnean, Wallacean, and Darwinian shortfalls in the conservation of primates in the Amazonian arc of deforestation.
Identification of lncRNA NR_028138.1 as a biomarker and construction of a ceRNA network for bipolar disorder
Authors: He Ling , Zou Pengtao , Sun Wanlei , Fu Yonghui , He Wenfeng , Li Juxiang
Published: August 2021

The pathogenesis of bipolar disorder (BD), a chronic mood disorder, is largely unknown. Noncoding RNAs play important roles in the pathogenesis of BD. However, little is known about the correlations of long noncoding RNAs (lncRNAs) with BD. Illumina high-throughput sequencing in BD patients and normal controls was used to identify differentially expressed (DE) genes. Two-step real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate DE-RNAs in the first cohort (50 BD and 50 control subjects). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and lncRNA-mRNA coexpression and lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network analyses were used to predict the functions of DE-RNAs. Receiver operating characteristic (ROC) curve analysis and logistic regression were applied to evaluate diagnostic performance in an additional testing group (80 BD and 66 control subjects). A total of 576 significantly DE-lncRNAs and 262 DE-mRNAs were identified in BD patients, and 95 lncRNA-miRNA-mRNA interactions were used to construct a ceRNA regulatory network. Analysis of the first cohort showed that six RNAs (NR_028138.1, TCONS_00018621, TCONS_00002186, TNF, PID1, and SDK1) were differentially expressed in the BD group (P < 0.01). NR_028138.1 was used to establish a BD diagnostic model (area under the ROC curve 0.923, P < 0.004, 95% CI: 0.830–0.999). Verification in the second cohort revealed uniformly significant differences in NR_028138.1 (P < 0.0001). This study constructed a ceRNA regulatory network and provided a hypothesis for the pathogenesis of BD. NR_028138.1 was identified as a central element involved in the transcriptional regulation in BD and a potential biomarker.
Catestatin in innate immunity and Cateslytin-derived peptides against superbugs
Authors: Scavello Francesco , Mutschler Angela , Hellé Sophie , Schneider Francis , Chasserot-Golaz Sylvette , Strub Jean-Marc , Cianferani Sarah , Haikel Youssef , Metz-Boutigue Marie-Hélène
Published: August 2021

Chromogranin A (CgA) is the precursor of several antimicrobial peptides, such as Catestatin (Cts, bovine CgA344-364), initially described as a potent inhibitor of catecholamines. This peptide displays direct antimicrobial activities and contributes to immune system regulation. The aim of the present study is to investigate a designed peptide based on Cts to fight infections against superbugs and more particularlyStaphylococcus aureus. In addition to Cateslytin (Ctl, bovine CgA344-358), the active domain of Catestatin, several peptides including dimers, D-isomer and the new designed peptide DOPA-K-DOPA-K-DOPA-TLRGGE-RSMRLSFRARGYGFR (Dopa5T-Ctl) were prepared and tested. Cateslytin is resistant to bacterial degradation and does not induce bacterial resistance. The interaction of Catestatin with immune dermal cells (dendritic cells DC1a, dermal macrophages CD14 and macrophages) was analyzed by using confocal microscopy and cytokine release assay. The dimers and D-isomer of Ctl were tested against a large variety of bacteria showing the potent antibacterial activity of the D-isomer. The peptide Dopa5T-Ctl is able to induce the self-killing ofS. aureusafter release of Ctl by the endoprotease Glu-C produced by this pathogen. It permits localized on-demand delivery of the antimicrobial drug directly at the infectious site.
Serum miR371 in testicular germ cell cancer before and after orchiectomy, assessed by digital-droplet PCR in a prospective study
Authors: Myklebust Mette Pernille , Thor Anna , Rosenlund Benedikte , Gjengstø Peder , Karlsdottir Ása , Brydøy Marianne , Bercea Bogdan S. , Olsen Christian , Johnson Ida , Berg Mathilde I. , Langberg Carl W. , Andreassen Kristine E. , Kjellman Anders , Haugnes Hege S. , Dahl Olav
Published: August 2021

MicroRNA-371a-3p (miR371) has been suggested as a sensitive biomarker in testicular germ cell cancer (TGCC). We aimed to compare miR371 with the classical biomarkers α-fetoprotein (AFP) and β-human chorionic gonadotropin (hCGβ). Overall, 180 patients were prospectively enrolled in the study, with serum samples collected before and after orchiectomy. We compared the use of digital droplet PCR (RT-ddPCR) with the quantitative PCR used by others for detection of miR371. The novel RT-ddPCR protocol showed high performance in detection of miR371 in serum samples. In the study cohort, miR371 was measured using RT-ddPCR. MiR371 detected CS1 of the seminoma and the non-seminoma sub-types with a sensitivity of 87% and 89%, respectively. The total sensitivity was 89%. After orchiectomy, miR371 levels declined in 154 of 159 TGCC cases. The ratio of miR371 pre- and post-orchiectomy was 20.5 in CS1 compared to 6.5 in systemic disease. AFP and hCGβ had sensitivities of 52% and 51% in the non-seminomas. MiR371 is a sensitive marker that performs better than the classical markers in all sub-types and clinical stages. Especially for the seminomas CS1, the high sensitivity of miR371 in detecting TGCC cells may have clinical implications.
A new silver coordination polymer based on 4,6-diamino-2-pyrimidinethiol: synthesis, characterization and catalytic application in asymmetric Hantzsch synthesis of polyhydroquinolines
Authors: Hussain-Khil Noorullah , Ghorbani-Choghamarani Arash , Mohammadi Masoud
Published: August 2021

A highly efficient and stable heterogeneous coordination polymer (CP) was successfully prepared by hydrothermal combination of silver and 4,6-diamino-2-pyrimidinethiol. The prepared coordination polymer was characterized by FT-IR, XRD, TGA, SEM, EDX, X-ray mapping and Nitrogen adsorption–desorption analysis. The prepared Ag–CP exhibit excellent catalytic activity in multicomponent Hantzsch synthesis of polyhydroquinolines under mild reaction conditions in relatively short reaction times. The heterogeneity of the catalyst was confirmed by the hot filtration test; also, the catalyst was reused for at least four times under the optimized reaction conditions without any significant loss of its catalytic activity.
Computational design of SARS-CoV-2 peptide binders with better predicted binding affinities than human ACE2 receptor
Authors: Sitthiyotha Thassanai , Chunsrivirot Surasak
Published: August 2021

SARS-CoV-2 is coronavirus causing COVID-19 pandemic. To enter human cells, receptor binding domain of S1 subunit of SARS-CoV-2 (SARS-CoV-2-RBD) binds to peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptor. Employing peptides to inhibit binding between SARS-CoV-2-RBD and ACE2-PD is a therapeutic solution for COVID-19. Previous experimental study found that 23-mer peptide (SBP1) bound to SARS-CoV-2-RBD with lower affinity than ACE2. To increase SBP1 affinity, our previous study used residues 21–45 of α1 helix of ACE2-PD (SPB25) to design peptides with predicted affinity better than SBP1 and SPB25 by increasing interactions of residues that do not form favorable interactions with SARS-CoV-2-RBD. To design SPB25 with better affinity than ACE2, we employed computational protein design to increase interactions of residues reported to form favorable interactions with SARS-CoV-2-RBD and combine newly designed mutations with the best single mutations from our previous study. Molecular dynamics show that predicted binding affinities of three peptides (SPB25Q22R, SPB25F8R/K11W/L25R and SPB25F8R/K11F/Q22R/L25R) are better than ACE2. Moreover, their predicted stabilities may be slightly higher than SBP1 as suggested by their helicities. This study developed an approach to design SARS-CoV-2 peptide binders with predicted binding affinities better than ACE2. These designed peptides are promising candidates as SARS-CoV-2 inhibitors.
Bone morphological feature extraction for customized bone plate design
Authors: Wang Lin , Guo Kaijin , He Kunjin , Zhu Hong
Published: August 2021

Fractures are difficult to treat because of individual differences in bone morphology and fracture types. Compared to serialized bone plates, the use of customized plates significantly improves the fracture healing process. However, designing custom plates often requires the extraction of skeletal morphology, which is a complex and time-consuming procedure. This study proposes a method for extracting bone morphological features to facilitate customized plate designs. The customized plate design involves three major steps: extracting the morphological features of the bone, representing the undersurface features of the plate, and constructing the customized plate. Among these steps, constructing the undersurface feature involves integrating a group of bone features with different anatomical morphologies into a semantic feature parameter set of the plate feature. The undersurface feature encapsulates the plate and bone features into a highly cohesive generic feature and then establishes an internal correlation between the plate and bone features. Using the femoral plate as an example, we further examined the validity and feasibility of the proposed method. The experimental results demonstrate that the proposed method improves the convenience of redesign through the intuitive editing of semantic parameters. In addition, the proposed method significantly improves the design efficiency and reduces the required design time.
Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on post-contrast acute kidney injury
Authors: Oh Hyewon , Choi Arom , Seo Nieun , Lim Joon Seok , You Je Sung , Chung Yong Eun
Published: August 2021

Post contrast-acute kidney injury (PC-AKI) is defined as the deterioration of renal function after administration of iodinated contrast media. HMGB1 is known to play an important role in the development of acute kidney injury. The purpose of this study was to investigate the association between HMGB1 and PC-AKI and the protective effect of glycyrrhizin, a direct inhibitor of HMGB1, in rats. Rats were divided into three groups: control, PC-AKI and PC-AKI with glycyrrhizin. Oxidative stress was measured with MDA levels and H2DCFDA fluorescence intensity. The mRNA expressions of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) and kidney injury markers (KIM-1, NGAL and IL-18) were assessed using RT-PCR and ELISA in kidney tissue. In addition, the serum and intracellular protein levels of HMGB1were analyzed with the enzyme-linked immunosorbent assay (ELISA) and western blotting. Histologic changes were assessed with H&E staining using the transmission electron microscope (TEM). Moreover, serum creatinine (SCr), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) levels were assessed. Oxidative stress, pro-inflammatory cytokines, kidney injury markers and LDH were significantly higher in PC-AKI compared to the controls, but were lower in PC-AKI with glycyrrhizin. Intracellular and serum HMGB1 levels significantly increased after contrast media exposure, whereas they markedly decreased after glycyrrhizin pretreatment. SCr and BUN also decreased in PC-AKI with glycyrrhizin compared to PC-AKI. In PC-AKI, we could frequently observe tubular dilatation with H&E staining and cytoplasmic vacuoles on TEM, whereas these findings were attenuated in PC-AKI with glycyrrhizin. Our findings indicate that HMGB1 plays an important role in the development of PC-AKI and that glycyrrhizin has a protective effect against renal injury and dysfunction by inhibiting HMGB1 and reducing oxidative stress.
Comparing COVID-19 risk factors in Brazil using machine learning: the importance of socioeconomic, demographic and structural factors
Authors: Baqui Pedro , Marra Valerio , Alaa Ahmed M. , Bica Ioana , Ercole Ari , van der Schaar Mihaela
Published: August 2021

The COVID-19 pandemic continues to have a devastating impact on Brazil. Brazil’s social, health and economic crises are aggravated by strong societal inequities and persisting political disarray. This complex scenario motivates careful study of the clinical, socioeconomic, demographic and structural factors contributing to increased risk of mortality from SARS-CoV-2 in Brazil specifically. We consider the Brazilian SIVEP-Gripe catalog, a very rich respiratory infection dataset which allows us to estimate the importance of several non-laboratorial and socio-geographic factors on COVID-19 mortality. We analyze the catalog using machine learning algorithms to account for likely complex interdependence between metrics. The XGBoost algorithm achieved excellent performance, producing an AUC-ROC of 0.813 (95% CI 0.810–0.817), and outperforming logistic regression. Using our model we found that, in Brazil, socioeconomic, geographical and structural factors are more important than individual comorbidities. Particularly important factors were: The state of residence and its development index; the distance to the hospital (especially for rural and less developed areas); the level of education; hospital funding model and strain. Ethnicity is also confirmed to be more important than comorbidities but less than the aforementioned factors. In conclusion, socioeconomic and structural factors are as important as biological factors in determining the outcome of COVID-19. This has important consequences for policy making, especially on vaccination/non-pharmacological preventative measures, hospital management and healthcare network organization.
Simultaneous estimation of multiple phases in generalised Mach–Zehnder interferometer
Authors: Markiewicz Marcin , Pandit Mahasweta , Laskowski Wiesław
Published: August 2021

In this work we investigate the problem of simultaneous estimation of phases using generalised three- and four-mode Mach–Zehnder interferometer. In our setup, we assume that the phases are placed in each of the modes in the interferometer, which introduces correlations between estimators of the phases. These correlations prevent simultaneous estimation of all these phases, however we show that we can still obtain the Heisenberg-like scaling of precision of joint estimation of any subset of $$d-1$$

d
-
1

phases, d being the number of modes, within completely fixed experimental setup, namely with the same initial state and set of measurements. Our estimation scheme can be applied to the task of quantum-enhanced sensing in three-dimensional interferometric configurations.
CENPL, ISG20L2, LSM4, MRPL3 are four novel hub genes and may serve as diagnostic and prognostic markers in breast cancer
Authors: Yin Jinbao , Lin Chen , Jiang Meng , Tang Xinbin , Xie Danlin , Chen Jingwen , Ke Rongqin
Published: August 2021

As a highly prevalent disease among women worldwide, breast cancer remains in urgent need of further elucidation its molecular mechanisms to improve the patient outcomes. Identifying hub genes involved in the pathogenesis and progression of breast cancer can potentially help to unveil mechanism and also provide novel diagnostic and prognostic markers. In this study, we integrated multiple bioinformatic methods and RNA in situ detection technology to identify and validate hub genes. EZH2 was recognized as a key gene by PPI network analysis. CENPL, ISG20L2, LSM4, MRPL3 were identified as four novel hub genes through the WGCNA analysis and literate search. Among these, many studies on EZH2 in breast cancer have been reported, but no studies are related to the roles of CENPL, ISG20L2, MRPL3 and LSM4 in breast cancer. These four novel hub genes were up-regulated in tumor tissues and associated with cancer progression. The receiver operating characteristic analysis and Kaplan–Meier survival analysis indicated that these four hub genes are promising candidate genes that can serve as diagnostic and prognostic biomarkers for breast cancer. Moreover, these four newly identified hub genes as aberrant molecules in the maintenance of breast cancer development, their exact functional mechanisms deserve further in-depth study.
Exploring the genes involved in biosynthesis of dihydroquercetin and dihydromyricetin in Ampelopsis grossedentata
Authors: Yu Zheng-Wen , Zhang Ni , Jiang Chun-Yan , Wu Shao-Xiong , Feng Xia-Yu , Feng Xiao-Ying
Published: August 2021

Dihydroquercetin (DHQ), an extremely low content compound (less than 3%) in plants, is an important component of dietary supplements and used as functional food for its antioxidant activity. Moreover, as downstream metabolites of DHQ, an extremely high content of dihydromyricetin (DHM) is up to 38.5% in Ampelopsis grossedentata. However, the mechanisms involved in the biosynthesis and regulation from DHQ to DHM in A. grossedentata remain unclear. In this study, a comparative transcriptome analysis of A. grossedentata containing extreme amounts of DHM was performed on the Illumina HiSeq 2000 sequencing platform. A total of 167,415,597 high-quality clean reads were obtained and assembled into 100,584 unigenes having an N50 value of 1489. Among these contigs, 57,016 (56.68%) were successfully annotated in seven public protein databases. From the differentially expressed gene (DEG) analysis, 926 DEGs were identified between the B group (low DHM: 210.31 mg/g) and D group (high DHM: 359.12 mg/g) libraries, including 446 up-regulated genes and 480 down-regulated genes (B vs. D). Flavonoids (DHQ, DHM)-related DEGs of ten structural enzyme genes, three myeloblastosis transcription factors (MYB TFs), one basic helix–loop–helix (bHLH) TF, and one WD40 domain-containing protein were obtained. The enzyme genes comprised three PALs, two CLs, two CHSs, one F3’H, one F3’5’H (directly converts DHQ to DHM), and one ANS. The expression profiles of randomly selected genes were consistent with the RNA-seq results. Our findings thus provide comprehensive gene expression resources for revealing the molecular mechanism from DHQ to DHM in A. grossedentata. Importantly, this work will spur further genetic studies about A. grossedentata and may eventually lead to genetic improvements of the DHQ content in this plant.
Introducing intrauterine antibiotic infusion as a novel approach in effectively treating chronic endometritis and restoring reproductive dynamics: a randomized pilot study
Authors: Pantos Konstantinos , Simopoulou Mara , Maziotis Evangelos , Rapani Anna , Grigoriadis Sokratis , Tsioulou Petroula , Giannelou Polina , Nitsos Nikolaos , Tzonis Panagiotis , Koutsilieris Michael , Sfakianoudis Konstantinos
Published: August 2021

The chronic nature of Chronic Endometritis (CE) along with the challenging management and infertility entailed, call for cutting-edge therapeutic approaches. This study introduces the novel treatment of intrauterine antibiotic infusion (IAI) combined with oral antibiotic administration (OAA), and it assesses respective performance against the gold standard treatment of OAA. Data sourced herein reports on treatment efficiency and fertility restoration for both patients aiming to conceive naturally or via In Vitro fertilization. Eighty CE patients, 40 presenting with recurrent implantation failure, and 40 with recurrent pregnancy loss, were enrolled in the IVF and the natural conception arm respectively. Treatment was subjected to randomization. Effectively treated patients proceeded with either a single IVF cycle or were invited to conceive naturally over a 6-month period. Combination of IAI and OAA provided a statistically significant enhanced effectiveness treatment rate (RR 1.40; 95%CI 1.07–1.82; p = 0.01). No statistically significant difference was observed regarding the side-effects rate (RR 1.33; 95%CI 0.80–2.22; p = 0.52). No statistically significant difference was observed for either arm regarding live-birth rate. Following an intention-to-treat analysis, employment of IAI corresponds to improved clinical pregnancy rate-albeit not reaching statistical significance. In conclusion, complimentary implementation of IAI could provide a statistically significant enhanced clinical treatment outcome.
Sarcopenia modifies the associations of nonalcoholic fatty liver disease with all-cause and cardiovascular mortality among older adults
Authors: Sun Xingxing , Liu Zhelong , Chen Fuqiong , Du Tingting
Published: August 2021

The contribution of nonalcoholic fatty liver disease (NAFLD) to all-cause and cardiovascular mortality remains controversial. Sarcopenia, a measure of muscle mass, strength and function, may identify which persons are most at risk for adverse effects of NAFLD. We aimed to test the hypothesis that sarcopenia modifies the associations between NAFLD and all-cause and cardiovascular mortality. A total of 2446 older adults (≥ 60 years) from the third National Health and Nutrition Examination Survey were enrolled. Their mortality data were linked to death certificates in the National Death Index. Sarcopenia was defined as having low skeletal muscle mass together with slow gait speed, which captures both muscle mass and muscle function. Ultrasound tests were used for the assessment of hepatic steatosis. During follow-up (median 16.8 years), 1530 older subjects died from any cause, of which 379 were cardiovascular-related. All-cause and cardiovascular mortality rates were 4.31 and 1.07 per 100 person-years, respectively. In a multivariate model, using participants without NAFLD and sarcopenia as the reference group, individuals with both NAFLD and sarcopenia had 1.69 times [95% confidence interval (CI) 1.23–2.31] and 2.17 times (95% CI 1.33–3.54) higher risks of all-cause and cardiovascular mortality, respectively. However, NAFLD persons without sarcopenia had hazard ratios for all-cause and cardiovascular mortality similar to those of the reference group. Sarcopenia modified the associations of NAFLD with all-cause and cardiovascular mortality. Sarcopenia may identify older adults who are at the highest risk for adverse outcomes associated with NAFLD.
Influences of conservation measures on runoff and sediment yield in different intra-event-based flood regimes in the Chabagou watershed
Authors: Wang Shan-Shan , Li Zhan-Bin , Zhang Le-Tao , Ma Bo
Published: August 2021

The Loess Plateau in China has suffered severe soil erosion. To control soil erosion, extensive conservation measures aimed at redistributing rainfall, hindering flow velocity and intercepting sediment were implemented on the Loess Plateau. To accurately evaluate the combined effect of conservation measures in the Chabagou watershed, this study classified intra-event-based floods into four regimes via cluster and discriminant analyses. Regime A was characterized by short flood duration and low erosive energy, regime B was characterized by short flood duration and high erosive energy, regime C was characterized by long flood duration and low erosive energy, and regime D was characterized by long flood duration and high erosive energy. The results indicated that peak discharge (qp), runoff depth (H), mean discharge (qm), and runoff erosion power (E) decreased by 75.2%, 56.0%, 68.0% and 89.2%, respectively, in response to conservation measures. Moreover, area-specific sediment yield (SSY), average suspended sediment concentration (SCE), and maximum suspended sediment concentration (MSCE) decreased by 69.2%, 33.3% and 11.9%, respectively, due to conservation measures. The nonlinear regression analysis revealed a power function relationship between SSY and E in both the baseline (1961–1969) and measurement period (1971–1990) in all regimes. Conservation measures reduced sediment yield by not only reducing the runoff amount and soil erosion energy but also transforming the flood regime, for example, transforming a high-sediment-yield regime into a low-sediment-yield regime. Moreover, conservation measures altered the SSY-E relationship in regime A, whereas no obvious difference in regime B or C/D was observed between the measurement period and the baseline period. This study provides a better understanding of the mechanism of runoff regulation and the sediment yield reduction under comprehensive conservation measures in a small watershed on the Chinese Loess Plateau.
The incremental value of computed tomography of COVID-19 pneumonia in predicting ICU admission
Authors: Bartolucci Maurizio , Benelli Matteo , Betti Margherita , Bicchi Sara , Fedeli Luca , Giannelli Federico , Aquilini Donatella , Baldini Alessio , Consales Guglielmo , Di Natale Massimo Edoardo , Lotti Pamela , Vannucchi Letizia , Trezzi Michele , Mazzoni Lorenzo Nicola , Santini Sandro , Carpi Roberto , Matarrese Daniela , Bernardi Luca , Mascalchi Mario ,   the COVID Working Group, Cavigli Edoardo , Bindi Alessandra , Cozzi Diletta , Miele Vittorio , Busoni Simone , Taddeucci Adriana , Allescia Germana , Zini Chiara , Dedola Giovanni Luca , Mazzocchi Silvia , Pozzessere Chiara , Viviani Adriano
Published: August 2021

Triage is crucial for patient’s management and estimation of the required intensive care unit (ICU) beds is fundamental for health systems during the COVID-19 pandemic. We assessed whether chest computed tomography (CT) of COVID-19 pneumonia has an incremental role in predicting patient’s admission to ICU. We performed volumetric and texture analysis of the areas of the affected lung in CT of 115 outpatients with COVID-19 infection presenting to the emergency room with dyspnea and unresponsive hypoxyemia. Admission blood laboratory including lymphocyte count, serum lactate dehydrogenase, D-dimer and C-reactive protein and the ratio between the arterial partial pressure of oxygen and inspired oxygen were collected. By calculating the areas under the receiver-operating characteristic curves (AUC), we compared the performance of blood laboratory-arterial gas analyses features alone and combined with the CT features in two hybrid models (Hybrid radiological and Hybrid radiomics)for predicting ICU admission. Following a machine learning approach, 63 patients were allocated to the training and 52 to the validation set. Twenty-nine (25%) of patients were admitted to ICU. The Hybrid radiological model comprising the lung %consolidation performed significantly (p = 0.04) better in predicting ICU admission in the validation (AUC = 0.82; 95% confidence interval 0.73–0.97) set than the blood laboratory-arterial gas analyses features alone (AUC = 0.71; 95% confidence interval 0.56–0.86). A risk calculator for ICU admission was derived and is available at: https://github.com/cgplab/covidapp. The volume of the consolidated lung in CT of patients with COVID-19 pneumonia has a mild but significant incremental value in predicting ICU admission.
Lipoprotein (a) level as a risk factor for stroke and its subtype: A systematic review and meta-analysis
Authors: Kumar Pradeep , Swarnkar Priyanka , Misra Shubham , Nath Manabesh
Published: August 2021

The role of lipoprotein-A [Lp (a)] as a risk factor for stroke is less well documented than for coronary heart disease. Hence, we conducted a systematic review and meta-analysis for the published observational studies in order to investigate the association of Lp (a) levels with the risk of stroke and its subtypes. In our meta-analysis, 41 studies involving 7874 ischemic stroke (IS) patients and 32,138 controls; 13 studies for the IS subtypes based on TOAST classification and 7 studies with 871 Intracerebral hemorrhage (ICH) cases and 2865 control subjects were included. A significant association between increased levels of Lp (a) and risk of IS as compared to control subjects was observed (standardized mean difference (SMD) 0.76; 95% confidence interval (CIs) 0.53–0.99). Lp (a) levels were also found to be significantly associated with the risk of large artery atherosclerosis (LAA) subtype of IS (SMD 0.68; 95% CI 0.01–1.34) as well as significantly associated with the risk of ICH (SMD 0.65; 95% CI 0.13–1.17) as compared to controls. Increased Lp (a) levels could be considered as a predictive marker for identifying individuals who are at risk of developing IS, LAA and ICH.
Nutrient availability and pH level affect germination traits and seedling development of Conyza canadensis
Authors: Follmer Caroline Maldaner , Hummes Ana Paula , Lângaro Nadia Canali , Petry Claudia , Moterle Diovane Freire , Bortoluzzi Edson Campanhola
Published: August 2021

Reducing pesticide application in agricultural land is a major challenge for the twenty-first century. Responses of weed seed’s germination and seedling’s early development to chemical soil conditions around the seed may be a promising way to aid weed control in a no-till system. Thus, the objective of this work was to test, under controlled conditions, whether different chemical conditions affect the germination and development of horseweed [Conyza canadensis (L.) Cronquist]. We used, as treatment, solutions containing different nutrients (P, K, Ca, and Mg), separately and in combination, and at two pH levels (4.8 and 6.5). Phosphorus alone inhibited horseweed seed germination at ~ 7 times while had ~ 4 times reduction in final germination percentage and germination speed index for both pH tested. Other nutrients tested had a no-effect in germination speed index compared to the control treatment. Potassium alone or associated with other ions (P, Ca, and Mg) at pH 4.8 had a synergistic effect on seedling development (root and shoot length). In the same way, K associated with Mg was synergistic to the root length at pH 6.5. Seeds in the control treatment (distilled water) presented a high germination speed index at pH 6.5, while at low pH this parameter was higher when in association with KMg, PMg and Ca. The findings demonstrate that seed germination traits and seedling development of horseweed depend on nutrient kind exposure and pH conditions in the seed environment. This work suggests that adequate topsoil management (i.e., pH and nutrient availability) may aid to reduce weed germination, because, it consists of an important factor of weed occurrence in agricultural areas.
KUS121 attenuates the progression of monosodium iodoacetate-induced osteoarthritis in rats
Authors: Iwai Sachiko , Ikeda Hanako O. , Mera Hisashi , Nishitani Kohei , Saito Motoo , Tsujikawa Akitaka , Kakizuka Akira
Published: August 2021

Currently there is no effective treatment available for osteoarthritis (OA). We have recently developed Kyoto University Substances (KUSs), ATPase inhibitors specific for valosin-containing protein (VCP), as a novel class of medicine for cellular protection. KUSs suppressed intracellular ATP depletion, endoplasmic reticulum (ER) stress, and cell death. In this study, we investigated the effects of KUS121 on chondrocyte cell death. In cultured chondrocytes differentiated from ATDC5 cells, KUS121 suppressed the decline in ATP levels and apoptotic cell death under stress conditions induced by TNFα. KUS121 ameliorated TNFα-induced reduction of gene expression in chondrocytes, such as Sox9 and Col2α. KUS121 also suppressed ER stress and cell death in chondrocytes under tunicamycin load. Furthermore, intraperitoneal administration of KUS121 in vivo suppressed chondrocyte loss and proteoglycan reduction in knee joints of a monosodium iodoacetate-induced OA rat model. Moreover, intra-articular administration of KUS121 more prominently reduced the apoptosis of the affected chondrocytes. These results demonstrate that KUS121 protects chondrocytes from stress-induced cell death in vitro and in vivo, and indicate that KUS121 is a promising novel therapeutic agent to prevent the progression of OA.
Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes
Authors: Kavalakatt Sina , Khadir Abdelkrim , Madhu Dhanya , Koistinen Heikki A. , Al-Mulla Fahd , Tuomilehto Jaakko , Abubaker Jehad , Tiss Ali
Published: August 2021

The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.
Metabolomics-based discrimination of patients with remitted depression from healthy controls using 1H-NMR spectroscopy
Authors: Hung Ching-I. , Lin Gigin , Chiang Meng-Han , Chiu Chih-Yung
Published: August 2021

The aim of the study was to investigate differences in metabolic profiles between patients with major depressive disorder (MDD) with full remission (FR) and healthy controls (HCs). A total of 119 age-matched MDD patients with FR (n = 47) and HCs (n = 72) were enrolled and randomly split into training and testing sets. A 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomics approach was used to identify differences in expressions of plasma metabolite biomarkers. Eight metabolites, including histidine, succinic acid, proline, acetic acid, creatine, glutamine, glycine, and pyruvic acid, were significantly differentially-expressed in the MDD patients with FR in comparison with the HCs. Metabolic pathway analysis revealed that pyruvate metabolism via the tricarboxylic acid cycle linked to amino acid metabolism was significantly associated with the MDD patients with FR. An algorithm based on these metabolites employing a linear support vector machine differentiated the MDD patients with FR from the HCs with a predictive accuracy, sensitivity, and specificity of nearly 0.85. A metabolomics-based approach could effectively differentiate MDD patients with FR from HCs. Metabolomic signatures might exist long-term in MDD patients, with metabolic impacts on physical health even in patients with FR.
Nerve growth factor and glutamate increase the density and expression of substance P-containing nerve fibers in healthy human masseter muscles
Authors: Alhilou Abdelrahman M. , Shimada Akiko , Svensson Camilla I. , Svensson Peter , Ernberg Malin , Cairns Brian E. , Christidis Nikolaos
Published: August 2021

Nocifensive behavior induced by injection of glutamate or nerve growth factor (NGF) into rats masseter muscle is mediated, in part, through the activation of peripheral NMDA receptors. However, information is lacking about the mechanism that contributes to pain and sensitization induced by these substances in humans. Immunohistochemical analysis of microbiopsies obtained from human masseter muscle was used to investigate if injection of glutamate into the NGF-sensitized masseter muscle alters the density or expression of the NMDA receptor subtype 2B (NR2B) or NGF by putative sensory afferent (that express SP) fibers. The relationship between expression and pain characteristics was also examined. NGF and glutamate administration increased the density and expression of NR2B and NGF by muscle putative sensory afferent fibers (P < 0.050). This increase in expression was greater in women than in men (P < 0.050). Expression of NR2B receptors by putative sensory afferent fibers was positively correlated with pain characteristics. Results suggest that increased expression of peripheral NMDA receptors partly contributes to the increased pain and sensitivity induced by intramuscular injection of NGF and glutamate in healthy humans; a model of myofascial temporomandibular disorder (TMD) pain. Whether a similar increase in peripheral NMDA expression occurs in patients with painful TMDs warrants further investigation.
Plasma expression of microRNA-425-5p and microRNA-451a as biomarkers of cardiovascular disease in rheumatoid arthritis patients
Authors: Taverner Delia , Llop Dídac , Rosales Roser , Ferré Raimon , Masana Luis , Vallvé Joan-Carles , Paredes Silvia
Published: August 2021

To validate in a cohort of 214 rheumatoid arthritis patients a panel of 10 plasmatic microRNAs, which we previously identified and that can facilitate earlier diagnosis of cardiovascular disease in rheumatoid arthritis patients. We identified 10 plasma miRs that were downregulated in male rheumatoid arthritis patients and in patients with acute myocardial infarction compared to controls suggesting that these microRNAs could be epigenetic biomarkers for cardiovascular disease in rheumatoid arthritis patients. Six of those microRNAs were validated in independent plasma samples from 214 rheumatoid arthritis patients and levels of expression were associated with surrogate markers of cardiovascular disease (carotid intima-media thickness, plaque formation, pulse wave velocity and distensibility) and with prior cardiovascular disease. Multivariate analyses adjusted for traditional confounders and treatments showed that decreased expression of microRNA-425-5p in men and decreased expression of microRNA-451 in women were significantly associated with increased (β = 0.072; p = 0.017) and decreased carotid intima-media thickness (β = −0.05; p = 0.013), respectively. MicroRNA-425-5p and microRNA-451 also increased the accuracy to discriminate patients with pathological carotid intima-media thickness by 1.8% (p = 0.036) in men and 3.5% (p = 0.027) in women, respectively. In addition, microRNA-425-5p increased the accuracy to discriminate male patients with prior cardiovascular disease by 3% (p = 0.008). Additionally, decreased expression of microRNA-451 was significantly associated with decreased pulse wave velocity (β = −0.72; p = 0.035) in overall rheumatoid arthritis population. Distensibility showed no significant association with expression levels of the microRNAs studied. We provide evidence of a possible role of microRNA-425-5p and microRNA-451 as useful epigenetic biomarkers to assess cardiovascular disease risk in patients with rheumatoid arthritis.
The possible association of clusterin fucosylation changes with male fertility disorders
Authors: Janiszewska Ewa , Kokot Izabela , Gilowska Iwona , Faundez Ricardo , Kratz Ewa Maria
Published: August 2021

In the seminal plasma (n = 118) and serum (n = 90) clusterin (CLU) the fucosylation and the expression of selected fucosyltransferases (FUTs) were analyzed. Samples from infertile men were divided into groups based on the results of the standard semen analysis: normozoospermic (N), teratozoospermic (T), asthenoteratozoospermic (AT) and oligoasthenoteratozoospermic (OAT). The CLU fucosylation was analyzed using lectin-ELISAs with biotinylated lectins specific to α1,3-, α1,2-linked antennary fucose, and α1,6-linked core fucose (LTA, UEA, and LCA, respectively). The concentrations of FUT3 and FUT4, reflecting the expression of Le oligosaccharide structures, were measured using ELISA tests. The differences in serum CLU and FUT4 concentrations, and in the expression of core fucose and antennary fucose α1,2-linked in CLU glycans between the N group and other groups examined suggest that the disturbances in sperm count, motility, and morphology are not the only cause of male infertility. Lack of similarities between levels of examined parameters in blood serum and seminal plasma may suggest the differences in mechanisms leading to glycoproteins glycosylation. It confirmed the observed differences in concentrations of seminal plasma CLU, FUT3, and FUT4 between the OAT group and N, T, AT groups, indicating that decreased sperm count may be related to these parameters expression. The serum CLU concentrations and expression of core fucose and fucose α1,2-linked in CLU, seem to be good markers differentiating normozoospermic men from those with abnormal sperm parameters, which was not observed for seminal plasma.
X-ray crystallography reveals molecular recognition mechanism for sugar binding in a melibiose transporter MelB
Authors: Guan Lan , Hariharan Parameswaran
Published: August 2021

Major facilitator superfamily_2 transporters are widely found from bacteria to mammals. The melibiose transporter MelB, which catalyzes melibiose symport with either Na+, Li+, or H+, is a prototype of the Na+-coupled MFS transporters, but its sugar recognition mechanism has been a long-unsolved puzzle. Two high-resolution X-ray crystal structures of a Salmonella typhimurium MelB mutant with a bound ligand, either nitrophenyl-α-d-galactoside or dodecyl-β-d-melibioside, were refined to a resolution of 3.05 or 3.15 Å, respectively. In the substrate-binding site, the interaction of both galactosyl moieties on the two ligands with MelBSt are virturally same, so the sugar specificity determinant pocket can be recognized, and hence the molecular recognition mechanism for sugar binding in MelB has been deciphered. The conserved cation-binding pocket is also proposed, which directly connects to the sugar specificity pocket. These key structural findings have laid a solid foundation for our understanding of the cooperative binding and symport mechanisms in Na+-coupled MFS transporters, including eukaryotic transporters such as MFSD2A.
Data-science driven autonomous process optimization
Authors: Christensen Melodie , Yunker Lars P. E. , Adedeji Folarin , Häse Florian , Roch Loïc M. , Gensch Tobias , dos Passos Gomes Gabriel , Zepel Tara , Sigman Matthew S. , Aspuru-Guzik Alán , Hein Jason E.
Published: August 2021

Autonomous process optimization involves the human intervention-free exploration of a range process parameters to improve responses such as product yield and selectivity. Utilizing off-the-shelf components, we develop a closed-loop system for carrying out parallel autonomous process optimization experiments in batch. Upon implementation of our system in the optimization of a stereoselective Suzuki-Miyaura coupling, we find that the definition of a set of meaningful, broad, and unbiased process parameters is the most critical aspect of successful optimization. Importantly, we discern that phosphine ligand, a categorical parameter, is vital to determination of the reaction outcome. To date, categorical parameter selection has relied on chemical intuition, potentially introducing bias into the experimental design. In seeking a systematic method for selecting a diverse set of phosphine ligands, we develop a strategy that leverages computed molecular feature clustering. The resulting optimization uncovers conditions to selectively access the desired product isomer in high yield.