bluuebunny/crossref_metadata_2025 huggingface dataset:
Telehealth in outpatient delivery of palliative care: A qualitative study of patient and physician views
Authors: Pasanen Leeanne , Le Gautier Roslyn , Wong Aaron , Wawryk Olivia , Collins Anna , Schwetlik Stephanie , Philip Jennifer
Published: July 2022

Objectives

The COVID-19 pandemic has widened the funded use of telehealth in Australia to support telehealth delivery to all patients in any setting. Increasing the use and experience of telehealth brings to light unique insights into the advantages and challenges of this new model of healthcare delivery This study aimed to qualitatively explore the experiences of both palliative care physicians and patients setting, including their views on its future role in healthcare.

Methods

This qualitative study was conducted across three metropolitan tertiary palliative care centers in Victoria, Australia between November 2020 and March 2021. Purposive sampling identified 23 participants (12 physicians and 11 patients). Semi-structured interviews focused on the last telehealth consultation, thoughts and impressions of telehealth, and the possibility of telehealth remaining in palliative care. A thematic approach was adopted to code and analyze the data.

Results

Telehealth transformed the ways physicians and patients in this study perceived and engaged with outpatient palliative care across the entire continuum of care. Four key themes were identified: (1) access to care; (2) delivery of care; (3) engagement with care; and (4) the future.

Significance of results

This study provides novel data bringing together the perspective of patients and physicians, which confirms the utility of telehealth in palliative care. Its convenience enables more frequent review, enables reviews to occur in response to lower levels of concern, and adds toward enhancing the continuity of care across and between settings. Moving forward, support seemed strongest for a hybrid model of telehealth and face-to-face consultations guided by key parameters relating to the level of anticipated complexity.
Co-Inheritance of Variation in All-Cause Mortality and Biochemical Risk Factors
Authors: Whitfield John B. , Colodro-Conde Lucía , Zhu Gu , Timmers Paul R. H. J. , Joshi Peter K. , Montgomery Grant W. , Martin Nicholas G
Published: July 2022

Biomarkers may be useful endophenotypes for genetic studies if they share genetic sources of variation with the outcome, for example, with all-cause mortality. Australian adult study participants who had reported their parental survival information were included in the study: 14,169 participants had polygenic risk scores (PRS) from genotyping and up to 13,365 had biomarker results. We assessed associations between participants’ biomarker results and parental survival, and between biomarker results and eight parental survival PRS at varying p-value cut-offs. Survival in parents was associated with participants’ serum bilirubin, C-reactive protein, HDL cholesterol, triglycerides and uric acid, and with LDL cholesterol for participants’ fathers but not for their mothers. PRS for all-cause mortality were associated with liver function tests (alkaline phosphatase, butyrylcholinesterase, gamma-glutamyl transferase), metabolic tests (LDL and HDL cholesterol, triglycerides, uric acid), and acute-phase reactants (C-reactive protein, globulins). Association between offspring biomarker results and parental survival demonstrates the existence of familial effects common to both, while associations between biomarker results and PRS for mortality favor at least a partial genetic cause of this covariation. Identification of genetic loci affecting mortality-associated biomarkers offers a route to the identification of additional loci affecting mortality.
Plant life span and persistence of soil seedbanks predict the emergence of herbicide resistance in noxious weeds
Authors: Hartway Cynthia R. , Ott Jacqueline P. , Grulke Nancy E.
Published: July 2022

Plant control methods have been developed to reduce weed species that are often problematic in agricultural systems. However, these methods can create new challenges, such as herbicide resistance. Determining which plant traits are associated with herbicide resistance can assist managers in identifying species with the potential to develop herbicide resistance and to better understand factors contributing to the evolution of herbicide resistance. We used random forest models to model herbicide resistance of noxious weeds as a function of 10 biological and ecological plant characteristics. Three noxious weed characteristics—plant life span, seedbank persistence, and occurrence in riparian or wetland microsites—predicted herbicide resistance with 87% accuracy. Species with persistent seedbanks and with short life spans (i.e., annuals) that occurred outside riparian or wetland areas were most likely to develop herbicide resistance. Short life spans indicate short generation times enabling faster evolution for herbicide resistance. Persistent seedbanks may increase the survival of resistant genotypes within a population or may be co-selected as an alternate form of escape from control methods. Species occurring in riparian or wetland microsites may be a case of “avoidance” rather than resistance, as managers typically avoid applying herbicide in these areas. Currently, 47 of the noxious weed species analyzed in this study are herbicide resistant, and our models identified an additional 63 species with traits that are highly associated with herbicide resistance, potentially indicating species that are at risk of developing resistance under conducive conditions. Further data-driven analyses with more plant traits and species from around the world could help refine current risk assessment of herbicide-resistance development.
An Analysis of Interhemispheric Transport Pathways Based on Three‐Dimensional Methane Data by GOSAT Observations and Model Simulations
Authors: Belikov Dmitry A. , Saitoh Naoko , Patra Prabir K.
Published: July 2022

Interhemispheric transport (IHT) of airmass is an important parameter for understanding the transport of air pollutants in the troposphere. Although the IHT time of surface emissions is about 1.39 years, the mechanisms and location for transport through the tropics and the role of monsoonal circulations are poorly understood due to lacking observational evidence. This study clarifies the transport pathways that connect the Northern and Southern Hemispheres by analyzing global three‐dimensional distributions of methane (CH4), observed by the thermal infrared (TIR) sensor onboard the Greenhouse gases Observation SATellite (GOSAT), and simulations of an atmospheric chemistry‐transport model (ACTM). CH4 has a chemical lifetime of about 1 year in the tropical troposphere and increased quickly to about 100 years in heights of the tropopause and above, which makes CH4 an ideal species for studying IHT. We found that the most active IHT occurs in the altitude region of the upper troposphere, in a layer of 200 hPa below the tropopause. The IHT over tropical South America and Africa is active almost all year long, while in the Asia region there is significant seasonality caused by the South Asian summer monsoon (ASM). We confirm and clarify the influence of zonally asymmetric heating on IHT in the ASM. We highlight an important role of the monsoon‐induced eddy circulation in the cross‐Equator transport of long‐lived trace gases in the extended zone between tropical Africa and Southeast Asia. The zones of the most active IHT are clearly marked and quantified over the Asian, African, and American continents.
The Domino Effect of Freshwater Suffocation
Authors: Beurteaux Danielle
Published: July 2022

As lakes and reservoirs become anoxic, they can promote poor water quality downstream.
Household income and maternal education in early childhood and risk of overweight and obesity in late childhood: Findings from seven birth cohort studies in six high-income countries
Authors: White Pär Andersson , Awad Yara Abu , Gauvin Lise , Spencer Nicholas James , McGrath Jennifer J. , Clifford Susan A. , Nikiema Béatrice , Yang-Huang Junwen , Goldhaber-Fiebert Jeremy D. , Markham Wolfgang , Mensah Fiona K. , van Grieken Amy , Raat Hein , Jaddoe V. W. V. , Ludvigsson Johnny , Faresjö Tomas ,   EPOCH Collaborative Group, McGrath Jennifer J. , Séguin Louise , Spencer Nicholas J. , Pickett Kate , Raat Hein , Awad Yara Abu , White Pär Andersson , Bai Guannan , Bird Philippa , Clifford Susan A. , Faresjö Åshild , Faresjö Tomas , Francis Kate L. , Gauvin Lise , Goldfeld Sharon , Goldhaber-Fiebert Jeremy D. , Ludvigsson Johnny , Markham Wolfgang , Mensah Fiona K. , Nikiéma Béatrice , O’Connor Elodie , Woolfenden Sue , Yang-Huang Junwen
Published: July 2022

Background/objectives

This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity.

Subjects/methods

Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total ofN = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8–11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income.

Results

Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts.

Conclusions

There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals.
A new electrochemical angular microaccelerometer with integrated sensitive electrodes perpendicular to flow channels
Authors: Liu Bowen , Liang Tian , Qi Wenjie , Zhong Anxiang , Chen Mingwei , Lu Yulan , Chen Jian , Chen Deyong , Wang Junbo
Published: July 2022

A new electrochemical angular microaccelerometer with integrated sensitive electrodes perpendicular to flow channels was developed in this paper. Based on a liquid inertial mass, an incoming angular acceleration was translated into varied concentrations of reactive ions around sensitive microelectrodes, generating a detection current. Key structural parameters of the sensitive microelectrodes were designed and compared based on theoretical analysis and numerical simulations. An angular microaccelerometer incorporating sensitive microelectrodes was then fabricated, assembled and characterized, producing a sensitivity of 338 V/(rad/s2), a −3 dB bandwidth of 0.01–10 Hz and a noise level of 4.67 × 10−8 (rad/s2)/Hz1/2 @ 1 Hz. These performances were better than their commercial counterparts based on traditional electrodes and previously reported microaccelerometers based on microsensitive electrodes in parallel with flow channels, which can be applied to measure rotational accelerations in earthquakes and buildings.
Enhancing metabolic activity and differentiation potential in adipose mesenchymal stem cells via high-resolution surface-acoustic-wave contactless patterning
Authors: Martinez Villegas Karina , Rasouli Reza , Tabrizian Maryam
Published: July 2022

Acoustofluidics has shown great potential for label-free bioparticle patterning with excellent biocompatibility. Acoustofluidic patterning enables the induction of cell–cell interactions, which play fundamental roles in organogenesis and tissue development. One of the current challenges in tissue engineering is not only the control of the spatial arrangement of cells but also the preservation of cell patterns over time. In this work, we developed a standing surface acoustic wave-based platform and demonstrated its capability for the well-controlled and rapid cell patterning of adipose-derived mesenchymal stem cells in a high-density homogenous collagen hydrogel. This biocompatible hydrogel is easily UV crosslinked and can be retrieved within 3 min. Acoustic waves successfully guided the cells toward pressure nodal lines, creating a contactless alignment of cells in <5 s in culture media and <1 min in the hydrogel. The acoustically patterned cells in the hydrogel did not show a decrease in cell viability (>90%) 48 h after acoustic induction. Moreover, 45.53% and 30.85% increases in metabolic activity were observed in growth and differentiation media, respectively, on Day 7. On Day 14, a 32.03% change in metabolic activity was observed using growth media, and no significant difference was observed using differentiation media. The alkaline phosphatase activity showed an increase of 80.89% and 24.90% on Days 7 and 14, respectively, for the acoustically patterned cells in the hydrogel. These results confirm the preservation of cellular viability and improved cellular functionality using the proposed high-resolution acoustic patterning technique and introduce unique opportunities for the application of stem cell regenerative patches for the emerging field of tissue engineering.
Tumor suppressive role of microRNA-139-5p in bone marrow mesenchymal stem cells-derived extracellular vesicles in bladder cancer through regulation of the KIF3A/p21 axis
Authors: Xiang Ying , Lv Dong , Song Tao , Niu Chao , Wang Ying
Published: July 2022

The emerging roles of extracellular vesicles (EVs) in bladder cancer have recently been identified. This study aims to elucidate the role of microRNA-139-5p (miR-139-5p) shuttled by bone marrow mesenchymal stem cells (BMSCs)-derived EVs (BMSCs-EVs) in bladder cancer, with the possible mechanism explored. Expression of miR-139-5p and KIF3A was tested, followed by an analysis of their correlation. EVs were isolated from BMSCs and co-cultured with T24 or BOY-12E cells with miR-139-5p mimic/inhibitor, oe-KIF3A, and/or si-p21 transfected to study the roles of miR-139-5p/KIF3A/p21 in bladder cancer cell functions. A nude mouse model of subcutaneous xenograft tumor was constructed to detect the effect of miR-139-5p in BMSCs-EVs on the tumorigenesis and lung metastasis of bladder cancer cells in vivo. It was identified that miR-139-5p was highly expressed in BMSCs-EVs, but poorly expressed in bladder cancer. BMSCs-EVs transferred miR-139-5p into bladder cancer cells where miR-139-5p inhibited the malignant features of bladder cancer cells in vitro. miR-139-5p in BMSCs-EVs targeted KIF3A and inhibited the expression of KIF3A, thereby activating p21. miR-139-5p in BMSCs-EVs arrested the tumorigenesis and lung metastasis of bladder cancer cells in vivo by modulation of the KIF3A/p21 axis. Altogether, BMSCs-EVs carried miR-139-5p targeted KIF3A to activate p21, thus delaying the occurrence of bladder cancer.
Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy
Authors: Ogura Yosuke , Sahashi Kentaro , Hirunagi Tomoki , Iida Madoka , Miyata Takaki , Katsuno Masahisa
Published: July 2022

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset hereditary neurodegenerative disease caused by the expansions of CAG repeats in the androgen receptor (AR) gene. Androgen-dependent nuclear accumulation of pathogenic AR protein causes degeneration of lower motor neurons, leading to progressive muscle weakness and atrophy. While the successful induction of SBMA-like pathology has been achieved in mouse models, mechanisms underlying motor neuron vulnerability remain unclear. In the present study, we performed a transcriptome-based screening for genes expressed exclusively in motor neurons and dysregulated in the spinal cord of SBMA mice. We found upregulation of Mid1 encoding a microtubule-associated RNA binding protein which facilitates the translation of CAG-expanded mRNAs. Based on the finding that lower motor neurons begin expressing Mid1 during embryonic stages, we developed an organotypic slice culture system of the spinal cord obtained from SBMA mouse fetuses to study the pathogenic role of Mid1 in SBMA motor neurons. Impairment of axonal regeneration arose in the spinal cord culture in SBMA mice in an androgen-dependent manner, but not in mice with non-CAG-expanded AR, and was either exacerbated or ameliorated by Mid1 overexpression or knockdown, respectively. Hence, an early Mid1 expression confers vulnerability to motor neurons, at least by inducing axonogenesis defects, in SBMA.
SNHG25 facilitates SNORA50C accumulation to stabilize HDAC1 in neuroblastoma cells
Authors: Zeng Huijuan , Pan Jing , Hu Chao , Yang Jiliang , Li Jiahao , Tan Tianbao , Zheng Manna , Shen Yuanchao , Yang Tianyou , Deng Yun , Zou Yan
Published: July 2022

Increasing studies have pointed out that small nucleolar RNAs (snoRNAs) and their host genes (SNHGs) have multi-functional roles in cancer progression. Bioinformatics analysis revealed the importance of snoRNA host gene 25 (SNHG25) in neuroblastoma (NB). Hence, we further explored the function and molecular mechanism of SNHG25 in NB. Our study revealed that SNHG25 expression was upregulated in NB cells. Through loss-of-function assays, we discovered that silencing of SNHG25 suppressed NB cell proliferation, invasion, and migration. Moreover, we found that SNHG25 positively regulated snoRNA small nucleolar RNA, H/ACA box 50 C (SNORA50C) in NB cells, and SNORA50C depletion had the same function as SNHG25 silencing in NB cells. Moreover, we proved that SNHG25 recruited dyskerin pseudouridine synthase 1 (DKC1) to facilitate SNORA50C accumulation and associated small nucleolar ribonucleoprotein (snoRNP) assembly. In addition, it was manifested that SNHG25 relied on SNORA50C to inhibit ubiquitination of histone deacetylase 1 (HDAC1), thereby elevating HDAC1 expression in NB cells. Further, HDAC1 was proven to be a tumor-facilitator in NB, and SNORA50C contributed to NB cell growth and migration through the HDAC1-mediated pathway. In vivo xenograft experiments further supported that SNHG25 promoted NB progression through SNORA50C/HDAC1 pathway. Our study might provide a novel sight for NB treatment.
Mitochondrial PKM2 deacetylation by procyanidin B2-induced SIRT3 upregulation alleviates lung ischemia/reperfusion injury
Authors: Zhao Jing , Wang Guorong , Han Kaitao , Wang Yang , Wang Lin , Gao Jinxia , Zhao Sen , Wang Gang , Chen Shengyang , Luo An , Wu Jianlin , Wang Guangzhi
Published: July 2022

Apoptosis is a critical event in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Sirtuin 3 (SIRT3), an important deacetylase predominantly localized in mitochondria, regulates diverse physiological processes, including apoptosis. However, the detailed mechanisms by which SIRT3 regulates lung I/R injury remain unclear. Many polyphenols strongly regulate the sirtuin family. In this study, we found that a polyphenol compound, procyanidin B2 (PCB2), activated SIRT3 in mouse lungs. Due to this effect, PCB2 administration attenuated histological lesions, relieved pulmonary dysfunction, and improved the survival rate of the murine model of lung I/R injury. Additionally, this treatment inhibited hypoxia/reoxygenation (H/R)-induced A549 cell apoptosis and rescued Bcl-2 expression. Using Sirt3-knockout mice and specific SIRT3 knockdown in vitro, we further found that SIRT3 strongly protects against lung I/R injury. Sirt3 deficiency or enzymatic inactivation substantially aggravated lung I/R-induced pulmonary lesions, promoted apoptosis, and abolished PCB2-mediated protection. Mitochondrial pyruvate kinase M2 (PKM2) inhibits apoptosis by stabilizing Bcl-2. Here, we found that PKM2 accumulates and is hyperacetylated in mitochondria upon lung I/R injury. By screening the potential sites of PKM2 acetylation, we found that SIRT3 deacetylates the K433 residue of PKM2 in A549 cells. Transfection with a deacetylated mimic plasmid of PKM2 noticeably reduced apoptosis, while acetylated mimic transfection abolished the protective effect of PKM2. Furthermore, PKM2 knockdown or inhibition in vivo significantly abrogated the antiapoptotic effects of SIRT3 upregulation. Collectively, this study provides the first evidence that the SIRT3/PKM2 pathway is a protective target for the suppression of apoptosis in lung I/R injury. Moreover, this study identifies K433 deacetylation of PKM2 as a novel modification that regulates its anti-apoptotic activity. In addition, PCB2-mediated modulation of the SIRT3/PKM2 pathway may significantly protect against lung I/R injury, suggesting a novel prophylactic strategy for lung I/R injury.
CircRNA mmu_circ_0000021 regulates microvascular function via the miR-143-3p/NPY axis and intracellular calcium following ischemia/reperfusion injury
Authors: Xiong Jingjie , Hu Yisen , Liu Yi , Zeng Xiaocong
Published: July 2022

Cardiac ischemia-reperfusion (I/R) is associated with a high rate of complications. Restoring microvascular function is crucial for cardiac repair. However, the molecular mechanisms by which the circRNAs repairs microvascular dysfunction are unknown. High-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) were used to measures circRNA levels in cardiac tissue samples. We found a total of 80 up-regulated and 54 down-regulated differentially expressed circRNAs, of which mmu_circ_0000021 were consistent with bioinformatics predictions. Next, mmu_circ_0000021 knockdown and overexpression were performed to indicate the functional role of mmu_circ_0000021. The interaction of mmu_circ_0000021, miR-143-3p and NPY were evaluated using dual-luciferase assays, RNA pull-down assays and RNA immunoprecipitation (RIP). Immunohistochemistry, transmission electron microscopy, and immunofluorescence were used to determine the presence of leukocytes and changes in microvascular morphology and function. Mechanistically, mmu_circ_0000021 involved in regulating microvascular dysfunction via miR-143-3p by targeting NPY. However, the contraction of microvascular spasm caused by NPY is related to calmodulin. By regulating NPY, Circular RNA (circRNA) further affects microvascular spasm, regulates microcirculation disorders, and restores cardiac function. Our findings highlight a novel role for mmu_circ_0000021 by regulating microvascular function following I/R injury.
Circular RNA circLDLR facilitates cancer progression by altering the miR-30a-3p/SOAT1 axis in colorectal cancer
Authors: Wang Ruoqin , Wang Jiayu , Chen Yanjun , Chen Yuqi , Xi Qinhua , Sun Linqing , Zhang Xueguang , Zhang Guangbo , Ding Xianglin , Shi Tongguo , Chen Weichang
Published: July 2022

Colorectal cancer (CRC) is the third most common malignancy worldwide. Circular RNAs (circRNAs) have been reported to play critical regulatory roles in tumorigenesis, serving as tumor biomarkers and therapeutic targets. However, the contributions of circRNAs to CRC tumorigenesis are unclear. In our study, high expression of circLDLR was found in CRC tissues and cells and was closely associated with the malignant progression and poor prognosis of CRC patients. We demonstrated that circLDLR boosts growth and metastasis of CRC cells in vitro and in vivo, and modulates cholesterol levels in vitro. Mechanistically, we showed that circLDLR competitively binds to miR-30a-3p and prevents it from reducing the SOAT1 level, facilitating the malignant progression of CRC. In sum, our findings illustrate that circLDLR participates in CRC tumorigenesis and metastasis via the miR-30a-3p/SOAT1 axis, serving as a potential biomarker and therapeutic target in CRC.
Self-assembly of tessellated tissue sheets by expansion and collision
Authors: Heinrich Matthew A. , Alert Ricard , Wolf Abraham E. , Košmrlj Andrej , Cohen Daniel J.
Published: July 2022

Tissues do not exist in isolation—they interact with other tissues within and across organs. While cell-cell interactions have been intensely investigated, less is known about tissue-tissue interactions. Here, we studied collisions between monolayer tissues with different geometries, cell densities, and cell types. First, we determine rules for tissue shape changes during binary collisions and describe complex cell migration at tri-tissue boundaries. Next, we propose that genetically identical tissues displace each other based on pressure gradients, which are directly linked to gradients in cell density. We present a physical model of tissue interactions that allows us to estimate the bulk modulus of the tissues from collision dynamics. Finally, we introduce TissEllate, a design tool for self-assembling complex tessellations from arrays of many tissues, and we use cell sheet engineering techniques to transfer these composite tissues like cellular films. Overall, our work provides insight into the mechanics of tissue collisions, harnessing them to engineer tissue composites as designable living materials.
Electrical resistance of the current collector controls lithium morphology
Authors: Oyakhire Solomon T. , Zhang Wenbo , Shin Andrew , Xu Rong , Boyle David T. , Yu Zhiao , Ye Yusheng , Yang Yufei , Raiford James A. , Huang William , Schneider Joel R. , Cui Yi , Bent Stacey F.
Published: July 2022

The electrodeposition of low surface area lithium is critical to successful adoption of lithium metal batteries. Here, we discover the dependence of lithium metal morphology on electrical resistance of substrates, enabling us to design an alternative strategy for controlling lithium morphology and improving electrochemical performance. By modifying the current collector with atomic layer deposited conductive (ZnO, SnO2) and resistive (Al2O3) nanofilms, we show that conductive films promote the formation of high surface area lithium deposits, whereas highly resistive films promote the formation of lithium clusters of low surface area. We reveal an electrodeposition mechanism in which radial diffusion of electroactive species is promoted on resistive substrates, resulting in lateral growth of large (150 µm in diameter) planar lithium deposits. Using resistive substrates, similar lithium morphologies are formed in three distinct classes of electrolytes, resulting in up to ten-fold improvement in battery performance. Ultimately, we report anode-free pouch cells using the Al2O3-modified copper that maintain 60 % of their initial discharge capacity after 100 cycles, displaying the benefits of resistive substrates for controlling lithium electrodeposition.
An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
Authors: Baker Ysobel R. , Thorpe Cameron , Chen Jinfeng , Poller Laura M. , Cox Lina , Kumar Pawan , Lim Wooi F. , Lie Lillian , McClorey Graham , Epple Sven , Singleton Daniel , McDonough Michael A. , Hardwick Jack S. , Christensen Kirsten E. , Wood Matthew J. A. , Hall James P. , El-Sagheer Afaf H. , Brown Tom
Published: July 2022

Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.
Deciphering polymorphism in 61,157 Escherichia coli genomes via epistatic sequence landscapes
Authors: Vigué Lucile , Croce Giancarlo , Petitjean Marie , Ruppé Etienne , Tenaillon Olivier , Weigt Martin
Published: July 2022

Characterizing the effect of mutations is key to understand the evolution of protein sequences and to separate neutral amino-acid changes from deleterious ones. Epistatic interactions between residues can lead to a context dependence of mutation effects. Context dependence constrains the amino-acid changes that can contribute to polymorphism in the short term, and the ones that can accumulate between species in the long term. We use computational approaches to accurately predict the polymorphisms segregating in a panel of 61,157 Escherichia coli genomes from the analysis of distant homologues. By comparing a context-aware Direct-Coupling Analysis modelling to a non-epistatic approach, we show that the genetic context strongly constrains the tolerable amino acids in 30% to 50% of amino-acid sites. The study of more distant species suggests the gradual build-up of genetic context over long evolutionary timescales by the accumulation of small epistatic contributions.
Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration
Authors: Balzer Michael S. , Doke Tomohito , Yang Ya-Wen , Aldridge Daniel L. , Hu Hailong , Mai Hung , Mukhi Dhanunjay , Ma Ziyuan , Shrestha Rojesh , Palmer Matthew B. , Hunter Christopher A. , Susztak Katalin
Published: July 2022

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic repair are poorly understood. We developed a model of adaptive and fibrotic kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level (> 110,000 cells) over time. Our analysis highlights kidney proximal tubule cells as key susceptible cells to injury. Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation. We identify a specific maladaptive/profibrotic proximal tubule cluster after long ischemia, which expresses proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. Druggability analysis highlights pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in vivo pushed cells towards adaptive repair and ameliorates fibrosis. In summary, our single-cell analysis defines key differences in adaptive and fibrotic repair and identifies druggable pathways for pharmacological intervention to prevent kidney fibrosis.
Gas permeation through graphdiyne-based nanoporous membranes
Authors: Zhou Zhihua , Tan Yongtao , Yang Qian , Bera Achintya , Xiong Zecheng , Yagmurcukardes Mehmet , Kim Minsoo , Zou Yichao , Wang Guanghua , Mishchenko Artem , Timokhin Ivan , Wang Canbin , Wang Hao , Yang Chongyang , Lu Yizhen , Boya Radha , Liao Honggang , Haigh Sarah , Liu Huibiao , Peeters Francois M. , Li Yuliang , Geim Andre K. , Hu Sheng
Published: July 2022

Nanoporous membranes based on two dimensional materials are predicted to provide highly selective gas transport in combination with extreme permeance. Here we investigate membranes made from multilayer graphdiyne, a graphene-like crystal with a larger unit cell. Despite being nearly a hundred of nanometers thick, the membranes allow fast, Knudsen-type permeation of light gases such as helium and hydrogen whereas heavy noble gases like xenon exhibit strongly suppressed flows. Using isotope and cryogenic temperature measurements, the seemingly conflicting characteristics are explained by a high density of straight-through holes (direct porosity of ∼0.1%), in which heavy atoms are adsorbed on the walls, partially blocking Knudsen flows. Our work offers important insights into intricate transport mechanisms playing a role at nanoscale.
Ductal keratin 15+ luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature
Authors: Kohler Katharina Theresa , Goldhammer Nadine , Demharter Samuel , Pfisterer Ulrich , Khodosevich Konstantin , Rønnov-Jessen Lone , Petersen Ole William , Villadsen René , Kim Jiyoung
Published: July 2022

Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine collection under the microscope of organoids from reduction mammoplasties and single-cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal duct lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes suggests a strong correlation between normal breast ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.
Classifying handedness in chiral nanomaterials using label error robust deep learning
Authors: Groschner C. K. , Pattison Alexander J. , Ben-Moshe Assaf , Alivisatos A. Paul , Theis Wolfgang , Scott M. C.
Published: July 2022

High-throughput scanning electron microscopy (SEM) coupled with classification using neural networks is an ideal method to determine the morphological handedness of large populations of chiral nanoparticles. Automated labeling removes the time-consuming manual labeling of training data, but introduces label error, and subsequently classification error in the trained neural network. Here, we evaluate methods to minimize classification error when training from automated labels of SEM datasets of chiral Tellurium nanoparticles. Using the mirror relationship between images of opposite handed particles, we artificially create populations of varying label error. We analyze the impact of label error rate and training method on the classification error of neural networks on an ideal dataset and on a practical dataset. Of the three training methods considered, we find that a pretraining approach yields the most accurate results across label error rates on ideal datasets, where size and other morphological variables are held constant, but that a co-teaching approach performs the best in practical application.
A geospatial inventory of regulatory information for wine protected designations of origin in Europe
Authors: Candiago Sebastian , Tscholl Simon , Bassani Leonardo , Fraga Helder , Egarter Vigl Lukas
Published: July 2022

The Wine Protected Designation of Origin (PDO) label is a European quality scheme that protects high quality wines by linking them to legally defined geographic areas and a set of specific production practices. Because of the tight relation between PDO wines and the specifications defined in the official regulatory documents, these products are highly susceptible to changes in climatic, environmental, or socioeconomic conditions. However, the content of these regulatory documents has never been systematically analysed and summarized in a single dataset. Here, we present the first geospatial inventory that organizes regulatory information about the 1177 wine PDO in Europe based on the documents from the official EU geographical indication register. It includes essential legal information that defines the wine PDO such as the geographic boundaries, authorized cultivars and maximum yields. This inventory opens new possibilities for researchers to accurately assess, compare and map the regulatory information in each wine region at an unprecedented level of detail, supporting decision makers in developing adaptation strategies for the preservation of PDO wine regions.
Data-driven discovery of the governing equations of dynamical systems via moving horizon optimization
Authors: Lejarza Fernando , Baldea Michael
Published: July 2022

Discovering the governing laws underpinning physical and chemical phenomena entirely from data is a key step towards understanding and ultimately controlling systems in science and engineering. Noisy measurements and complex, highly nonlinear underlying dynamics hinder the identification of such governing laws. In this work, we introduce a machine learning framework rooted in moving horizon nonlinear optimization for identifying governing equations in the form of ordinary differential equations from noisy experimental data sets. Our approach evaluates sequential subsets of measurement data, and exploits statistical arguments to learn truly parsimonious governing equations from a large dictionary of basis functions. The proposed framework reduces gradient approximation errors by implicitly embedding an advanced numerical discretization scheme, which improves robustness to noise as well as to model stiffness. Canonical nonlinear dynamical system examples are used to demonstrate that our approach can accurately recover parsimonious governing laws under increasing levels of measurement noise, and outperform state of the art frameworks in the literature. Further, we consider a non-isothermal chemical reactor example to demonstrate that the proposed framework can cope with basis functions that have nonlinear (unknown) parameterizations.
Stochastic model of ERK-mediated progesterone receptor translocation, clustering and transcriptional activity
Authors: Marquez-Lago Tatiana T. , Steinberg Stanly
Published: July 2022

Progesterone receptor (PR) transcriptional activity is a key factor in the differentiation of the uterine endometrium. By consequence, progestin has been identified as an important treatment modality for endometrial cancer. PR transcriptional activity is controlled by extracellular-signal-regulated kinase (ERK) mediated phosphorylation, downstream of growth factor receptors such as EGFR. However, phosphorylation of PR also targets it for ubiquitination and destruction in the proteasome. Quantitative studies of these opposing roles are much needed toward validation of potential new progestin-based therapeutics. In this work, we propose a spatial stochastic model to study the effects of the opposing roles for PR phosphorylation on the levels of active transcription factor. Our numerical simulations confirm earlier in vitro experiments in endometrial cancer cell lines, identifying clustering as a mechanism that amplifies the ability of progesterone receptors to influence gene transcription. We additionally show the usefulness of a statistical method we developed to quantify and control variations in stochastic simulations in general biochemical systems, assisting modelers in defining minimal but meaningful numbers of simulations while guaranteeing outputs remain within a pre-defined confidence level.
Intrauterine growth restriction and its impact on intestinal morphophysiology throughout postnatal development in pigs
Authors: Santos Thaís Garcia , Fernandes Saffir Dominique , de Oliveira Araújo Stefany Bruna , Felicioni Fernando , de Mérici Domingues e Paula Thaís , Caldeira-Brant André Lucas , Ferreira Soraia Viana , de Paula Naves Luciana , de Souza Stefânia Priscilla , Campos Paulo Henrique Reis Furtado , Chiarini-Garcia Hélio , Dias Ana Luísa Neves Alvarenga , de Almeida Fernanda Radicchi Campos Lobato
Published: July 2022

Intrauterine growth restriction (IUGR) compromises fetal development, leading to low birth weight, and predisposes to gastrointestinal disorders. Pigs that suffered IUGR present poor postnatal development, resulting in great economic losses to the industry. The small intestine may be involved with impaired development, but studies investigating this issue are still limited. Thus, the present study aimed to investigate small intestine morphofunctional alterations in IUGR pigs throughout the production phases (birth to 150 days). IUGR pigs presented lower body weight from birth to the finishing phase (P < 0.05). Although histomorphometrical parameters were not affected during the pre-weaning period, their commitment was observed specifically in the duodenum of the IUGR group at older ages (P < 0.05). The most detrimental effects on the small intestine, such as deeper duodenum crypts’ depth, lower villus height:crypt depth ratio and absorptive area, increased apoptosis and lower proliferation of the duodenum epithelium were noticed at 70 days of age (P < 0.05). Additionally, IUGR pigs presented the lowest chymotrypsin and amylase activities at 70 and 150 days of age, respectively (P < 0.05). These findings may contribute to the elucidation of morphofunctional disorders of the small intestine in IUGR pigs throughout the different production phases, suggesting that poor postnatal development may be due to intestinal damage.
On the mechanism of marine fouling-prevention performance of oil-containing silicone elastomers
Authors: Kolle Stefan , Ahanotu Onyemaechi , Meeks Amos , Stafslien Shane , Kreder Michael , Vanderwal Lyndsi , Cohen Lucas , Waltz Grant , Lim Chin Sing , Slocum Dave , Greene Elisa Maldonado , Hunsucker Kelli , Swain Geoffrey , Wendt Dean , Teo Serena Lay-Ming , Aizenberg Joanna
Published: July 2022

For many decades, silicone elastomers with oil incorporated have served as fouling-release coating for marine applications. In a comprehensive study involving a series of laboratory-based marine fouling assays and extensive global field studies of up to 2-year duration, we compare polydimethylsiloxane (PDMS) coatings of the same composition loaded with oil via two different methods. One method used a traditional, one-pot pre-cure oil addition approach (o-PDMS) and another method used a newer post-cure infusion approach (i-PDMS). The latter displays a substantial improvement in biofouling prevention performance that exceeds established commercial silicone-based fouling-release coating standards. We interpret the differences in performance between one-pot and infused PDMS by developing a mechanistic model based on the Flory–Rehner theory of swollen polymer networks. Using this model, we propose that the chemical potential of the incorporated oil is a key consideration for the design of future fouling-release coatings, as the improved performance is driven by the formation and stabilization of an anti-adhesion oil overlayer on the polymer surface.
A human IgM enriched immunoglobulin preparation, Pentaglobin, reverses autoimmune diabetes without immune suppression in NOD mice
Authors: Wilson Christopher S. , Hoopes Emilee M. , Falk Alexander C. , Moore Daniel J.
Published: July 2022

The immune system of healthy individuals is capable of regulating autoimmunity through multiple mechanisms. In Type 1 Diabetes (T1D) we recently discovered natural IgM, although present at normal levels, is unable to perform its normal immunoregulatory function. Treating diabetic mice with IgM from healthy donors led to reversal of disease without immune depletion. To investigate the therapeutic potential of a human preparation of IgM, we administered an IgM-enriched preparation of immunoglobulin called Pentaglobin. Administration of Pentaglobin therapy reversed disease in diabetic NOD mice and boosted CD4 + Foxp3 + Tregs. Importantly, the impact of Pentaglobin on the immune system was limited to inhibiting beta cell destruction but was not immune depleting nor did it inhibit the immunization response to an irrelevant antigen. These findings indicate that inhibition of deleterious autoimmunity in T1D is possible while leaving protective immunity fully intact.
Reduced cerebral vascular fractal dimension among asymptomatic individuals as a potential biomarker for cerebral small vessel disease
Authors: Aminuddin Niferiti , Achuthan Anusha , Ruhaiyem Nur Intan Raihana , Che Mohd Nassir Che Mohd Nasril , Idris Nur Suhaila , Mustapha Muzaimi
Published: July 2022

Cerebral small vessel disease is a neurological disease frequently found in the elderly and detected on neuroimaging, often as an incidental finding. White matter hyperintensity is one of the most commonly reported neuroimaging markers of CSVD and is linked with an increased risk of future stroke and vascular dementia. Recent attention has focused on the search of CSVD biomarkers. The objective of this study is to explore the potential of fractal dimension as a vascular neuroimaging marker in asymptomatic CSVD with low WMH burden. Df is an index that measures the complexity of a self-similar and irregular structure such as circle of Willis and its tributaries. This exploratory cross-sectional study involved 22 neurologically asymptomatic adult subjects (42 ± 12 years old; 68% female) with low to moderate 10-year cardiovascular disease risk prediction score (QRISK2 score) who underwent magnetic resonance imaging/angiography (MRI/MRA) brain scan. Based on the MRI findings, subjects were divided into two groups: subjects with low WMH burden and no WMH burden, (WMH+; n = 8) and (WMH−; n = 14) respectively. Maximum intensity projection image was constructed from the 3D time-of-flight (TOF) MRA. The complexity of the CoW and its tributaries observed in the MIP image was characterised using Df. The Df of the CoW and its tributaries, i.e., Df (w) was significantly lower in the WMH+ group (1.5172 ± 0.0248) as compared to WMH− (1.5653 ± 0.0304, p = 0.001). There was a significant inverse relationship between the QRISK2 risk score and Df (w), (rs = − .656, p = 0.001). Df (w) is a promising, non-invasive vascular neuroimaging marker for asymptomatic CSVD with WMH. Further study with multi-centre and long-term follow-up is warranted to explore its potential as a biomarker in CSVD and correlation with clinical sequalae of CSVD.
Electrochemical behavior of 2205 duplex stainless steel in simulated solution containing high concentration Cl− and saturated CO2 at different temperatures
Authors: Li Yanpeng , Zhu Shidong , Xian Jun , Li Xuanpeng , Zhao Yuqin , Wang Shusen
Published: July 2022

2205 duplex stainless steel (DSS) has good corrosion resistance due to its typical duplex organization, but the increasingly harsh CO2-containing oil and gas environment leads to different degrees of corrosion, especially pitting corrosion, which seriously threatens the safety and reliability of oil and gas development. In this paper, the effect of temperature on the corrosion behavior of 2205 DSS in a simulated solution containing 100 g/L Cl−and saturated CO2was investigated with immersion tests and electrochemical tests and combined with characterization techniques such as laser confocal microscopy and X-ray photoelectron spectroscopy. The results show that the average critical pitting temperature of 2205 DSS was 66.9 °C. When the temperature was higher than 66.9 °C, the pitting breakdown potential, passivation interval, and self-corrosion potential decreased, while the dimensional passivation current density increased, and the pitting sensitivity was enhanced. With a further increase in temperature, the capacitive arc radius of 2205 DSS decreased, the film resistance and charge transfer resistance gradually decreased, the carrier density of the donor and acceptor in the product film layer with n + p bipolar characteristics also increased and the inner layer of the film with Cr oxide content decreased, while the outer layer with Fe oxide content increased, the dissolution of the film layer increased, the stability decreased, and the number and pore size of pits increased.