bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of romosozumab versus denosumab treatment on bone mineral density after 1 year in rheumatoid arthritis patients with severe osteoporosis: A randomized clinical pilot study
Authors: Mochizuki Takeshi , Yano Koichiro , Ikari Katsunori , Hiroshima Ryo , Okazaki Ken
Published: June 2022

Objectives

To investigate the effect of romosozumab versus denosumab treatment on bone mineral density (BMD), disease activity, and joint damage in patients with rheumatoid arthritis and severe osteoporosis.

Methods

Fifty-one postmenopausal women were enrolled and randomized equally into two groups to receive either romosozumab or the denosumab. Changes (Δ) in the BMD (at lumbar spine, total hip, and femoral neck), disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR), and van der Heijde-modified Total Sharp Score (TSS) from baseline to 12 months after treatment were evaluated.

Results

The ΔBMD at 12 months in the romosozumab and denosumab groups were 10.2 ± 5.6% and 5.0 ± 3.1% (p = .002) for the lumbar spine, 3.7 ± 4.9% and 3.5 ± 3.0% (p = .902) for the total hip, and 3.6 ± 4.7% and 3.2 ± 4.9% (p = .817) for the femoral neck, respectively. The ΔDAS28-ESR and ΔTSS at 12 months did not differ between these two groups.

Conclusions

Our results suggest that romosozumab treatment was more effective in increasing the BMD at the lumbar spine than denosumab and may be selected for patients who require a significant increase in the lumbar spine BMD.
A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells
Authors: Rana Marium , Perotti Alessio , Bisset Lucy M , Smith James D , Lamden Emma , Khan Zahra , Ismail Media K , Ellis Katherine , Armstrong Katie A , Hodder Samantha L , Bertoli Cosetta , Meneguello Leticia , de Bruin Robertus A M , Morris Joanna R , Romero-Canelon Isolda , Tucker James H R , Hodges Nikolas J
Published: June 2022

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.
Removing race from the CKD-EPI equation and its impact on prognosis in a predominantly White European population
Authors: Fu Edouard L , Coresh Josef , Grams Morgan E , Clase Catherine M , Elinder Carl-Gustaf , Paik Julie , Ramspek Chava L , Inker Lesley A , Levey Andrew S , Dekker Friedo W , Carrero Juan J
Published: June 2022

Background

While American nephrology societies recommend using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation without a Black race coefficient, it is unknown how this would impact disease distribution, prognosis and kidney failure risk prediction in predominantly White non-US populations.

Methods

We studied 1.6 million Stockholm adults with serum/plasma creatinine measurements between 2007 and 2019. We calculated changes in eGFR and reclassification across KDIGO GFR categories when changing from the 2009 to 2021 CKD-EPI equation; estimated associations between eGFR and the clinical outcomes kidney failure with replacement therapy (KFRT), (cardiovascular) mortality and major adverse cardiovascular events using Cox regression; and investigated prognostic accuracy (discrimination and calibration) of both equations within the Kidney Failure Risk Equation.

Results

Compared with the 2009 equation, the 2021 equation yielded a higher eGFR by a median [interquartile range (IQR)] of 3.9 (2.9–4.8) mL/min/1.73 m2, which was larger at older age and for men. Consequently, 9.9% of the total population and 36.2% of the population with CKD G3a–G5 was reclassified to a higher eGFR category. Reclassified individuals exhibited a lower risk of KFRT, but higher risks of all-cause/cardiovascular death and major adverse cardiovascular events, compared with non-reclassified participants of similar eGFR. eGFR by both equations strongly predicted study outcomes, with equal discrimination and calibration for the Kidney Failure Risk Equation.

Conclusions

Implementing the 2021 CKD-EPI equation in predominantly White European populations would raise eGFR by a modest amount (larger at older age and in men) and shift a major proportion of CKD patients to a higher eGFR category. eGFR by both equations strongly predicted outcomes.
Inverse design with deep generative models: next step in materials discovery
Authors: Lu Shuaihua , Zhou Qionghua , Chen Xinyu , Song Zhilong , Wang Jinlan
Published: June 2022

Data-driven inverse design for inorganic functional materials is a rapidly emerging field, which aims to automatically design innovative materials with target properties and to enable property-to-structure material discovery.
Two Attitudes towards Textuality in International Law: The Battle for Dualism
Authors: d’Aspremont Jean
Published: June 2022

This article sketches out two distinct attitudes towards textuality in international law, namely international hermeneutics and international poetics. It argues that these two attitudes towards textuality espouse very different types of dualism of thought. This difference bears major implications on how the international lawyer approaches international legal texts. In exposing these two attitudes towards textuality and the distinct types of dualism they reveal, this article makes a plea for a greater embrace of international poetics by international lawyers, and thus for a complete remoulding of international lawyers’ dualist patterns of thought.
Construct Validity of the Revised High-Level Mobility Assessment Tool for Children Who Are Developing Typically
Authors: Hill Bridget , Eldridge Beverly , Williams Gavin
Published: June 2022

Objective

The aim of this project was to evaluate the construct validity of the high-level mobility assessment tool (HiMAT) for children who are developing typically with no underlying condition that may affect mobility.

Methods

The HiMAT is a revised 8-item measure of high-level mobility. Rasch analysis was used to assess fit to the Rasch model indicating unidimensionality, person separation index local dependency, targeting of items, and differential item functioning.

Results

Children with typical development aged 5 to 12 years (n = 1091; 554 girls and 537 boys) were recruited from 8 schools. The mean HiMAT score was 22.4/32 (range, 8–32). Data fit the Rasch model, indicating that the HiMAT was a unidimensional scale assessing a single construct (high-level mobility). The person separation index was .86, indicating good reliability. The skip item exhibited differential item functioning by sex. Although items were well targeted, the fit residual mean for persons was 2.40, indicating most found the tasks easy to complete. Unlike in adult populations, 2 items (walk and walk over obstacle) exhibited local dependency >0.2.

Conclusion

The HiMAT is a unidimensional targeted performance measure of high-level mobility for children with typical development aged 5 to 12 years. Further examination of the relationship between the test items “walk” and “walk over an obstacle” may be required to ensure that scores on these items are truly independent of one another.
Bicephalic Transcranial Direct-Current Stimulation Does Not Add Benefits to a Footdrop Stimulator for Improving Functional Mobility in People With Chronic Hemiparesis After Stroke: A Double-Blind, Randomized Controlled Trial
Authors: da Cunha Maira Jaqueline , Pinto Camila , Schifino Giulia Palermo , Sant’Anna Py Isabela , Cimolin Veronica , Pagnussat Aline Souza
Published: June 2022

Objective

The aim of this study was to assess the effects of applying transcranial direct-current stimulation (tDCS), a footdrop stimulator (FDS), and gait training simultaneously on functional mobility in people with chronic hemiparesis after stroke.

Methods

In this double-blind controlled trial, 32 individuals with mild, moderate, and severe chronic hemiparesis after stroke were randomized to tDCS plus FDS or sham tDCS plus FDS groups. Both groups underwent 10 concurrent tDCS and FDS gait training sessions 5 times per week for 2 weeks. Functional mobility was evaluated by the Timed “Up & Go” test (TUG). Secondary outcomes included spasticity of plantarflexors, knee extensors, and hip adductors; quality of life; and walking endurance (distance covered during each treadmill gait training session). Clinical assessments were performed before treatment, after treatment, and at a 1-month follow-up. A generalized estimating equation was used to compare the effects of time, group, and time × group interaction.

Results

No difference between groups was observed during performance of the TUG or other outcomes. TUG performance was improved in both the tDCS plus FDS group (before treatment = 24.29 [95% CI = 17.72–33.28]; after treatment = 21.75 [95% CI = 15.75–30.08]) and the sham tDCS plus FDS group (before treatment = 19.63 [95% CI = 16.06–23.0]; after treatment = 18.45 [95% CI = 15.26–22.3]). This improvement remained at the follow-up evaluation. Both groups also showed reduced spasticity of plantarflexors and knee extensors, increased quality of life, and increased total distance walked.

Conclusion

This study provided no evidence that bicephalic tDCS improves functional mobility, spasticity, quality of life, or walking endurance in people with chronic hemiparesis after stroke.

Impact

Bicephalic tDCS does not add relevant benefits to FDS and gait training in people who have chronic hemiparesis after stroke. Given that tDCS has few additional effects and given its costs for clinical practice, tDCS for rehabilitation in people with chronic hemiparesis after stroke is discouraged. FDS and gait training improve functional mobility, walking resistance, and quality of life in people with chronic hemiparesis after stroke.
The polycaprolactone/silk fibroin/carbonate hydroxyapatite electrospun scaffold promotes bone reconstruction by regulating the polarization of macrophages
Authors: Jia Xiaoshi , Zhou Jing , Ning Jinqiu , Li Maoquan , Yao Yitong , Wang Xiaodong , Jian Yutao , Zhao Ke
Published: June 2022

Macrophages are known to modulate the osteogenic environment of bone regeneration elicited by biological bone grafts. Alteration in certain chemical components tends to affect macrophages polarization. Comparatively to hydroxyapatite (HAp), carbonate hydroxyapatite (CHA) consists of 7.4 (wt%) carbonate ions and more closely resembles the mineral content of bone. It remains unknown whether CHA scaffolds or HA scaffolds have better osteogenic properties. In this study, we fabricated PCL/SF scaffold, PCL/SF/HAp scaffold and PCL/SF/CHA scaffold using the electrospinning technique. Despite comparable mechanical properties, the PCL/SF/CHA scaffold exhibited better osteogenic properties than the PCL/SF/HAp scaffold. Although no significant differences were observed between the two scaffolds for promoting osteoblast differentiation in vitro, the PCL/SF/CHA group appeared to be more effective at promoting bone regeneration in cranial defects in vivo. The PCL/SF/CHA scaffold was found to promote macrophage polarization toward M2 via activating the JAK/STAT5 pathway which caused a pro-osteogenic microenvironment to facilitate osteoblast differentiation. The results of this study indicated a higher potential of CHA to substitute HAp in the production of bone scaffolds for better bone regeneration.
Outcomes During and After Early Intervention Services for First-Episode Psychosis: Results Over 5 Years From the RAISE-ETP Site-Randomized Trial
Authors: Robinson Delbert G , Schooler Nina R , Marcy Patricia , Gibbons Robert D , Hendricks Brown C , John Majnu , Mueser Kim T , Penn David L , Rosenheck Robert A , Addington Jean , Brunette Mary F , Correll Christoph U , Estroff Sue E , Mayer-Kalos Piper S , Gottlieb Jennifer D , Glynn Shirley M , Lynde David W , Gingerich Susan , Pipes Ronny , Miller Alexander L , Severe Joanne B , Kane John M
Published: June 2022

To examine long-term effects of early intervention services (EIS) for first-episode psychosis, we compared Heinrichs-Carpenter Quality of Life (QLS) and Positive and Negative Syndrome Scale (PANSS) scores and inpatient hospitalization days over 5 years with data from the site-randomized RAISE-ETP trial that compared the EIS NAVIGATE (17 sites; 223 participants) and community care (CC) (17 sites; 181 participants). Inclusion criteria were: age 15–40 years; DSM-IV diagnoses of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, or psychotic disorder not otherwise specified; first psychotic episode; antipsychotic medication taken for ≤6 months. NAVIGATE-randomized participants could receive NAVIGATE from their study entry date until NAVIGATE ended when the last-enrolled NAVIGATE participant completed 2 years of treatment. Assessments occurred every 6 months. 61% of participants had assessments conducted ≥2 years; 31% at 5 years. Median follow-up length was CC 30 months and NAVIGATE 38 months. Primary analyses assumed data were not-missing-at-random (NMAR); sensitivity analyses assumed data were missing-at-random (MAR). MAR analyses found no significant treatment-by-time interactions for QLS or PANSS. NMAR analyses revealed that NAVIGATE was associated with a 13.14 (95%CI:6.92,19.37) unit QLS and 7.73 (95%CI:2.98,12.47) unit PANSS better improvement and 2.53 (95%CI:0.59,4.47) fewer inpatient days than CC (all comparisons significant). QLS and PANSS effect sizes were 0.856 and 0.70. NAVIGATE opportunity length (mean 33.8 (SD = 5.1) months) was not associated (P = .72) with QLS outcome; duration of untreated psychosis did not moderate (P = .32) differential QLS outcome. While conclusions are limited by the low rate of five-year follow-up, the data support long-term benefit of NAVIGATE compared to community care.
Within-night repeatability and long-term consistency of sleep apnea endotypes: the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study
Authors: Alex Raichel M , Sofer Tamar , Azarbarzin Ali , Vena Daniel , Gell Laura K , Wellman Andrew , White David P , Redline Susan , Sands Scott A
Published: June 2022

Study Objectives

Obstructive sleep apnea (OSA) is characterized by multiple “endotypic traits,” including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h).

Methods

Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from “odd” and “even” 30-min periods were correlated and regression (error vs. N windows available) provided a recommended amount of data for acceptable repeatability (Rthreshold = 0.7). Long-term consistency was assessed using the Osteoporotic Fractures in Men Study (MrOS) at two time points 6.5 ± 0.7 years apart, before and after accounting for across-year body position and sleep state differences. Within-night dependence of traits on position and state (MESA plus MrOS data) was estimated using bootstrapping.

Results

Within-night repeatability for traits ranged from R = 0.62–0.79 and improved to R = 0.69–0.83 when recommended amounts of data were available (20–35 7-min windows, available in 94%–98% of participants); repeatability was similar for collapsibility, loop gain, and arousal threshold (R = 0.79–0.83), but lower for compensation (R = 0.69). Long-term consistency was modest (R = 0.30–0.61) and improved (R = 0.36–0.63) after accounting for position and state differences. Position/state analysis revealed reduced loop gain in REM and reduced collapsibility in N3.

Conclusions

Endotypic traits can be obtained with acceptable repeatability. Long-term consistency was modest but improved after accounting for position and state changes. These data support the use of endotypic assessments in large-scale epidemiological studies.

Clinical Trial Information

The data used in the manuscript are from observational cohort studies and are not a part of the clinical trial.
Macroevolutionary Analyses Provide New Evidence of Phasmid Wings Evolution as a Reversible Process
Authors: Forni Giobbe , Martelossi Jacopo , Valero Pablo , Hennemann Frank H , Conle Oskar , Luchetti Andrea , Mantovani Barbara
Published: June 2022

The concept that complex ancestral traits can never be recovered after their loss is still widely accepted, despite phylogenetic and molecular approaches suggest instances where phenotypes may have been lost throughout the evolutionary history of a clade and subsequently reverted back in derived lineages. One of the first and most notable examples of such a process is wing evolution in phasmids; this polyneopteran order of insects, which comprises stick and leaf insects, has played a central role in initiating a long-standing debate on the topic. In this study, a novel and comprehensive time tree including over 300 Phasmatodea species is used as a framework for investigating wing evolutionary patterns in the clade. Despite accounting for several possible biases and sources of uncertainty, macroevolutionary analyses consistently revealed multiple reversals to winged states taking place after their loss, and reversibility is coupled with higher species diversification rates. Our findings support a loss of or reduction in wings that occurred in the lineage leading to the extant phasmid most recent common ancestor, and brachyptery is inferred to be an unstable state unless co-opted for nonaerodynamic adaptations. We also explored how different assumptions of wing reversals probability could impact their inference: we found that until reversals are assumed to be over 30 times more unlikely than losses, they are consistently inferred despite uncertainty in tree and model parameters. Our findings demonstrate that wing evolution is a reversible and dynamic process in phasmids and contribute to our understanding of complex trait evolution. [Dollo’s law; Phasmatodea; phylogenetic comparative methods; polyneoptera; reversals; wing.]
Single Lung Transplant Remains a Viable Option for Patients With Severe Secondary Pulmonary Hypertension
Authors: Sunagawa Gengo , Kehara Hiromu , Mangukia Chirantan , Brann Stacey , Leotta Eros , Yanagida Roh , Minakata Kenji , Shenoy Kartik V. , Mamary Albert James , Marchetti Nathaniel , Cordova Francis , Criner Gerard J. , Toyoda Yoshiya , Shigemura Norihisa
Published: June 2022

Background.

Although double lung transplant is recommended in patients with severe secondary pulmonary hypertension (SPH), our institutional experiences suggest a role for single lung transplant in these patients. Here, we review our experience prioritizing single lung transplant in patients with SPH to minimize their surgical burden.

Methods.

We conducted a retrospective review of our lung transplant database to identify patients with SPH who underwent single lung transplant. Patients were stratified as either mild SPH (mean pulmonary artery pressure 25–40 mm Hg) or severe SPH (mean pulmonary artery pressure >40 mm Hg). Singe lung recipients without PH transplanted over the same time were also examined.

Results.

Between January 2017 and December 2019, 318 patients underwent single lung transplantation; 217 had mild SPH (68%), and 59 had severe SPH (18.5%). Forty-two patients without PH underwent single lung transplant. When the groups were compared, significantly higher pulmonary vascular resistance was noted in the severe SPH group, and obesity was noted in both the mild and severe SPH groups. Although the severe SPH group required more intraoperative cardiopulmonary support (37.3% versus 10.3% versus 4.7%, P < 0.05), there were no significant differences in most major postoperative parameters, including the duration of postoperative mechanical ventilation or the incidence of severe primary graft dysfunction. Survival 1 y posttransplant was not significantly different among the groups (93.2% versus 89.4% versus 92.9%, P = 0.58).

Conclusions.

Our experience supports the option of single lung transplantation with appropriate intraoperative mechanical circulatory support in patients with SPH. This strategy is worth pursuing, especially with ongoing donor lung shortages.
A meta-analysis of genome-wide association studies in 614,243 individuals identifies 59 novel susceptibility loci underlying Dupuytren’s contracture
Authors: Rahimov Fedik , Degner Jacob F. , Lee John S. , Zheng Xiuwen ,   FinnGen, Karman Jozsef , Jacob Howard J. , Waring Jeffrey F.
Published: June 2022

Dupuytren’s contracture or disease (DD) is a disabling, fibroproliferative disease of the hand that affects up to 25% of people of northwestern European descent. It typically manifests in adulthood and many affected individuals have a positive family history, yet the genetic architecture of DD is not completely understood. We conducted genome-wide association studies (GWAS) of DD in 8,846 cases and 347,659 population controls from the UK Biobank resource, and 4,616 cases and 253,122 population controls from the FinnGen study. We combined these datasets with a meta-analysis, which represents the largest GWAS conducted in DD to date including 13,462 cases. We identified 83 loci with genome-wide significance of p < 5 × 10-8. We replicated association at the 24 previously reported loci and discovered 59 novel loci, substantially increasing the number of risk loci for DD. Colocalization with expression quantitative trait loci and overlap with genes linked to phenotypically matched human Mendelian disorders or animal models support causal roles for at least 30 genes with high confidence. Among these, fifteen genes cause rare limb abnormalities when mutated, an observation that may potentially shed light on hand specificity of DD phenotype. Gene enrichment analysis revealed predominant role of connective tissue development and maintenance and extracellular matrix homeostasis but limited or no role of inflammatory processes in disease causality. These findings provide key insights into the biological mechanisms underlying DD and identify genetically informed therapeutic targets for DD and possibly for other fibrotic diseases.
Lymphoma cells are circulating in blood of Enzootic Bovine Leukosis and clonality value of virus-infected cells is a useful information for the diagnostic test
Authors: Hossain Md Belal , Kobayashi Tomoko , Makimoto Sakurako , Matsuo Misaki , Nishikaku Kohei , Tan Benjy Jek Yang , Rahman Akhinur , Rajib Samiul Alam , Sugata Kenji , Ohnuki Nagaki , Saito Masumichi , Inenaga Toshiaki , Imakawa Kazuhiko , Satou Yorifumi
Published: June 2022

Bovine leukemia virus (BLV), a retrovirus, causes Enzootic Bovine Leukosis (EBL) in cattle following a latent infection period. The BLV infection results in polyclonal expansion of infected B-lymphocytes and ∼5% of infected cattle develop monoclonal leukosis. Since the clonal expansion of virus-infected cell is a key in the pathogenesis of EBL, assessing the clonality of malignant cells is crucial for both understanding viral pathogenesis, which might be useful for EBL diagnosis.

For the investigation of clonality of BLV-infected cells in non-EBL and EBL cattle, two methods were used to evaluate the status of EBL; BLV-DNA-capture-seq method with high sensitivity and specificity and simple and cost-effective Rapid Amplification of Integration Site for BLV (BLV-RAIS) method. We found that the RAIS method efficiently detect expanded clone in EBL tissue sample as BLV-DNA-capture-seq method. Taking advantage of high frequency of BLV-infected cells in blood, we simplified RAIS method and showed that similar to BLV-DNA-capture-seq, this method could reliably provide quantitative value about clonal abundance of BLV-infected cells.

Next, we aimed to establish a diagnostic blood test for EBL by using the clonality information. First, we compared clonality of BLV-infected cells in blood with that in tumor tissue in EBL cattle. There was a remarkably similar clonality between blood and tissue in each animal. Furthermore, BLV integration site information clearly showed that the same clone was the most expanded in both blood and tumor tissue, indicating that tumor cells were circulating in blood in the disease cattle. We also analyzed tumor tissue at two independent anatomical regions and found the same clones was most expanded in both regions, supporting the idea that tumor cells are systemically circulating in the diseased cattle. Finally, we compared clonality value between non-EBL and EBL cattle by using BLV-RAIS method and found that there was clear difference between non-EBL and EBL. More importantly, we found that clonality value was low in asymptomatic phase but high in EBL phase in the longitudinal cohort study.

These findings have demonstrated that BLV integration site and clonality value are is a useful information to establish diagnostic blood test for EBL. That would contribute to reduction of economic damage caused by EBL and improvement of productivity in cattle industry.
A general deep hybrid model for bioreactor systems: combining first Principles equations with deep neural networks
Authors: Pinto José , Mestre Mykaella , Costa Rafael S. , Striedner Gerald , Oliveira Rui
Published: June 2022

Numerous studies have reported the use of hybrid semiparametric systems that combine shallow neural networks with mechanistic models for bioprocess modeling. Here we revisit the general bioreactor hybrid modeling problem and introduce some of the most recent deep learning techniques. The single layer networks were extended to multi-layer networks with varying depths and combined with First Principles equations in the form of deep hybrid models. Deep learning techniques, namely the adaptive moment estimation method (ADAM), stochastic regularization and depth-dependent weights initialization were evaluated. Modified sensitivity equations are proposed for the computation of gradients in order to reduce CPU time for the training of deep hybrid models. The methods are illustrated with applications to a synthetic dataset and a pilot 50 L MUT+ Pichia pastoris process expressing a single chain antibody fragment. All in all, the results point to a systematic generalization improvement of deep hybrid models over its shallow counterpart. Moreover, the CPU cost to train the deep hybrid models is shown to be lower than for the shallow counterpart. In the pilot 50L MUT+ Pichia pastoris data set, the prediction accuracy was increased by 18.4% and the CPU decreased by 43.4%.

Highlights

Shallow hybrid models have been widely used for bioprocess modeling and optimization

Non-deep training using e.g. the Levenberg – Marquardt method, cross-validation and indirect sensitivity equations have been the methods of choice

Deep learning with ADAM, stochastic regularization and indirect sensitivity significantly reduces the training CPU

The generalization capacity of deep hybrid models systematically outperforms that of shallow hybrid models
Endocytosis at Extremes: Formation and Internalization of Giant Clathrin-coated Pits Under Elevated Membrane Tension
Authors: Akatay Ahmet Ata , Wu Tianyao , Djakbarova Umidahan , Thompson Cristopher , Cocucci Emanuele , Zandi Roya , Rudnick Joseph , Kural Comert
Published: June 2022

Internalization of clathrin-coated vesicles from the plasma membrane constitutes the major endocytic route for receptors and their ligands. Dynamic and structural properties of endocytic clathrin coats are regulated by the mechanical properties of the plasma membrane. Here, we used conventional fluorescence imaging and multiple modes of structured illumination microscopy (SIM) to image formation of endocytic clathrin coats within live cells and tissues of developing fruit fly embryos. High resolution in both spatial and temporal domains allowed us to detect and characterize distinct classes of clathrin-coated structures. For the first time, we show that membrane tension induces formation of giant coated pits (GCPs) that can be up to two orders of magnitude larger than the canonical clathrin-coated pits. GCPs take longer to form but their mechanism of curvature generation is the same as the canonical pits. We also demonstrate that GCPs can split into smaller fragments during internalization. Considering the supporting roles played by actin filament dynamics in clathrin-mediated endocytosis under mechanically stringent conditions, we suggest that local changes in the coat curvature driven by actin machinery can drive splitting and internalization of GCPs.
Proteotype Co-evolution and Diversity in Mammals
Authors: Ba Qian , Hei Yuanyuan , Dighe Anasuya , Li Wenxue , Maziarz Jamie , Pak Irene , Wang Shisheng , Wagner Günter P. , Liu Yansheng
Published: June 2022

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomic variability as reference. The co-variation analysis indicates that transcript and protein expression robustness across mammals remarkably follows functional role, with extracellular matrix-associated expressions being most variable, demonstrating strong transcriptome-proteome co-evolution. Interestingly, the variability control of gene expression is universal at both inter-individual and inter-species scales, but of different extent. RNA metabolism processes particularly show the higher inter-species versus inter-individual variations. Our results further uncover that while ubiquitin-proteasome system is extremely conserved in mammals, the lysosome-mediated protein degradation exhibits a remarkable variation between mammalian lineages. Additionally, the phosphosite profiles reveals phosphorylation co-evolution network independent of protein abundance.
Nature’s design of the osteochondral unit: microstructural differences between terrestrial and aquatic mammals
Authors: Mancini I.A.D. , Levato R. , Castilho M. , Chen M. , van Rijen M.H.P. , IJsseldijk L.L. , Kik M. , van Weeren P.R. , Malda J.
Published: June 2022

During evolution, animals have returned from land to water, adapting with morphological modifications to life in an aquatic environment. We compared the osteochondral units of the humeral head of marine and terrestrial mammals across species spanning a wide range of body weights, focusing on microstructural organization and biomechanical performance. Aquatic mammals feature cartilage with essentially random collagen fiber configuration, lacking the depth-dependent, arcade-like organization characteristic of terrestrial mammalian species. They have a less stiff articular cartilage at equilibrium with a significantly lower peak modulus, and at the osteochondral interface do not have a calcified cartilage layer, displaying only a thin, highly porous subchondral bone plate. This totally different constitution of the osteochondral unit in aquatic mammals reflects that accommodation of loading is the primordial function of the osteochondral unit. Recognizing the crucial importance of the microarchitecture-function relationship is pivotal for understanding articular biology and, hence, for the development of durable functional regenerative approaches for treatment of joint damage, which are thus far lacking.
SOX2dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating theFOSL2/IL6axis
Authors: Njouendou Abdel Jelil , Tiofack Arnol Auvaker Zebaza , Kenfack Rovaldo Nguims , Ananga Sidonie Noa , Dina Bell Esther H. M. , Simo Gustave , Hoheisel Jörg D. , Siveke Jens T. , Lueong Smiths S.
Published: June 2022

Background

Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and subsequent consequences on disease aggressiveness is less understood.

Methods

Multi-omic analyses of 27 (~ 5000 samples) entities from the TCGA, GEO and in-house data was performed to investigate the molecular determinant of tumor aggressiveness. Using molecular loss of function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness was addressed.

Results

The data revealed a significant association between somatic copy number alterations (sCNA) and tumor aggressiveness, with amplification of the transcription factorSOX2being the most important feature among novel and known aggressiveness-associated genes such asZIC5andMYEOV.

Mechanistically,SOX2regulates a group of aggressiveness-related genes including theAP1transcription factorFOSL2to sustain pro-inflammatory pathway such asIL6-JAK-STAT3, TNFAandIL17signaling pathways. Prolonged inflammation induces immunosuppression and further leads to activation of cytidine deamination and consequential DNA damage evidenced by enrichment in cytidine deamination mutational signatures in aggressive tumors.

The resulting DNA damage affects tumor suppressor genes such asTP53,which was the most mutated gene in aggressive tumors compared with less aggressive tumors (38% vs 14%), thereby releasing cell cycle control. This was exemplified in Glioblastoma multiform, whereTP53andIDH1mutations are predominant.IDH1mutations were almost only seen in younger patients (>45 years, > 90%) and may explain the previously reported favorable prognosis.

Conclusion

Taken together, our data demonstrate the implication ofSOX2in promoting DNA damage and genome instability by sustaining inflammation viaFOSL2/IL6,resulting in tumor aggressiveness.
Genetic exchange in Leishmania is facilitated by IgM natural antibodies
Authors: Serafim Tiago D. , Iniguez Eva , Barletta Ana Beatriz F. , Doehl Johannes S.P. , Short Mara , Lack Justin , Cecilio Pedro , Nair Vinod , Disotuar Maria , Wilson Timothy , Coutinho-Abreu Iliano V. , Oliveira Fabiano , Meneses Claudio , Barillas-Mury Carolina , Andersen John , Ribeiro José M.C. , Beverley Stephen M. , Kamhawi Shaden , G.Valenzuela Jesus
Published: June 2022

Host factors mediating Leishmania genetic exchange are not well defined. Here, we demonstrate that IgM antibodies, but not IgG or IgA, facilitate parasite genetic hybridization in vitro and in vivo. IgM induces the gradual and transient formation of a structured Leishmania clump that releases viable parasites in a process essential for L. major and L. tropica hybridization in vitro. Parasite hybrids and 3-nucleated parasites were observed inside this structure, named the Leishmania mating clump. IgM was also required for or significantly increased Leishmania hybrid formation in vivo. At minimum, we observed a 12-fold increase in the proportion of hybrids recovered from sand flies provided a second blood meal containing IgM compared to controls. Notably, genetic backcross events in sand flies were only observed in the presence of IgM, and were reproducibly recovered, reinforcing the relevance of IgM for Leishmania genetic exchange in vivo. The in vitro and in vivo Leishmania crosses reported here resulted in full genome hybrids with comparable recombination structures that arose by fusion of the two parental lines. Leishmania co-option of a host antibody to facilitate mating in the insect vector establishes a new paradigm of parasite-host-vector coevolution that promotes parasite diversity and fitness through genetic exchange.
Strain dependent differences in coordination of yeast signaling networks
Authors: Scott Taylor D. , Xu Ping , McClean Megan N.
Published: June 2022

The yeast mitogen activated protein kinase pathways serve as a model system for understanding how network interactions affect the way in which cells coordinate the response to multiple signals. We have quantitatively compared two yeast strain backgrounds YPH499 and Σ1278b (both of which have previously been used to study these pathways) and found several important differences in how they coordinate the interaction between the high osmolarity glycerol (HOG) and mating pathways. In the Σ1278b background, in response to simultaneous stimulus, mating pathway activation is dampened and delayed in a dose dependent manner. In the YPH499 background, only dampening is dose dependent. Further, leakage from the HOG pathway into the mating pathway (crosstalk) occurs during osmostress alone in the Σ1278b background only. The mitogen activated protein kinase Hog1p suppresses crosstalk late in an induction time course in both strains but does not affect the early crosstalk seen in the Σ1278b background. Finally, the kinase Rck2p plays a greater role suppressing late crosstalk in the Σ1278b background than in the YPH499 background. Our results demonstrate that comparisons between laboratory yeast strains provide an important resource for understanding how signaling network interactions are tuned by genetic variation without significant alteration to network structure.
Modulation of multiple gene clusters expression by a single PAS-LuxR transcriptional regulator
Authors: M. Vicente Cláudia , Payero Tamara D. , Rodríguez-García Antonio , Barreales Eva G. , de Pedro Antonio , Santos-Beneit Fernando , F. Aparicio Jesús
Published: June 2022

PAS-LuxR transcriptional regulators are highly conserved enzymes governing polyene macrolide antifungal biosynthesis. PteF is one of such regulators, situated in the polyene macrolide filipin gene cluster from Streptomyces avermitilis. Its mutation leads to a drastic filipin production decline, but also to a severe loss of oligomycin production, an ATP-synthase inhibitor of macrolide structure, and a delay in sporulation, thus it has been considered as a transcriptional activator. Transcriptomic analyses were carried out in S. avermitilis ΔpteF and its parental strain S. avermitilis NRRL 8165 as control. Both strains were grown in YEME medium without sucrose, and samples were taken in the exponential and stationary growth phases. 257 genes showed altered expression in the PteF-deleted mutant, most of them in the exponential phase of growth. Surprisingly, despite PteF being an activator of filipin biosynthesis, a majority of the genes affected upon mutation showed overexpression thus suggesting a negative modulation of those genes. Genes affected were related to various metabolic processes, including genetic information processing; DNA, energy, carbohydrate, and lipid metabolism; morphological differentiation; and transcriptional regulation; among others, but particularly to secondary metabolite biosynthesis. Notably, ten secondary metabolite gene clusters out of 38 encoded by the genome, some of them encoding cryptic compounds, showed altered expression profiles in the mutant, suggesting a regulatory role for PteF wider than expected. Transcriptomic results were validated by quantitative reverse transcription polymerase chain reaction. These findings provide important clues to understand the intertwined regulatory machinery that modulates antibiotic biosynthesis in Streptomyces.
Strand-resolved mutagenicity of DNA damage and repair
Authors: Anderson Craig J. , Talmane Lana , Luft Juliet , Nicholson Michael D. , Connelly John , Pich Oriol , Campbell Susan , Sundaram Vasavi , Connor Frances , Ginno Paul A. ,   Liver Cancer Evolution Consortium, López-Bigas Núria , Flicek Paul , Semple Colin A. , Odom Duncan T. , Aitken Sarah J. , Taylor Martin S.
Published: June 2022

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here, we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small DNA adducts, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky adducts5. We find that DNA damage tolerance is also common during transcription, where RNA-polymerases frequently bypass lesions without triggering repair. At multiple genomic scales, we show the pattern of DNA damage induced mutations is largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can corrupt the fidelity of nucleotide excision repair and actively drive oncogenic mutagenesis. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance, and repair of DNA damage, thereby shaping cancer genome evolution.
Robo-advisor based on unified theory of acceptance and use of technology
Authors: Yeh Hui-Chung , Yu Min-Chun , Liu Chih-Hsing , Huang Chia-I
Published: June 2022

Purpose

Following the advancement of financial technology (FinTech) in modern society to assist investment decisions, robo-advisers had become widely used in mean-variance analyses to allow investors to formulate efficiently diversified investment portfolios. However, the concept of robo-advisers is new, and few studies have addressed issues related to them. To help readers to better understand robo-advisor adoption by a wide range of potential customers, this study explores integrated models of the attitudes (ATT) and behavioural intentions (BI) of users towards robo-advisors.

Design/methodology/approach

A survey was used to gather data to determine how the unified theory of acceptance and use of technology (UTAUT) applies to robo-advisors. A total of 242 valid questionnaires were collected.

Findings

The results of our study show that performance expectations (PE), effort expectancy (EE), and social influences (SI) may have indirect influences on robo-advisor behavioural intention (BI) through attitudes. Furthermore, behavioural intention was also positively influenced by facilitating conditions (FC). Moreover, the investment to income ratio (IIR) moderated the relationship between the PE, EE, and SI influence on ATT. Additionally, experience is found to positively strengthen the relationship between EE and SI on ATT, and it moderated the relationship between FC and BI.

Originality/value

This research is expected to expand the use of UTAUT to tools in the field of financial investments and help financial sectors formulate suitable marketing strategies.
A study of loyalty programs in the Chinese market: the impacts of reward type, reward characteristic and product involvement
Authors: Zhang Jun , Wang Jingwen
Published: June 2022

Purpose

This study investigates how reward type (single vs. plural), reward characteristic (utilitarian vs. hedonic) and product involvement (high vs. low) affect the design of reward programs.

Design/methodology/approach

A 2 ✕ 2 ✕ 2 fractional factorial experimental design is constructed to explore the main factors influencing the effectiveness of reward programs on a sample of 436 Chinese customers.

Findings

The results indicate that reward type is an important determinant of customers' preference toward reward programs. Plural rewards are preferable to a single reward when the alternatives provide the same benefits, particularly in the low level of product involvement. In the high level of product involvement, reward characteristic has a significant effect on customers' preference. Hedonic rewards are more effective in building a program's value than utilitarian rewards. Moreover, reward characteristic interacts with reward type, positively impacting customers' preference toward reward programs.

Originality/value

This study suggests that managers should consider the effects of reward type, reward characteristic and product involvement to formulate attractive reward programs for sustainable business in China.
Battle between psychological ownership and consumer animosity to influence consumers' buying behavior: a moderated mediation model
Authors: Mishra Sita , Saxena Garima , Chatterjee Ravi
Published: June 2022

Purpose

This study aims to understand the effect of consumers' national identity (NI) on their willingness to buy (WTB) domestic (Indian) products vis-à-vis foreign (Chinese) products. Secondly, it explores the role of psychological ownership (PO) and consumers' animosity in explaining their WTB domestic products.

Design/methodology/approach

In this paper data were collected online from Indian consumers (N = 408) through the survey method, using a structured questionnaire. Data analysis was conducted using SPSS AMOS Version 24 and the PROCESS SPSS macro, using mediations and moderated mediation models.

Findings

This study establishes the positive effect of consumers' NI on their WTB domestic products over Chinese ones. With a long history of hostility between India and China in the backdrop, the authors find a significant mediating role of PO and consumer animosity (CA) in the relationship between NI and WTB . The results also demonstrate that while consumer ethnocentrism (CET) positively moderates the mediating path via PO at all levels from low to high, it moderates the path via CA only at the mean and high levels.

Originality/value

This study applies the Psychological Ownership Theory, Social Identity Theory (SIT) and the Attribution Theory to explore the interplay between consumers' NI, PO , CA and ethnocentrism in the Indian context. The study asserts the distinction between these constructs by analyzing the interaction and inter-relationships between these variables. Further, it provides a comprehensive understanding of Indian consumers' preference for domestic products over Chinese ones.