bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Vegetation Patch Patterns on Channel Morphology: A Numerical Study
Authors: Li Jiaze , Claude Nicolas , Tassi Pablo , Cordier Florian , Vargas‐Luna Andrés , Crosato Alessandra , Rodrigues Stéphane
Published: May 2022

This study investigates the effects of vegetation patch patterns on the morphological evolution of alluvial river channels at the reach‐scale. For this, a new two‐dimensional numerical biomorphodynamic model has been developed using the Telemac‐Mascaret system. Considering the newest development in the topic, the effects of vegetation on bedload transport are included by extending Einstein's parameters for the sediment transport formula. The model was subsequently validated by published laboratory experiments reproducing alternate bar dynamics with different vegetation establishment scenarios. The validated model was then used to study the influence of vegetation patch patterns on the channel morphological evolution considering the two most observed ones: (a) the filled pattern with plants well distributed within the patch, and (b) the stripe pattern with plants established only along the patch edges. 14 scenarios were simulated in total, including sensitivity analyses on the coefficients of vegetation characteristics. The results indicate that the morphological responses of an alternate bar system to the stripe pattern consist of channel widening, steeper slope and reduced water depth, with increased sediment transport rates. The effects of the filled pattern are similar but weaker. The results also show that with the stripe pattern, the alternate bars tend to migrate toward the centerline forming center bars. Besides, the scroll bars forming downstream are shorter, corresponding to less visible chute channels, compared to the filled pattern. Despite much less vegetation coverage, the stripe pattern decreases the bar elongation rates in a way similar to the filled pattern.
Kinematics of Cenozoic Shortening of the Hotan Anticline Along the Northwestern Margin of the Tibetan Plateau (Western Kunlun, China)
Authors: Baby Guillaume , Simoes Martine , Barrier Laurie , Guilbaud Christelle , Li Haibing , Van der Woerd Jérôme
Published: May 2022

Kinematic constraints on the Cenozoic deformation along the northwestern edge of the Tibetan Plateau remain limited. Combining surface geological data and seismic profiles, we document the structural geometry and kinematics of the large‐scale east‐west striking Hotan anticline, along the foothills of the Western Kunlun Range. Four new balanced cross sections are constructed, and the temporal evolution of deformation is deciphered from the exceptionally well‐imaged growth strata at the front of the fold. This anticline results from a broad fault‐bend fold, subsequently deformed by a footwall duplex. The total shortening across the whole structure is relatively constant along strike, from ∼40 to ∼35 km. However, the shortening accommodated by the duplex varies laterally from ∼50–40% to 0% of the total shortening. Two distinct successive patterns of growth strata are recognized and are interpreted to be representative of deformation on the ramp anticline, followed by deformation on the duplex. The onset of deformation initiated by ∼16 Ma. Deformation of the underlying duplex began at ∼12 Ma to the west and subsequently propagated eastward. From these results, we determine a shortening rate of ∼5 mm/yr from ∼16 to ∼8–9 Ma across the Hotan thrust system, followed by a significant decrease in shortening rate, possibly down to <0.5 mm/yr. We explore the significance of this deceleration of deformation at the scale of the Western Kunlun foothills and at a broader regional scale as it may point to a regional kinematic reorganization by the late Miocene.
Cord blood metabolites and rapid postnatal growth as multiple mediators in the prenatal propensity to childhood overweight
Authors: Alfano Rossella , Plusquin Michelle , Robinson Oliver , Brescianini Sonia , Chatzi Lida , Keski-Rahkonen Pekka , Handakas Evangelos , Maitre Lea , Nawrot Tim , Robinot Nivonirina , Roumeliotaki Theano , Sassi Franco , Scalbert Augustin , Vrijheid Martine , Vineis Paolo , Richiardi Lorenzo , Zugna Daniela
Published: May 2022

Background

The mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite.

Methods

Within four European birth-cohorts (N = 375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach.

Results

Single mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal.

Conclusion

Our findings provide evidence of the involvement of in utero metabolism in the propensity to rapid postnatal growth and of rapid postnatal growth in the propensity to childhood overweight. We did not find evidence supporting a mediating role of the studied metabolites alone between the studied prenatal exposures and the propensity to childhood overweight.
A game changer for bipolar disorder diagnosis using RNA editing-based biomarkers
Authors: Salvetat Nicolas , Checa-Robles Francisco Jesus , Patel Vipul , Cayzac Christopher , Dubuc Benjamin , Chimienti Fabrice , Abraham Jean-Daniel , Dupré Pierrick , Vetter Diana , Méreuze Sandie , Lang Jean-Philippe , Kupfer David J. , Courtet Philippe , Weissmann Dinah
Published: May 2022

In clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is a challenge due to the depressive symptoms, which are the core presentations of both disorders. This misdiagnosis during depressive episodes results in a delay in proper treatment and a poor management of their condition. In a first step, using A-to-I RNA editome analysis, we discovered 646 variants (366 genes) differentially edited between depressed patients and healthy volunteers in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, candidate biomarkers from 8 genes were singled out and tested in a validation cohort of 410 participants. Combining the selected biomarkers with a machine learning approach achieved to discriminate depressed patients (n = 267) versus controls (n = 143) with an AUC of 0.930 (CI 95% [0.879–0.982]), a sensitivity of 84.0% and a specificity of 87.1%. In a second step by selecting among the depressed patients those with unipolar depression (n = 160) or BD (n = 95), we identified a combination of 6 biomarkers which allowed a differential diagnosis of bipolar disorder with an AUC of 0.935 and high specificity (Sp = 84.6%) and sensitivity (Se = 90.9%). The association of RNA editing variants modifications with depression subtypes and the use of artificial intelligence allowed developing a new tool to identify, among depressed patients, those suffering from BD. This test will help to reduce the misdiagnosis delay of bipolar patients, leading to an earlier implementation of a proper treatment.
SP1-mediated up-regulation of lncRNA TUG1 underlines an oncogenic property in colorectal cancer
Authors: Liu Wei , Meng Jin , Su Rongjun , Shen Changjun , Zhang Shuai , Zhao Yantao , Liu Wenqi , Du Jiang , Zhu Shuai , Li Pan , Wang Zhigang , Li Xiaoxia
Published: May 2022

The long non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) acts as tumor-promoting factor in colorectal cancer (CRC). We aimed to elucidate the mechanism by which the transcription factor specificity protein 1 (SP1) regulates TUG1 and microRNAs (miRs)/mRNAs in the context of CRC, which has not been fully studied before. Expression patterns of TUG1 and SP1 were determined in clinical CRC samples and cells, followed by identification of their interaction. Next, the functional significance of TUG1 in CRC was investigated. An in vivo CRC model was established to validate the effect of TUG1. The results demonstrated that TUG1 and SP1 were highly-expressed in CRC, wherein SP1 bound to the TUG1 promoter and consequently, positively regulated its expression. Silencing of TUG1 caused suppression of CRC cell growth and promotion of cell apoptosis. TUG1 could bind to miR-421 to increase KDM2A expression, a target gene of miR-421. TUG1 could activate the ERK pathway by impairing miR-421-targeted inhibition of KDM2A. Additionally, SP1 could facilitate the tumorigenesis of CRC cells in vivo by regulating the TUG1/miR-421/KDM2A/ERK axis. Altogether, the current study emphasizes the oncogenic role of TUG1 in CRC, and illustrates its interactions with the upstream transcription factor SP1 and the downstream modulatory axis miR-421/KDM2A/ERK, thus offering novel insights into the cancerogenic mechanism in CRC.
KLF4 regulates TERT expression in alveolar epithelial cells in pulmonary fibrosis
Authors: Wang Hui , Xu Hongyang , Lyu Wenting , Xu Qinghua , Fan Shiwen , Chen Haoran , Wang Dongjin , Chen Jingyu , Dai Jinghong
Published: May 2022

Idiopathic pulmonary fibrosis (IPF) was considered as a telomere-mediated disease. TERT and TERC correlated with telomere length. Although telomerase gene mutations were associated with IPF, majority patients did not carry mutations. The mechanism by which telomerase expression was regulated in IPF are still unclear. In this study, we aimed to delineate the mechanisms that how TERT protein expression were regulated in alveolar epithelial cells (AECs) in pulmonary fibrosis. Here, we found that P16, P21 and fibrosis markers (αSMA and Collagen-I) were prominently increased in lung tissues of IPF patients and bleomycin-induced mouse models, while the expression of KLF4 and TERT were decreased in AECs. In vivo experiments, AAV-6 vectors mediated KLF4 over-expression with specific SP-C promoter was constructed. Over-expression of KLF4 in AECs could protect TERT expression and suppress the development of pulmonary fibrosis in bleomycin-induced mouse models. In the mechanism exploration of TERT regulation, KLF4 and TERT were both down-regulated in bleomycin-induced senescent MLE-12 and BEAS-2B cells. Compared with control group, small-interfering RNA targeting KLF4 significantly reduced the TERT expression and telomerase activity, while overexpression of KLF4 can increased the expression of TERT and telomerase activity in senescent AECs. Furthermore, ChIP showed that KLF4 protein could bind to the TERT promoter region in MLE-12 cells, suggesting that KLF4 could implicate in pathogenesis of lung fibrosis through regulating TERT transcription in AECs. Taken together, this study identified that KLF4 might be a promising potential target for further understanding the mechanism and developing novel strategy for the treatment of lung fibrosis in IPF.
Changes in 12-month outcomes over time for age-related macular degeneration, diabetic macular oedema and retinal vein occlusion
Authors: Bhandari Sanjeeb , Nguyen Vuong , Hunt Adrian , Gabrielle Pierre-Henry , Viola Francesco , Mehta Hemal , Manning Les , Squirrell David , Arnold Jennifer , McAllister Ian L. , Barthelmes Daniel , Gillies Mark
Published: May 2022

Objectives

To identify whether the outcomes of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in routine clinical practice have changed over time.

Methods

We analysed 12-month outcomes in treatment-naïve eyes that started aflibercept or ranibizumab for nAMD (3802 eyes), DMO (975 eyes), Branch RVO (BRVO, 357 eyes), Central RVO (CRVO, 371 eyes) and Hemi-RVO (HRVO, 54 eyes) from 2015 and 2019 tracked in the prospectively designed observational Fight Retinal Blindness! Registry.

Results

The mean VA change at 12-month for each year between 2015 and 2019 remained stable or otherwise showed no discernible trends over time in eyes with nAMD (+3.3 to +6 letters), DMO (+3.6 to +6.7 letters) and RVO (+10.3 to +11.7 letters for BRVO, +5.9 to +17.7 letters for CRVO and 10.2 to 20.7 letters for HRVO). The median number of VEGF-inhibitor injections in eyes that completed 12-month follow-up also remained stable at 8–9 for nAMD, 6–7 for DMO, 7–9 for RVO. Fewer eyes (<one-fourth) that started treatment between 2015 and 2018 and more eyes starting in 2019 did not complete 12-month’s follow-up visit. The mean VA in non-completers at their last visit was higher than that of their baseline visit.

Conclusions

Treatment patterns and outcomes for nAMD, DMO and RVO in routine clinical practice have stabilised over the past 5 years at levels inferior to those reported by the pivotal phase 3 studies. A conscious effort to treat these conditions more intensively, or with longer lasting agents, would likely improve outcomes further in our patients.
Elucidating Human Milk Oligosaccharide biosynthetic genes through network-based multi-omics integration
Authors: Kellman Benjamin P. , Richelle Anne , Yang Jeong-Yeh , Chapla Digantkumar , Chiang Austin W. T. , Najera Julia A. , Liang Chenguang , Fürst Annalee , Bao Bokan , Koga Natalia , Mohammad Mahmoud A. , Bruntse Anders Bech , Haymond Morey W. , Moremen Kelley W. , Bode Lars , Lewis Nathan E.
Published: May 2022

Human Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we use a systems biology framework that integrates glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we construct models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. Our model aggregation approach recovers 2 of 2 previously known gene-enzyme relations and 2 of 3 empirically confirmed gene-enzyme relations. The top genes we propose for the remaining 5 linkage reactions are consistent with previously published literature. These results provide the molecular basis of HMO biosynthesis necessary to guide progress in HMO research and application with the goal of understanding and improving infant health and development.
Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF
Authors: Gorbovytska Vladyslava , Kim Seung-Kyoon , Kuybu Filiz , Götze Michael , Um Dahun , Kang Keunsoo , Pittroff Andreas , Brennecke Theresia , Schneider Lisa-Marie , Leitner Alexander , Kim Tae-Kyung , Kuhn Claus-D.
Published: May 2022

Enhancer RNAs (eRNAs) are long non-coding RNAs that originate from enhancers. Although eRNA transcription is a canonical feature of activated enhancers, the molecular features required for eRNA function and the mechanism of how eRNAs impinge on target gene transcription have not been established. Thus, using eRNA-dependent RNA polymerase II (Pol II) pause release as a model, we here investigate the requirement of sequence, structure and length of eRNAs for their ability to stimulate Pol II pause release by detaching NELF from paused Pol II. We find eRNAs not to exert their function through common structural or sequence motifs. Instead, eRNAs that exhibit a length >200 nucleotides and that contain unpaired guanosines make multiple, allosteric contacts with NELF subunits -A and -E to trigger efficient NELF release. By revealing the molecular determinants of eRNA function, our study establishes eRNAs as an important player in Pol II pause release, and it provides new insight into the regulation of metazoan transcription.
E(3)-equivariant graph neural networks for data-efficient and accurate interatomic potentials
Authors: Batzner Simon , Musaelian Albert , Sun Lixin , Geiger Mario , Mailoa Jonathan P. , Kornbluth Mordechai , Molinari Nicola , Smidt Tess E. , Kozinsky Boris
Published: May 2022

This work presents Neural Equivariant Interatomic Potentials (NequIP), an E(3)-equivariant neural network approach for learning interatomic potentials from ab-initio calculations for molecular dynamics simulations. While most contemporary symmetry-aware models use invariant convolutions and only act on scalars, NequIP employs E(3)-equivariant convolutions for interactions of geometric tensors, resulting in a more information-rich and faithful representation of atomic environments. The method achieves state-of-the-art accuracy on a challenging and diverse set of molecules and materials while exhibiting remarkable data efficiency. NequIP outperforms existing models with up to three orders of magnitude fewer training data, challenging the widely held belief that deep neural networks require massive training sets. The high data efficiency of the method allows for the construction of accurate potentials using high-order quantum chemical level of theory as reference and enables high-fidelity molecular dynamics simulations over long time scales.
Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination
Authors: Ghorbani Samira , Jelinek Emily , Jain Rajiv , Buehner Benjamin , Li Cenxiao , Lozinski Brian M. , Sarkar Susobhan , Kaushik Deepak K. , Dong Yifei , Wight Thomas N. , Karimi-Abdolrezaee Soheila , Schenk Geert J. , Strijbis Eva M. , Geurts Jeroen , Zhang Ping , Ling Chang-Chun , Yong V. Wee
Published: May 2022

Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP+ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.
Using sero-epidemiology to monitor disparities in vaccination and infection with SARS-CoV-2
Authors: Routledge Isobel , Takahashi Saki , Epstein Adrienne , Hakim Jill , Janson Owen , Turcios Keirstinne , Vinden Jo , Risos John Tomas , Baniqued Margaret Rose , Pham Lori , Di Germanio Clara , Busch Michael , Kushel Margot , Greenhouse Bryan , Rodríguez-Barraquer Isabel
Published: May 2022

As SARS-CoV-2 continues to spread and vaccines are rolled-out, the “double burden” of disparities in exposure and vaccination intersect to determine patterns of infection, immunity, and mortality. Serology provides a unique opportunity to measure prior infection and vaccination simultaneously. Leveraging algorithmically-selected residual sera from two hospital networks in the city of San Francisco, cross-sectional samples from 1,014 individuals from February 4–17, 2021 were each tested on two assays (Ortho Clinical Diagnostics VITROS Anti-SARS-CoV-2 and Roche Elecsys Anti-SARS-CoV-2), capturing the first year of the epidemic and early roll-out of vaccination. We estimated, using Bayesian estimation of infection and vaccination, that infection risk of Hispanic/Latinx residents was five times greater than of White residents aged 18–64 (95% Credible Interval (CrI): 3.2–10.3), and that White residents over 65 were twice as likely to be vaccinated as Black/African American residents (95% CrI: 1.1–4.6). We found that socioeconomically-deprived zipcodes had higher infection probabilities and lower vaccination coverage than wealthier zipcodes. While vaccination has created a ‘light at the end of the tunnel’ for this pandemic, ongoing challenges in achieving and maintaining equity must also be considered.
Understanding the rheology of nanocontacts
Authors: Khosravi Ali , Lainé Antoine , Vanossi Andrea , Wang Jin , Siria Alessandro , Tosatti Erio
Published: May 2022

Mechanical stiffness, as opposed to softness, is a fundamental property of solids. Its persistence or rheological evolution in vibrating solid-solid nanocontacts is important in physics, materials science and technology. A puzzling apparent liquefaction under oscillatory strain, totally unexpected at room temperature, was suggested by recent experiments on solid gold nano-junctions. Here we show theoretically that realistically simulated nanocontacts actually remain crystalline even under large oscillatory strains. Tensile and compressive slips, respectively of “necking” and “bellying” types, do take place, but recover reversibly even during fast oscillatory cycles. We also show that, counterintuitively, the residual stress remains tensile after both slips, driving the averaged stiffness from positive to negative, thus superficially mimicking a liquid’s. Unlike a liquid, however, rheological softening occurs by stick-slip, predicting largely frequency independent stiffness with violent noise in stress and conductance, properties compatible with experiments. The baffling large amplitude rheology of gold nanocontacts and its consequences should apply, with different parameters, to many other metals.
Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates
Authors: Milani Michela , Canepari Cesare , Liu Tongyao , Biffi Mauro , Russo Fabio , Plati Tiziana , Curto Rosalia , Patarroyo-White Susannah , Drager Douglas , Visigalli Ilaria , Brombin Chiara , Albertini Paola , Follenzi Antonia , Ayuso Eduard , Mueller Christian , Annoni Andrea , Naldini Luigi , Cantore Alessio
Published: May 2022

Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional >10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application.
Cofilactin filaments regulate filopodial structure and dynamics in neuronal growth cones
Authors: Hylton Ryan K. , Heebner Jessica E. , Grillo Michael A. , Swulius Matthew T.
Published: May 2022

Cofilin is best known for its ability to sever actin filaments and facilitate cytoskeletal recycling inside of cells, but at higher concentrations in vitro, cofilin stabilizes a more flexible, hyper-twisted state of actin known as “cofilactin”. While this filament state is well studied, a structural role for cofilactin in dynamic cellular processes has not been observed. With a combination of cryo-electron tomography and fluorescence imaging in neuronal growth cones, we observe that filopodial actin filaments switch between a fascin-linked and a cofilin-decorated state, and that cofilactin is associated with a variety of dynamic events within filopodia. The switch to cofilactin filaments occurs in a graded fashion and correlates with a decline in fascin cross-linking within the filopodia, which is associated with curvature in the bundle. Our tomographic data reveal that the hyper-twisting of actin from cofilin binding leads to a rearrangement of filament packing, which largely excludes fascin from the base of filopodia. Our results provide mechanistic insight into the fundamentals of cytoskeletal remodeling inside of confined cellular spaces, and how the interplay between fascin and cofilin regulates the dynamics of searching filopodia.
Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Authors: Zhang Yun , Li Shuaijun , Jin Peisheng , Shang Ting , Sun Ruizhu , Lu Laiya , Guo Kaijin , Liu Jiping , Tong Yongjuan , Wang Junbang , Liu Sanhong , Wang Chen , Kang Yubin , Zhu Wenmin , Wang Qian , Zhang Xiaoren , Yin Feng , Sun Yi Eve , Cui Lei
Published: May 2022

Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) “difficult-to-treat”. Cartilage destruction is central to OA patho-etiology and is mediated by matrix degrading enzymes. Here we report decreased expression of miR-17 in osteoarthritic chondrocytes and its deficiency contributes to OA progression. Supplementation of exogenous miR-17 or its endogenous induction by growth differentiation factor 5, effectively prevented OA by simultaneously targeting pathological catabolic factors including matrix metallopeptidase-3/13 (MMP3/13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2). Single-cell RNA sequencing of hyaline cartilage revealed two distinct superficial chondrocyte populations (C1/C2). C1 expressed physiological catabolic factors including MMP2, and C2 carries synovial features, together with C3 in the middle zone. MiR-17 is highly expressed in both superficial and middle chondrocytes under physiological conditions, and maintains the physiological catabolic and anabolic balance potentially by restricting HIF-1α signaling. Together, this study identified dual functions of miR-17 in maintaining cartilage homeostasis and prevention of OA.
Recyclable cooperative catalyst for accelerated hydroaminomethylation of hindered amines in a continuous segmented flow reactor
Authors: Ibrahim Malek Y. S. , Abolhasani Milad
Published: May 2022

Synthesis of hindered amines using the atom-efficient hydroaminomethylation (HAM) route remains a challenge. Here, we report a general and accelerated HAM in segmented flow, achieved via a cooperative effect between rhodium (Rh)/N-Xantphos and a co-catalyst (2-Fluoro-4-methylbenzoic acid) to increase the reactivity by 70 fold when compared to Rh/Xantphos in batch reactors. The cooperation between Rh and the co-catalyst facilitates the cleavage of the H–H bond and drives the equilibrium-limited condensation step forward. Online reaction optimization expands the scope to include alkyl, aryl, and primary amines. In-flow solvent tuning enables selectivity switching from amine to enamine without the need for changing the ligand. Furthermore, leveraging the ionic nature of the catalyst, we present a robust Rh recovery strategy up to 4 recycles without loss of activity.
Decarboxylative tandem C-N coupling with nitroarenes via SH2 mechanism
Authors: Wang Shuaishuai , Li Tingrui , Gu Chengyihan , Han Jie , Zhao Chuan-Gang , Zhu Chengjian , Tan Hairen , Xie Jin
Published: May 2022

Aromatic tertiary amines are one of the most important classes of organic compounds in organic chemistry and drug discovery. It is difficult to efficiently construct tertiary amines from primary amines via classical nucleophilic substitution due to consecutive overalkylation. In this paper, we have developed a radical tandem C-N coupling strategy to efficiently construct aromatic tertiary amines from commercially available carboxylic acids and nitroarenes. A variety of aromatic tertiary amines can be furnished in good yields (up to 98%) with excellent functional group compatibility under mild reaction conditions. The use of two different carboxylic acids also allows for the concise synthesis of nonsymmetric aromatic tertiary amines in satisfactory yields. Mechanistic studies suggest the intermediacy of the arylamine–(TPP)Fe(III) species and might provide a possible evidence for an SH2 (bimolecular homolytic substitution) pathway in the critical C-N bond formation step.
Antipsychotic prescription, assumption and conversion to psychosis: resolving missing clinical links to optimize prevention through precision
Authors: Zhang TianHong , Raballo Andrea , Zeng JiaHui , Gan RanPiao , Wu GuiSen , Wei YanYan , Xu LiHua , Tang XiaoChen , Hu YeGang , Tang YingYing , Liu HaiChun , Chen Tao , Li ChunBo , Wang JiJun
Published: May 2022

The current concept of clinical high-risk(CHR) of psychosis relies heavily on “below-threshold” (i.e. attenuated or limited and intermittent) psychotic positive phenomena as predictors of the risk for future progression to “above-threshold” positive symptoms (aka “transition” or “conversion”). Positive symptoms, even at attenuated levels are often treated with antipsychotics (AP) to achieve clinical stabilization and mitigate the psychopathological severity. The goal of this study is to contextually examine clinicians’ decision to prescribe AP, CHR individuals’ decision to take AP and psychosis conversion risk in relation to prodromal symptoms profiles. CHR individuals (n = 600) were recruited and followed up for 2 years between 2016 and 2021. CHR individuals were referred to the participating the naturalistic follow-up study, which research procedure was independent of the routine clinical treatment. Clinical factors from the Structured Interview for Prodromal Syndromes (SIPS) and global assessment of function (GAF) were profiled via exploratory factor analysis (EFA), then the extracted factor structure was used to investigate the relationship of prodromal psychopathology with clinicians’ decisions to AP-prescription, CHR individuals’ decisions to AP-taking and conversion to psychosis. A total of 427(71.2%) CHR individuals were prescribed AP at baseline, 532(88.7%) completed the 2-year follow-up, 377(377/532, 70.9%) were taken AP at least for 2 weeks during the follow-up. EFA identified six factors (Factor-1-Negative symptoms, Factor-2-Global functions, Factor-3-Disorganized communication & behavior, Factor-4-General symptoms, Factor-5-Odd thoughts, and Factor-6-Distorted cognition & perception). Positive symptoms (Factor-5 and 6) and global functions (Factor-2) factors were significant predictors for clinicians’ decisions to AP-prescription and CHR individuals’ decisions to assume AP, whereas negative symptoms (Factor-1) and global functions (Factor-2) factors predicted conversion. While decisions to AP-prescription, decisions to AP-taking were associated to the same factors (positive symptoms and global functions), only one of those was predictive of conversion, i.e. global functions. The other predictor of conversion, i.e. negative symptoms, did not seem to be contemplated both on the clinician and patients’ sides. Overall, the findings indicated that a realignment in the understanding of AP usage is warranted.
Organocatalytic stereoselective cyanosilylation of small ketones
Authors: Zhou Hui , Zhou Yu , Bae Han Yong , Leutzsch Markus , Li Yihang , De Chandra Kanta , Cheng Gui-Juan , List Benjamin
Published: May 2022

Enzymatic stereoselectivity has typically been unrivalled by most chemical catalysts, especially in the conversion of small substrates. According to the ‘lock-and-key theory’1,2, enzymes have confined active sites to accommodate their specific reacting substrates, a feature that is typically absent from chemical catalysts. An interesting case in this context is the formation of cyanohydrins from ketones and HCN, as this reaction can be catalysed by various classes of catalysts, including biological, inorganic and organic ones3–7. We now report the development of broadly applicable confined organocatalysts for the highly enantioselective cyanosilylation of aromatic and aliphatic ketones, including the challenging 2-butanone. The selectivity (98:2 enantiomeric ratio (e.r.)) obtained towards its pharmaceutically relevant product is unmatched by any other catalyst class, including engineered biocatalysts. Our results indicate that confined chemical catalysts can be designed that are as selective as enzymes in converting small, unbiased substrates, while still providing a broad scope.
Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs
Authors: Eschweiler Simon , Ramírez-Suástegui Ciro , Li Yingcong , King Emma , Chudley Lindsey , Thomas Jaya , Wood Oliver , von Witzleben Adrian , Jeffrey Danielle , McCann Katy , Simon Hayley , Mondal Monalisa , Wang Alice , Dicker Martina , Lopez-Guadamillas Elena , Chou Ting-Fang , Dobbs Nicola A. , Essame Louisa , Acton Gary , Kelly Fiona , Halbert Gavin , Sacco Joseph J. , Schache Andrew Graeme , Shaw Richard , McCaul James Anthony , Paterson Claire , Davies Joseph H. , Brennan Peter A. , Singh Rabindra P. , Loadman Paul M. , Wilson William , Hackshaw Allan , Seumois Gregory , Okkenhaug Klaus , Thomas Gareth J. , Jones Terry M. , Ay Ferhat , Friberg Greg , Kronenberg Mitchell , Vanhaesebroeck Bart , Vijayanand Pandurangan , Ottensmeier Christian H.
Published: May 2022

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
Experimental investigation of four-point bending of thin walled open section steel beam loaded and set in the shear center
Authors: Obst Maciej , Wasilewicz Piotr , Adamiec Jarosław
Published: May 2022

Thin walled cold formed structures were, and still are, very popular structural elements used in mechanical engineering. Modern technology and the progress in materials engineering allow to fabricate various shapes of thin walled cold formed components. Therefore, combinations between technology possibilities, material properties, loads and engineering requirements are wide and unlimited for thin walled components. The aim of this paper is to perform an experimental study of cold formed C-channel steel beams under four-points bending loads based on the global and the local buckling phenomena. A test rig was developed with a specially designed support system to subject thin-walled steel beams to a four-point bending load, where the support and loads were applied to the shear center of the open section steel beam. It is shown that it is not possible to completely eliminate the torque load on a thin-walled beam with an open section where load and support are applied in the shear center because investigated beams weren’t ideal made. Thin walled open section beams are very sensitive for boundary conditions and geometrical accuracy. The force of gravity is also working. The presented research methodology can be improved and do test with other open section thin walled beams.
Pulsed electromagnetic fields inhibit mandibular bone deterioration depending on the Wnt3a/β-catenin signaling activation in type 2 diabetic db/db mice
Authors: Li Jianjun , Cai Jing , Liu Liheng , Wu Yuwei , Chen Yan
Published: May 2022

Type 2 diabetes mellitus (T2DM) patients have compromised mandibular bone architecture/quality, which markedly increase the risks of tooth loosening, tooth loss, and failure of dental implantation. However, it remains lacks effective and safe countermeasures against T2DM-related mandibular bone deterioration. Herein, we studied the effects of pulsed electromagnetic fields (PEMF) on mandibular bone microstructure/quality and relevant regulatory mechanisms in T2DM db/db mice. PEMF exposure (20 Gs, 15 Hz) for 12 weeks preserved trabecular bone architecture, increased cortical bone thickness, improved material properties and stimulated bone anabolism in mandibles of db/db mice. PEMF also upregulated the expression of canonical Wnt3a ligand (but not Wnt1 or Wnt5a) and its downstream β-catenin. PEMF improved the viability and differentiation of primary osteoblasts isolated from the db/db mouse mandible, and stimulated the specific activation of Wnt3a/β-catenin signaling. These positive effects of PEMF on mandibular osteoblasts of db/db mice were almost totally abolished after Wnt3a silencing in vitro, which were equivalent to the effects following blockade of canonical Wnt signaling using the broad-spectrum antagonist DKK1. Injection with Wnt3a siRNA abrogated the therapeutic effects of PEMF on mandibular bone quantity/quality and bone anabolism in db/db mice. Our study indicates that PEMF might become a non-invasive and safe treatment alternative resisting mandibular bone deterioration in T2DM patients, which is helpful for protecting teeth from loosening/loss and securing the dental implant stability.
Author Correction: Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids
Authors: Wammers Marianne , Schupp Anna-Kathrin , Bode Johannes G. , Ehlting Christian , Wolf Stephanie , Deenen René , Köhrer Karl , Häussinger Dieter , Graf Dirk
Published: May 2022

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Antioxidative and osmoprotecting mechanisms in carrot plants tolerant to soil salinity
Authors: Kamińska Iwona , Lukasiewicz Aneta , Klimek-Chodacka Magdalena , Długosz-Grochowska Olga , Rutkowska Julia , Szymonik Kamil , Baranski Rafal
Published: May 2022

Soil salinization is a growing problem for agriculture worldwide and carrot is one the most salt-sensitive vegetable species. However, some varieties are capable of withstanding high salt concentrations due to unknown genetic and physiological mechanisms. The aim of this work was to reveal protecting mechanisms against osmotic and ionic stresses that contribute to salt tolerance in carrot. For this purpose, changes in biochemical traits due to soil salinity occurring in the salt-tolerant and salt-sensitive plants were determined. The obtained results showed that the tolerance of the salt-tolerant variety was partially determined constitutively, however, the exposition to saline soil triggered a physiological response that was more evident in the root than in the leaves. The most noticeable changes were the high increase in the content of osmoprotective proline and other low molecular antioxidants such as glutathione and ascorbic acid, and the decrease in the ratio of reduced to oxidized glutathione forms. These changes imply an efficient operation of the ascorbate–glutathione cycle that together with a high activity of antioxidative enzymes such as peroxidases, indicate on the induction of mechanisms associated mainly with protection against excessive reactive oxygen species.
Highly efficient hole injection from Au electrode to fullerene-doped triphenylamine derivative layer
Authors: Matsuda Shofu , Itagaki Chikara , Tatsuguchi Kyoya , Ito Masamichi , Sasaki Hiroto , Umeda Minoru
Published: May 2022

Triphenylamine derivatives are superior hole-transport materials. For their application to high-functional organic semiconductor devices, efficient hole injection at the electrode/triphenylamine derivative interface is required. Herein, we report the design and evaluation of a Au/fullerene-doped α-phenyl-4′-[(4-methoxyphenyl)phenylamino]stilbene (TPA) buffer layer/TPA/Au layered device. It exhibits rectification conductivity, indicating that hole injection occurs more easily at the Au/fullerene-doped TPA interface than at the Au/TPA interface. The Richardson-Schottky analysis of the device reveals that the hole injection barrier (ΦB) at the Au/fullerene-doped TPA interface decreases to 0.021 eV upon using C70 as a dopant, and ΦB of Au/TPA is as large as 0.37 eV. The reduced ΦB of 0.021 eV satisfies the condition for ohmic contact at room temperature (ΦB$$\le $$
≤
0.025 eV). Notably, C70 doping has a higher barrier-reduction effect than C60 doping. Furthermore, a noteworthy hole-injection mechanism, in which the ion–dipole interaction between TPA and fullerenes plays an important role in reducing the barrier height, is considered based on cyclic voltammetry. These results should facilitate the design of an electrode/organic semiconductor interface for realizing low-voltage driven organic devices.
Associations between serum levels of brain-derived neurotrophic factor, corticotropin releasing hormone and mental distress in vitiligo patients
Authors: Kussainova Assiya , Kassym Laura , Akhmetova Almira , Dvoryankova Eugenia , Glushkova Natalya , Khismetova Zaituna , Adilgozhina Saltanat , Tuleutayeva Raikhan , Kaskabayeva Alida , Massabayeva Meruyert , Pak Laura , Semenova Yuliya
Published: May 2022

Vitiligo is clinically characterized by the appearance of non-symptomatic depigmented macules, but the disorder is highly correlated with a wide range of psychiatric disorders and psychological problems. The aim of our study was to investigate serum brain-derived neurotrophic factor (BDNF) and corticotropin releasing hormone (CRH) levels in vitiligo patients and healthy controls in relation to the observed symptoms of depression and anxiety disorders. This study comprised 96 vitiligo patients and 96 healthy controls who filled out the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scales. Serum levels of BDNF and CRH were measured using enzyme-linked immunosorbent assay (ELISA) technique. There was a significant increase of depression and anxiety scores in vitiligo patients as compared with healthy controls (P < 0.05). The serum levels of BDNF were significantly lower in vitiligo patients than in healthy individuals (Z = 4.002; P < 0.001), while the serum levels of CRH were markedly higher in cases than those in controls (Z = 3.764; P < 0.001). The significant positive correlations between serum CRH levels and GAD-7, PHQ-9 scores were observed. However, the aforementioned psychometric scales did not correlate significantly with serum BDNF level. Vitiligo is associated with the depression and is closely linked with lower BDNF levels.
Different effects of hydrogen-rich water intake and hydrogen gas inhalation on gut microbiome and plasma metabolites of rats in health status
Authors: Xie Fei , Jiang Xue , Yi Yang , Liu Zi-Jia , Ma Chen , He Jin , Xun Zhi-ming , Wang Meng , Liu Meng-yu , Mawulikplimi Adzavon Yao , Zhao Peng-xiang , Ma Xue-mei
Published: May 2022

The potential for preventive and therapeutic applications of H2 have now been confirmed in various disease. However, the effects of H2 on health status have not been fully elucidated. Our previous study reported changes in the body weight and 13 serum biochemical parameters during the six-month hydrogen intervention. To obtain a more comprehensive understanding of the effects of long-term hydrogen consumption, the plasma metabolome and gut microbiota were investigated in this study. Compared with the control group, 14 and 10 differential metabolites (DMs) were identified in hydrogen-rich water (HRW) and hydrogen inhalation (HI) group, respectively. Pathway enrichment analysis showed that HRW intake mainly affected starch and sucrose metabolism, and DMs in HI group were mainly enriched in arginine biosynthesis. 16S rRNA gene sequencing showed that HRW intake induced significant changes in the structure of gut microbiota, while no marked bacterial community differences was observed in HI group. HRW intake mainly induced significant increase in the abundance of Lactobacillus, Ruminococcus, Clostridium XI, and decrease in Bacteroides. HI mainly induced decreased abundances of Blautia and Paraprevotella. The metabolic function was determined by metabolic cage analysis and showed that HI decreased the voluntary intake and excretions of rats, while HRW intake did not. The results of this study provide basic data for further research on hydrogen medicine. Determination of the effects of hydrogen intervention on microbiota profiles could also shed light on identification of mechanism underlying the biological effects of molecular hydrogen.
The influence of land use in the catchment area of small waterbodies on the quality of water and plant species composition
Authors: Szpakowska Barbara , Świerk Dariusz , Dudzińska Anna , Pajchrowska Maria , Gołdyn Ryszard
Published: May 2022

Land use significantly affects the function of waterbodies in landscape. Although there have been numerous studies on the influence of the catchment area on the trophic and ecological status of waterbodies, still is not reached an agreement on the width of the buffer zone that is necessary for effective protection of waterbodies. The aim of the study was to show whether small waterbodies are predominantly influenced by land use in the entire catchment area or only in the zone extending 100 or 200 m away from the shoreline. For two years the waters in six small waterbodies located in the Wielkopolska region (Poland) were analysed. The canonical correspondence analysis (CCA) showed that the influence of land use, especially agricultural land, was much greater within the zone extending 100 m from the shore line of the waterbodies than in the total catchment area. Therefore, it would be advisable to move the border of intensive farming areas beyond the entire 100-m-wide buffer zone, or at least to reduce the intensity of agriculture and to introduce diversified and perennial vegetation creating effective biogeochemical barriers.