bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term safety profile of tirabrutinib: final results of a Japanese Phase I study in patients with relapsed or refractory B-cell malignancies
Authors: Munakata Wataru , Ando Kiyoshi , Yokoyama Masahiro , Fukuhara Noriko , Yamamoto Kazuhito , Fukuhara Suguru , Ohmachi Ken , Mishima Yuko , Ichikawa Satoshi , Ogiya Daisuke , Aoi Arata , Hatsumichi Masahiro , Tobinai Kensei
Published: December 2022

Tirabrutinib is a Bruton’s tyrosine kinase inhibitor for treating B-cell malignancies. We report the final results of a Phase I study of tirabrutinib in 17 Japanese patients with B-cell malignancies. Patients were administered tirabrutinib at a dose of 160 mg, 320 mg, or 480 mg once daily, or 300 mg twice daily (N = 3, 3, 4, and 7, respectively). Three patients continued tirabrutinib until study completion (November 30, 2020). Adverse events (AEs) occurred in all 17 patients, with Grade 3–4 AEs in 8 (47.1%), serious AEs in 7 (41.2%), drug-related AEs in 16 (94.1%), and Grade 3–4 drug-related AEs in 6 (35.3%). Drug-related AEs reported in 3 or more patients were rash, vomiting, neutropenia, arthralgia, and malaise. One additional serious AE (benign neoplasm of the lung, unrelated to tirabrutinib) occurred after the previous data cutoff (January 4, 2018). Tirabrutinib administration and response assessment were continued for over 4 years in 4 patients. The overall response rate was 76.5% (13/17 patients). The median (range) time to response and duration of response were 0.9 (0.9–5.9) months and 2.59 (0.08–5.45) years, respectively. These findings demonstrate the long-term safety and efficacy of tirabrutinib in Japanese patients with B-cell malignancies.

Clinical trial registration: JapicCTI-142682 (http://www.clinicaltrials.jp/).
A Systematic Review of Direct Outputs from the Cerebellum to the Brainstem and Diencephalon in Mammals
Authors: Novello Manuele , Bosman Laurens W. J. , De Zeeuw Chris I.
Published: December 2022

The cerebellum is involved in many motor, autonomic and cognitive functions, and new tasks that have a cerebellar contribution are discovered on a regular basis. Simultaneously, our insight into the functional compartmentalization of the cerebellum has markedly improved. Additionally, studies on cerebellar output pathways have seen a renaissance due to the development of viral tracing techniques. To create an overview of the current state of our understanding of cerebellar efferents, we undertook a systematic review of all studies on monosynaptic projections from the cerebellum to the brainstem and the diencephalon in mammals. This revealed that important projections from the cerebellum, to the motor nuclei, cerebral cortex, and basal ganglia, are predominantly di- or polysynaptic, rather than monosynaptic. Strikingly, most target areas receive cerebellar input from all three cerebellar nuclei, showing a convergence of cerebellar information at the output level. Overall, there appeared to be a large level of agreement between studies on different species as well as on the use of different types of neural tracers, making the emerging picture of the cerebellar output areas a solid one. Finally, we discuss how this cerebellar output network is affected by a range of diseases and syndromes, with also non-cerebellar diseases having impact on cerebellar output areas.
Influence of co-substrate existence, temperature, pH, and salt concentration on phenol removal, desalination, and power generation using microbial desalination cells
Authors: Safwat S. M. , Meshref M. N. A. , Salama M. , Elawwad A.
Published: December 2022

Microbial desalination cells (MDCs) exhibited an economical value with large promises as a useful desalination treatment solution. MDCs threefold applications to efficiently treat wastewater and to produce electricity and simultaneously accomplish desalination were investigated in this work. The study examined the influence of various performance parameters including co-substrate, temperature, pH, and salt concentrations on the response of three-chamber MDCs with respect to energy recovery and contaminant removal (Phenol). The system evaluation criteria encompassed chemical oxygen demand (COD), phenol removal efficiency, Coulombic efficiency, desalination efficiency, and other system parameters such as voltage generation and power density. The maximum COD and phenol removal efficiencies obtained at temperature = 37 °C, pH = 7, and salt concentration = 10,000 ppm, were 80% and 74%, respectively. The maximum Coulombic efficiency was 5.3% and was observed at temperature = 18 °C, pH = 7, and salt concentration = 10,000 ppm. The results show that the presence of a co-substrate improved power density; the maximum power density obtained was 52.9 mW/m2. The principal component analysis elucidated the impact of pH on COD and phenol removal rates. With our findings confirmed trends in the improvement of the voltage generation, COD and phenol removal efficiencies with the addition of a co-substrate, the temperature and pH increase.
Public Health Approach to Problems Related to Excessive and Addictive Use of the Internet and Digital Media
Authors: Chung Sulki , Lee Hae Kook
Published: December 2022

Purpose of Review

Advances in digital technology and media have provided convenience and advantages in all areas of our daily lives. However, there is a risk of excessive and addictive use, which increases the risk of addiction as a disease and other related mental and physical problems. This article reviews the public health approach to problems related to excessive and addictive use of the Internet and digital media.

Recent Findings

The public health model views addiction as the result of interactions among individuals, digital media, and the environment; therefore, interventions should aim to reduce risk factors and increase protective factors in these three areas. This includes developing and providing evidence-based services according to each individual’s problem type and severity. Regarding interventions for digital media and the environment, restricting accessibility and regulating content may be necessary. This calls for an integrative, comprehensive, and continuous intervention strategy, and to achieve such a framework, we need to establish an information system to monitor the magnitude and patterns of related problems.

This review suggests a surveillance system that provides a list of evidence-based policies from the public health perspective. Suggestions for an advanced international information, policy, and monitoring system are discussed.
A Feasibility Study to Minimize the Carbon Footprint of Cast Iron Production While Maintaining the Technical Requirements
Authors: Abdelshafy Ali , Franzen Daniel , Mohaupt Amelie , Schüssler Johannes , Bührig-Polaczek Andreas , Walther Grit
Published: December 2022

The industrial sector is responsible for significant amounts of CO2 emissions. Although research activities have already given their attention to major industries such as steel, small sectors such as metal casting have been overlooked. Therefore, there are evident knowledge gaps regarding the environmental impact of the foundry industry and the possibilities of decarbonizing the sector. Herein, this study focuses on the CO2 emissions associated with cast iron production and introduces an interdisciplinary framework in order to study the environmental impact, technical performance and production costs. The theoretical and experimental analyses illustrate the interconnections between the environmental, technical and economic aspects of cast iron production. The results emphasize the role of the smelting process and renewable energies in decreasing the carbon footprint. In terms of the input materials, the outcomes demonstrate that increasing the steel scrap content achieves considerable reductions in the CO2 emissions. An alloy composition with a steel scrap content of 25% leads to a minimum carbon footprint of 650 kg CO2 eq./ton. However, increasing the steel scrap content further results in higher carbon footprints due to the additional materials required to maintain the alloy composition. Moreover, a higher strength and lower ductility of the alloy were recorded due to higher amounts of carbide stabilizing elements. The study highlights the importance of adopting a holistic approach in order to define the optimal material combinations. Hence, the presented interdisciplinary approach can be applied by the foundries in order to achieving the technical, economic and ecological goals of the sector.

Graphical Abstract
Therapeutic dilemmas with benzodiazepines and Z-drugs: insomnia and anxiety disorders versus increased fall risk: a clinical review
Authors: Capiau Andreas , Huys Liesbeth , van Poelgeest Eveline , van der Velde Nathalie , Petrovic Mirko , Somers Annemie ,   the EuGMS Task, Finish Group on FRIDs
Published: December 2022

Purpose

The aim of this clinical review was to summarise the existing knowledge on fall risk associated with benzodiazepines (BZDs) and Z-drugs in older people with focus on appropriate prescribing, including deprescribing.

Methods

We conducted a literature search in June 2021 in PubMed and Embase with citation and reference checking. Personal reference libraries and international websites were also used. Keywords for the searches included “benzodiazepines”, “Z-drugs”, “falls”, “deprescribing”, “fall-risk-increasing-drugs”, “inappropriate prescribing”, “older people” and matching synonyms. We discuss use of BZDs and Z-drugs, potential fall-related adverse reactions, alternatives for and deprescribing of BZDs and Z-drugs in older persons.

Results

BZDs and Z-drugs differ in fall-related adverse effect profile. They contribute to fall risk through orthostatic hypotension, dizziness and/or imbalance, sedation, muscular weakness, ataxia, etc. Fall incidents contribute significantly to mortality and morbidity. Therefore, there is a need for appropriate prescribing and use of BZDs and Z-drugs in older people. In practice, this means pertaining to a strict indication, strongly consider to non-pharmacological alternatives, limit use to the lowest dose and the shortest duration possible. Judicious deprescribing should be considered and encouraged as well. Practical resources, tools and algorithms are available to guide and assist clinicians in deprescribing BZDs and Z-drugs.

Conclusions

Prescribing BZDs and Z-drugs should be done in a well-considered way in fall-prone older people. A good overview and insight in the fall-related adverse effects of these drugs, as well as the availability of different strategies to increase the appropriate use, including deprescribing initiatives, can assist clinicians in clinical decision-making.
Dynamical Stability of a 3-DOF Auto-Parametric Vibrating System
Authors: Amer T. S. , Moatimid Galal M. , Amer W. S.
Published: December 2022

Purpose

This article concentrates on the oscillating movement of an auto-parametric dynamical system comprising of a damped Duffing oscillator and an associated simple pendulum in addition to a rigid body as main and secondary systems, respectively.

Methods

According to the system generalized coordinates, the controlling equations of motion are derived utilizing Lagrange's approach. These equations are solved applying the perturbation methodology of multiple scales up to higher orders of approximation to achieve further precise unique outcomes. The fourth-order Runge–Kutta algorithm is employed to obtain numerical outcomes of the governing system.

Results

The comparison between both solutions demonstrates their high level of consistency and highlights the great accuracy of the adopted analytical strategy. Despite the conventional nature of the applied methodology, the obtained results for the studied dynamical system are considered new.

Conclusions

In light of the solvability criteria, all resonance scenarios are classified, in which two of the fundamental exterior resonances are examined simultaneously with one of the interior resonances. Therefore, the modulation equations are achieved. The conditions of Routh–Hurwitz are employed to inspect the stability/instability regions and to analyze them in accordance with the solutions in the steady-state case. For various factors of the examined structure, the temporary history solutions, the curves of resonance in terms of the adjusted amplitudes and phases, and the stability zones are graphically presented and discussed.

Applications

The results of the current study will be of interest to wide range experts in the fields of mechanical and aerospace technology, as well as those working to reduce rotors dynamical vibrations and attenuate vibration caused by swinging structures.
Pyrolytic synthesis of graphene-encapsulated zero-valent iron nanoparticles supported on biochar for heavy metal removal
Authors: Karunaratne Tharindu N. , Nayanathara R. M. Oshani , Navarathna Chanaka M. , Rodrigo Prashan M. , Thirumalai Rooban V. K. G. , Pittman Charles U. , Kim Yunsang , Mlsna Todd , Zhang Jilei , Zhang Xuefeng
Published: December 2022

Biochar (BC)-supported graphene-encapsulated zero-valent iron nanoparticle composites (BC-G@Fe0) are promising engineering nanocomposites that can be used to scavenge heavy metal from wastewater. However, the production of BC-G@Fe0 through carbothermal reduction using biomass as a carbon source remains challenging because of biomass pyrolysis complications. Here, we examined two carbothermal reduction routes for preparing BC-G@Fe0 using bamboo as the carbon source. The first route impregnated Fe ions (Fe2+/3+) into unpyrolyzed bamboo particles initially, followed by carbonization at 600–1000 °C. This process produced BC-G@Fe0 dominated by iron carbide (Fe3C), which led to low heavy metal removal efficiency (i.e., Cu2+ capacity of < 0.3 mmol g−1). In the second route, bamboo particles were pyrolyzed (600 °C) to biochar first, followed by impregnating this biochar with Fe ions, and then  carbonized at 600–1000 °C. This route produces zero-valent iron nanoparticles, which resulted in high heavy metal removal capacities (i.e., 0.30, 1.58, and 1.91 mmol g−1 for Pb2+, Cu2+, and Ag+, respectively). The effects of carbonization temperature (600–1000 °C), iron source (i.e., iron nitrates, iron sulfate, ferrous chloride, and ferric chloride), and iron loading (5–40%) on the morphology, structure, and heavy metal ion aqueous uptake performance of BC-G@Fe0 were also investigated. This study revealed the formation mechanisms of BC-G@Fe0 through biomass carbothermal reduction, which could guide the application-oriented design of multifunctional iron-BC composites for water remediation.

Graphical Abstract
Beyond digital shadows: A Digital Twin for monitoring earthwork operation in large infrastructure projects
Authors: Rogage Kay , Mahamedi Elham , Brilakis Ioannis , Kassem Mohamad
Published: December 2022

Current research on Digital Twin (DT) is largely focused on the performance of built assets in their operational phases as well as on urban environment. However, Digital Twin has not been given enough attention to construction phases, for which this paper proposes a Digital Twin framework for the construction phase, develops a DT prototype and tests it for the use case of measuring the productivity and monitoring of earthwork operation. The DT framework and its prototype are underpinned by the principles of versatility, scalability, usability and automation to enable the DT to fulfil the requirements of large-sized earthwork projects and the dynamic nature of their operation. Cloud computing and dashboard visualisation were deployed to enable automated and repeatable data pipelines and data analytics at scale and to provide insights in near-real time. The testing of the DT prototype in a motorway project in the Northeast of England successfully demonstrated its ability to produce key insights by using the following approaches: (i) To predict equipment utilisation ratios and productivities; (ii) To detect the percentage of time spent on different tasks (i.e., loading, hauling, dumping, returning or idling), the distance travelled by equipment over time and the speed distribution; and (iii) To visualise certain earthwork operations.
Impact of LMS-mediated readiness assurance testing on performance in pharmacy calculations
Authors: Bell Edward C.
Published: December 2022

Objective

Readiness assurance testing has enjoyed increased use as a tool for the delivery and reinforcement of pharmacy concepts. This study was conducted to determine the influence of the readiness assurance test (RAT) on major examination outcomes in pharmacy calculations.

Methods

The Blackboard Learning Management System was identified as an efficient platform for RAT implementation. The outcomes of three consecutive offerings of pharmacy calculations were compared. Cohorts 1 and 2 were exposed to recitation and standard assessments in lecture and laboratory sessions. Cohort 3 was additionally administered weekly individual (IRAT) and team (TRAT) readiness assurance tests for concept areas. All cohorts were exposed to a common comprehensive final exam.

Results

Significant differences were observed in major lecture exam scores among cohorts. Cohort 3’s mean final exam score was significantly greater than that of Cohort 1, which received the most conventional method of subject delivery. Students feedback was generally positive regarding use of RAT.

Conclusions

Use of RAT assessment was positively associated with final exam score outcomes in pharmacy calculations, including a positive shift in final exam score distribution in Cohort 3. Use of RAT promotes increased student exposure to conceptual material and instruction in pharmacy calculations.
“Maduro Board” of the Central Bank of Venez. v. “Guaidó Board” of the Central Bank of Venez. (UKSC)
Authors: Waseem Mubarak
Published: December 2022

On December 20, 2021, the U.K. Supreme Court (the Supreme Court) delivered a unanimous decision in the highly publicized Maduro Board v. Guaidó Board litigation. The decision partially overturned that of the England and Wales Court of Appeal (Civil Division) and is an important decision on both issues raised in the case: the recognition of governments and the “Act of State” doctrine. The first of those is examined in more detail in this note.
Settlements and plantations are sites of human–tiger interactions in Riau, Indonesia
Authors: Neo Wivian Hui Yuan , Lubis Muhammad I. , Lee Janice Ser Huay
Published: December 2022

Interactions between the Sumatran tiger Panthera tigris sumatrae and people (e.g. injury or loss of lives of people and tigers, evacuation of injured tigers, loss of livestock and sightings of tigers) can negatively affect the conservation of the subspecies. Land-use change in Sumatra has reduced habitat for tigers, forcing them into human-dominated landscapes and increasing the probability of interactions with people. Although the number of such interactions is high in South-east Asia, few studies have been published since 2000 and for Sumatra there is a lack of information regarding where these events occur. We collated data on human–tiger interactions in the province of Riau using web scraping of news sources published during 2010–2020, and mapped these data to village boundaries. We recorded 101 interaction events, with a total of 107 interactions, which we categorized into seven types (people injured or killed, livestock killed, sightings of tigers, tigers killed, injured or evacuated), in 78 villages. Most interactions with reported locations occurred close to settlements (35%), followed by in plantations (26%) and smallholdings (25%), with forests and forest edges comprising 14% of such events. Interactions were dominated by sightings of tigers, but severe interaction types (human death or injury and attacks on livestock) were also reported. The mean annual number of human–tiger interactions was 4.6 during 2011–2017 and 21.3 during 2017–2020. We highlight the need for mitigation and prevention, such as establishing conflict mitigation teams, improving animal husbandry practices, and providing training and education on human–tiger interactions focused in plantations and settlements.
A zero density estimate and fractional imaginary parts of zeros for L-functions
Authors: BECKWITH OLIVIA , LIU DI , THORNER JESSE , ZAHARESCU ALEXANDRU
Published: December 2022

We prove an analogue of Selberg’s zero density estimate for
$\zeta(s)$
that holds for any
$\textrm{GL}_2$
L-function. We use this estimate to study the distribution of the vector of fractional parts of
$\gamma\boldsymbol{\alpha}$
, where
$\boldsymbol{\alpha}\in\mathbb{R}^n$
is fixed and
$\gamma$
varies over the imaginary parts of the nontrivial zeros of a
$\textrm{GL}_2$
L-function.
Tidal Motion Enhancement on Spitsbergen Bank, Barents Sea
Authors: Kowalik Z. , Marchenko A.
Published: December 2022

The higher resolution numerical model investigates the semidiurnal and diurnal tides over the shallow Spitsbergen Bank. The tidal wave is trapped around Bear Island, Hopen Island, and Central Hill at the Bank in the semidiurnal range of oscillations. Semidiurnal waves around Bear and Hopen Islands generate a trapped dipole in the sea level distribution revealed by sea level maximum and minimum traveling on the opposite sides of the island. The dipole induces significant sea‐level differences and amplified velocity around the island perimeter. The role of the tidal currents over the Bank is connected through the mixing and transport to the generation of frontal regions. Tidal mixing directly relates to the local ice formation on Spitsbergen Bank as these areas coincide with the regions of strong tidal currents. The trapping of the semidiurnal tides leads to residual (permanent) circulation of up to 15 cm s−1. As this motion interconnects different bathymetric regions of the Bank, it influences the exchange of properties between these regions. The strength of residual currents shows that the large‐scale slow thermohaline motion cannot be complete without residual tidal motion. The diurnal tides show a different distribution since higher spatial resolution reveals sea‐level variability in many locations. These short‐wavelength shelf waves occur at seamounts, submarine peninsulas, and bays. We investigate in detail the wave dynamics in proximity to Central Hill and Hopen Island. We use observations of the buoys deployed on the ice floes to compare the drift velocity to the computed tidal velocity.
Influence of Target Properties on Wall Slumping in Lunar Impact Craters Within the Simple‐To‐Complex Transition
Authors: Chandnani M. , Herrick R. R.
Published: December 2022

The 15–20 km crater diameter range on the Moon spans simple to transitional to complex crater morphologies. Simple craters in this range are only in the highlands. Transitional craters that contain localized slumps are scattered across the lunar surface. Most craters with localized slumps in the highlands superpose pre‐impact topography with obvious slope breaks. We interpret this as a condition favorable for post‐excavation internal slumping. However, some of these craters formed on terrains with topographic variation like the settings of simple craters: flat or gradually sloping surface, or degraded structures of older craters such as rims and terraces. To resolve the conundrum of two morphologies on one terrain type, we performed investigations of the local geology and topography of the inferred pre‐impact terrains. We assessed if the localized slumping in the craters happened during or well after crater formation, looked for spatial variations in the strength of the highlands crust, detected topographic breaks (through elevation data) that were unnoticeable in the optical data, and examined rim circularity. Our findings corroborate the influence of pre‐existing slopes on mass wasting along crater walls. Most of the craters with localized slumps have walls superposing topographic breaks that slope toward the crater interior. These walls are located near the uphill sector of the rims which initiated localized slumping. Most simple craters were found to have formed on surfaces with topographic breaks/slopes that face away from the adjoining crater walls, so that any immediate mass wasting would likely be outside the crater cavity.
Golgi apparatus, endoplasmic reticulum and mitochondrial function implicated in Alzheimer’s disease through polygenic risk and RNA sequencing
Authors: Crawford Karen , Leonenko Ganna , Baker Emily , Grozeva Detelina , Lan-Leung Benoit , Holmans Peter , Williams Julie , O’Donovan Michael C. , Escott-Price Valentina , Ivanov Dobril K.
Published: December 2022

Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and they have been shown to predict lifetime risk of Alzheimer’s disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. To this end, we performed a differential gene-expression and associated disrupted biological pathway analyses of AD PRS vs. case/controls in human brain-derived cohort sample (cerebellum/temporal cortex; MayoRNAseq). The results highlighted already implicated mechanisms: immune and stress response, lipids, fatty acids and cholesterol metabolisms, endosome and cellular/neuronal death, being disrupted biological pathways in both case/controls and PRS, as well as previously less well characterised processes such as cellular structures, mitochondrial respiration and secretion. Despite heterogeneity in terms of differentially expressed genes in case/controls vs. PRS, there was a consensus of commonly disrupted biological mechanisms. Glia and microglia-related terms were also significantly disrupted, albeit not being the top disrupted Gene Ontology terms. GWAS implicated genes were significantly and in their majority, up-regulated in response to different PRS among the temporal cortex samples, suggesting potential common regulatory mechanisms. Tissue specificity in terms of disrupted biological pathways in temporal cortex vs. cerebellum was observed in relation to PRS, but limited tissue specificity when the datasets were analysed as case/controls. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.
Structural racism is associated with adverse postnatal outcomes among Black preterm infants
Authors: Karvonen Kayla L. , McKenzie-Sampson Safyer , Baer Rebecca J. , Jelliffe-Pawlowski Laura , Rogers Elizabeth E. , Pantell Matthew S. , Chambers Brittany D.
Published: December 2022

Background

Structural racism contributes to racial disparities in adverse perinatal outcomes. We sought to determine if structural racism is associated with adverse outcomes among Black preterm infants postnatally.

Methods

Observational cohort study of 13,321 Black birthing people who delivered preterm (gestational age 22–36 weeks) in California in 2011–2017 using a statewide birth cohort database and the American Community Survey. Racial and income segregation was quantified by the Index of Concentration at the Extremes (ICE) scores. Multivariable generalized estimating equations regression models were fit to test the association between ICE scores and adverse postnatal outcomes: frequent acute care visits, readmissions, and pre- and post-discharge death, adjusting for infant and birthing person characteristics and social factors.

Results

Black birthing people who delivered preterm in the least privileged ICE tertiles were more likely to have infants who experienced frequent acute care visits (crude risk ratio [cRR] 1.3 95% CI 1.2–1.4), readmissions (cRR 1.1 95% CI 1.0–1.2), and post-discharge death (cRR 1.9 95% CI 1.2–3.1) in their first year compared to those in the privileged tertile. Results did not differ significantly after adjusting for infant or birthing person characteristics.

Conclusion

Structural racism contributes to adverse outcomes for Black preterm infants after hospital discharge.

Impact statement

Structural racism, measured by racial and income segregation, was associated with adverse postnatal outcomes among Black preterm infants including frequent acute care visits, rehospitalizations, and death after hospital discharge.

This study extends our understanding of the impact of structural racism on the health of Black preterm infants beyond the perinatal period and provides reinforcement to the concept of structural racism contributing to racial disparities in poor postnatal outcomes for preterm infants.

Identifying structural racism as a primary cause of racial disparities in the postnatal period is necessary to prioritize and implement appropriate structural interventions to improve outcomes.
Diagnostic potential of the amniotic fluid cells transcriptome in deciphering mendelian disease: a proof-of-concept
Authors: Lee Mianne , Kwong Anna K. Y. , Chui Martin M. C. , Chau Jeffrey F. T. , Mak Christopher C. Y. , Au Sandy L. K. , Lo Hei Man , Chan Kelvin Y. K. , Yépez Vicente A. , Gagneur Julien , Kan Anita S. Y. , Chung Brian H. Y.
Published: December 2022

RNA sequencing (RNA-seq) is emerging in genetic diagnoses as it provides functional support for the interpretation of variants of uncertain significance. However, the use of amniotic fluid (AF) cells for RNA-seq has not yet been explored. Here, we examined the expression of clinically relevant genes in AF cells (n = 48) compared with whole blood and fibroblasts. The number of well-expressed genes in AF cells was comparable to that in fibroblasts and much higher than that in blood across different disease categories. We found AF cells RNA-seq feasible and beneficial in prenatal diagnosis (n = 4) as transcriptomic data elucidated the molecular consequence leading to the pathogenicity upgrade of variants in CHD7 and COL1A2 and revising the in silico prediction of a variant in MYRF. AF cells RNA-seq could become a reasonable choice for postnatal patients with advantages over fibroblasts and blood as it prevents invasive procedures.
Regulation of stem cell fate by HSPGs: implication in hair follicle cycling
Authors: Colin-Pierre Charlie , El Baraka Oussama , Danoux Louis , Bardey Vincent , André Valérie , Ramont Laurent , Brézillon Stéphane
Published: December 2022

Heparan sulfate proteoglycans (HSPGs) are part of proteoglycan family. They are composed of heparan sulfate (HS)-type glycosaminoglycan (GAG) chains covalently linked to a core protein. By interacting with growth factors and/or receptors, they regulate numerous pathways including Wnt, hedgehog (Hh), bone morphogenic protein (BMP) and fibroblast growth factor (FGF) pathways. They act as inhibitor or activator of these pathways to modulate embryonic and adult stem cell fate during organ morphogenesis, regeneration and homeostasis. This review summarizes the knowledge on HSPG structure and classification and explores several signaling pathways regulated by HSPGs in stem cell fate. A specific focus on hair follicle stem cell fate and the possibility to target HSPGs in order to tackle hair loss are discussed in more dermatological and cosmeceutical perspectives.
Mechanics of the cellular microenvironment as probed by cells in vivo during zebrafish presomitic mesoderm differentiation
Authors: Mongera Alessandro , Pochitaloff Marie , Gustafson Hannah J. , Stooke-Vaughan Georgina A. , Rowghanian Payam , Kim Sangwoo , Campàs Otger
Published: December 2022

Tissue morphogenesis, homoeostasis and repair require cells to constantly monitor their three-dimensional microenvironment and adapt their behaviours in response to local biochemical and mechanical cues. Yet the mechanical parameters of the cellular microenvironment probed by cells in vivo remain unclear. Here, we report the mechanics of the cellular microenvironment that cells probe in vivo and in situ during zebrafish presomitic mesoderm differentiation. By quantifying both endogenous cell-generated strains and tissue mechanics, we show that individual cells probe the stiffness associated with deformations of the supracellular, foam-like tissue architecture. Stress relaxation leads to a perceived microenvironment stiffness that decreases over time, with cells probing the softest regime. We find that most mechanical parameters, including those probed by cells, vary along the anteroposterior axis as mesodermal progenitors differentiate. These findings expand our understanding of in vivo mechanosensation and might aid the design of advanced scaffolds for tissue engineering applications.
An accurate deep learning model for wheezing in children using real world data
Authors: Kim Beom Joon , Kim Baek Seung , Mun Jeong Hyeon , Lim Changwon , Kim Kyunghoon
Published: December 2022

Auscultation is an important diagnostic method for lung diseases. However, it is a subjective modality and requires a high degree of expertise. To overcome this constraint, artificial intelligence models are being developed. However, these models require performance improvements and do not reflect the actual clinical situation. We aimed to develop an improved deep-learning model learning to detect wheezing in children, based on data from real clinical practice. In this prospective study, pediatric pulmonologists recorded and verified respiratory sounds in 76 pediatric patients who visited a university hospital in South Korea. In addition, structured data, such as sex, age, and auscultation location, were collected. Using our dataset, we implemented an optimal model by transforming it based on the convolutional neural network model. Finally, we proposed a model using a 34-layer residual network with the convolutional block attention module for audio data and multilayer perceptron layers for tabular data. The proposed model had an accuracy of 91.2%, area under the curve of 89.1%, precision of 94.4%, recall of 81%, and F1-score of 87.2%. The deep-learning model proposed had a high accuracy for detecting wheeze sounds. This high-performance model will be helpful for the accurate diagnosis of respiratory diseases in actual clinical practice.
Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol
Authors: Mieremet Arnout , van der Stoel Miesje , Li Siyu , Coskun Evrim , van Krimpen Tsveta , Huveneers Stephan , de Waard Vivian
Published: December 2022

Patients with Marfan syndrome (MFS) develop thoracic aortic aneurysms as the aorta presents excessive elastin breaks, fibrosis, and vascular smooth muscle cell (vSMC) death due to mutations in the FBN1 gene. Despite elaborate vSMC to aortic endothelial cell (EC) signaling, the contribution of ECs to the development of aortic pathology remains largely unresolved. The aim of this study is to investigate the EC properties in Fbn1C1041G/+ MFS mice. Using en face immunofluorescence confocal microscopy, we showed that EC alignment with blood flow was reduced, EC roundness was increased, individual EC surface area was larger, and EC junctional linearity was decreased in aortae of Fbn1C1041G/+ MFS mice. This modified EC phenotype was most prominent in the ascending aorta and occurred before aortic dilatation. To reverse EC morphology, we performed treatment with resveratrol. This restored EC blood flow alignment, junctional linearity, phospho-eNOS expression, and improved the structural integrity of the internal elastic lamina of Fbn1C1041G/+ mice. In conclusion, these experiments identify the involvement of ECs and underlying internal elastic lamina in MFS aortic pathology, which could act as potential target for future MFS pharmacotherapies.
Multi-omics network model reveals key genes associated with p-coumaric acid stress response in an industrial yeast strain
Authors: Ciamponi F. E. , Procópio D. P. , Murad N. F. , Franco T. T. , Basso T. O. , Brandão M. M.
Published: December 2022

The production of ethanol from lignocellulosic sources presents increasingly difficult issues for the global biofuel scenario, leading to increased production costs of current second-generation (2G) ethanol when compared to first-generation (1G) plants. Among the setbacks encountered in industrial processes, the presence of chemical inhibitors from pre-treatment processes severely hinders the potential of yeasts in producing ethanol at peak efficiency. However, some industrial yeast strains have, either naturally or artificially, higher tolerance levels to these compounds. Such is the case ofS. cerevisiae SA-1, a Brazilian fuel ethanol industrial strain that has shown high resistance to inhibitors produced by the pre-treatment of cellulosic complexes. Our study focuses on the characterization of the transcriptomic and physiological impact of an inhibitor of this type,p-coumaric acid (pCA), on this strain under chemostat cultivation via RNAseq and quantitative physiological data. It was found that strain SA-1 tend to increase ethanol yield and production rate while decreasing biomass yield when exposed to pCA, in contrast to pCA-susceptible strains, which tend to decrease their ethanol yield and fermentation efficiency when exposed to this substance. This suggests increased metabolic activity linked to mitochondrial and peroxisomal processes. The transcriptomic analysis also revealed a plethora of differentially expressed genes located in co-expressed clusters that are associated with changes in biological pathways linked to biosynthetic and energetical processes. Furthermore, it was also identified 20 genes that act as interaction hubs for these clusters, while also having association with altered pathways and changes in metabolic outputs, potentially leading to the discovery of novel targets for metabolic engineering toward a more robust industrial yeast strain.
Variation between glaucous and non-glaucous near-isogenic lines of rye (Secale cereale L.) under drought stress
Authors: Laskoś Kamila , Myśków Beata , Dziurka Michał , Warchoł Marzena , Dziurka Kinga , Juzoń Katarzyna , Czyczyło-Mysza Ilona M.
Published: December 2022

Glaucous (811, L35, and RXL10) and non-glaucous (811bw, L35bw, and RXL10bw) near-isogenic lines (NILs) of rye (Secale cereale L.) forming three pairs of inbred lines were the subject of the research. The research aimed to study the relationship between wax cover attributes and the physio-biochemical drought reactions and yield of rye NILs and to uncover the differences in drought resistance levels of these lines. The greatest differences between glaucous and non-glaucous NILs were observed in the RXL10/RXL10bw pair. Of particular note were the stable grain number and the thousand grain weight of the non-glaucous line RXL10bw under drought and the accompanying reactions, such as an approximately 60% increase in MDA and a two-fold increase in wax amount, both of which were significantly higher than in the glaucous line RXL10 and in other NILs. The surprisingly high level of MDA in the RXL10bw line requires further analysis. Moreover, additional wax crystal aggregates were found under drought conditions on the abaxial leaf surface of the glaucous lines 811 and RXL10. The use of rye NILs indicated that line-specific drought resistance could be associated with wax biosynthetic pathways involved in physiological and biochemical responses important for increased drought resistance.
Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy
Authors: Margara Francesca , Psaras Yiangos , Wang Zhinuo Jenny , Schmid Manuel , Doste Ruben , Garfinkel Amanda C. , Repetti Giuliana G. , Seidman Jonathan G. , Seidman Christine E. , Rodriguez Blanca , Toepfer Christopher N. , Bueno-Orovio Alfonso
Published: December 2022

Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+,TNNI3R21C/+) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7R403Q/+variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7R403Q/+phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2R92Q/+and TNNI3R21C/+display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2R92Q/+and TNNI3R21C/+hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design.
Evaluation of congenital and acquired heart diseases in a Spanish cohort of adults with Down syndrome
Authors: Rabes Laura , Adán-Lirola Laura , González-Molina María del Pilar , Galván-Román José María , Moldenhauer Fernando , Roy-Vallejo Emilia , Real de Asúa Diego
Published: December 2022

To describe congenital and acquired heart diseases in a Spanish cohort of adults with Down syndrome (DS), which could inform potential health recommendations for this population. Cross-sectional, observational study of adults with DS evaluated consecutively at a tertiary care, outpatient center between January 1 and December 31, 2019. The study population comprised 937 patients (51.8% men; median [IQR] age, 42 [18] years). An echocardiogram was available in the clinical chart of 420 patients (44.8%). The diagnosis of any form of heart disease was confirmed in 211 patients (22.5%): 101 (10.8%) had congenital heart defects, 80 (8.5%) simultaneous congenital and valvular heart diseases, and 30 (3.2%) isolated valvular heart disease. 111 patients (52.6% of those with congenital or valvular heart disease) had received corrective cardiac surgery. A total of 65 individuals were receiving medical management alone (30.8%), while 35 did not require any treatment because their cardiac disease was mild (16.6%). We found a high overall prevalence of heart disease in patients with DS, higher than previously reported for the pediatric population. Management of cardiovascular disease in adults with DS differs from that of the general population and should include universal echocardiography-based screening.
In situ transduction of cells in human corneal limbus using adeno-associated viruses: an ex vivo study
Authors: Son Hyeck-Soo , Jun Albert S. , Foster James W. , Wang Wei , Daoud Yassine , Auffarth Gerd U. , Roy Madhuparna
Published: December 2022

This study aimed to evaluate the efficacy of in situ adeno-associated virus (AAV)-mediated gene delivery into the human corneal limbal region via targeted sub-limbal injection technique. Human cadaveric corneal tissues were fixed on an artificial anterior chamber. Feasibility of sub-limbal injection technique was tested using trypan blue and black India ink. An enhanced green fluorescent protein (eGFP) encoding AAV DJ was injected into sub-limbal region. After AAV injection, corneal tissues were incubated in air-lift culture and prepared for immunohistochemical analysis. Cell survivial and expression of eGFP, stem cell markers (p63α and cytokeratin 19 (KRT19)), and differentiation marker cytokeratin 3 (KRT3) were evaluated using confocal microscopy. Both trypan blue and black India ink stained and were retained sub-limbally establishing specificity of the injection technique. Immunohistochemical analysis of corneas injected with AAV DJ-eGFP indicated that AAV-transduced cells in the limbal region co-express eGFP, p63α, and KRT19 and that these transduced cells were capable of differentiating to KRT3 postitive corneal epithelial cells. Our sub-limbal injection technique can target cells in the human limbus in a reproducible and efficient manner. Thus, we demonstrate that in situ injection of corneal limbus may provide a feasible mode of genetic therapy for corneal disorders with an epithelial etiology.
Bottom-hole pressure drawdown management of fractured horizontal wells in shale gas reservoirs using a semi-analytical model
Authors: Xu Yingying , Liu Xiangui , Hu Zhiming , Duan Xianggang , Chang Jin
Published: December 2022

Due to strong stress sensitivity resulted from unconventional tight formationsit is of practical interest to formulate a reasonable pressure drawdown plan to improve gas extraction recovery. The impact of water-shale interactions on the reservoir permeability was previously ignored in the managed pressure drawdown optimization. The controlled-pressure production dynamic analysis was mostly conducted using numerical simulation, lack of rigorous theoretical support. Hence in this paper, a theoretical production prediction model was proposed and verified with HIS RTA 2015by incorporating multiple pressure drawdown mechanisms and various non-linear gas flow process. The on-site production effects dominated by two different pressure drop methods was further compared, indicating that compared to depressurization production, the production reversion can occur in the controlled pressure production process and the EUR of single well can be increased by about 30% under the control of managed pressure drawdown approach. Finally, the pressure drawdown optimization strategy was carried out on the field test from the both production effect and economic benefits, which demonstrated that the best economic solution can generally be obtained in the early stage of production. The research results can be closely linked to the on-site production practice of shale gas wells, providing insights into designing optimized production strategy scheme.
Development of a simple multiple mutation detection system using seed-coat flavonoid pigments in irradiated Arabidopsis M1 plants
Authors: Kitamura Satoshi , Hirata Shoya , Satoh Katsuya , Inamura Rie , Narumi Issay , Oono Yutaka
Published: December 2022

Ionizing radiation induces genetic variations in plants, which makes it useful for plant breeding. A theory that the induced mutations occur randomly in the genome has long been accepted, but is now controversial. Nevertheless, a comparative analysis of the mutations at multiple loci has not been conducted using irradiated M1 genomes that contain all types of mutations. In this study, we identified Arabidopsis mutants (pab2 and pab3) in a mutagenized population of an anthocyanin-positive seed mutant (ban). Both pab2 and pab3 were revealed to be double mutants (tt4 ban and tt8 ban, respectively) that produced similar anthocyanin-less immature seeds, but differentially colored mature seeds. These features enabled the seed color-based detection of de novo M1 mutations in TT4 or TT8 following the irradiation of double heterozygous plants (TT4/tt4 TT8/tt8 ban/ban). Most of the irradiated double heterozygous plants produced anthocyanin-positive immature seeds, but 19 plants produced anthocyanin-less immature seeds. Of these 19 mutants, 2 and 17 exhibited tt4- and tt8-type mature seed coloration, respectively. The molecular analysis of the seed coat DNA from randomly selected anthocyanin-less seeds detected mutations at the locus predicted on the basis of the phenotype. Thus, the simple system developed in this study can reliably detect radiation-induced mutations at multiple loci in irradiated Arabidopsis M1 plants.