bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic linkage of systemic lupus erythematosus and nutrition
Authors: Montoya Tatiana , Castejón María Luisa , Muñoz-García Rocío , Alarcón-de-la-Lastra Catalina
Published: August 2021

The term ‘epigenetics’ refers to a series of meiotically/mitotically inheritable alterations in gene expression, related to environmental factors, without disruption on DNA sequences of bases. Recently, the pathophysiology of autoimmune diseases (ADs) has been closely linked to epigenetic modifications. In fact, epigenetic mechanisms can modulate gene expression or repression of targeted cells and tissues involved in autoimmune/inflammatory conditions acting as keys effectors in regulation of adaptive and innate responses. ADs, as systemic lupus erythematosus (SLE), a rare disease that still lacks effective treatment, is characterised by epigenetic marks in affected cells. Taking into account that epigenetic mechanisms have been proposed as a winning strategy in the search of new, more specific and personalised therapeutics agents, pharmacology and pharmaco-epigenetic studies about epigenetic regulations of ADs may provide novel individualised therapies. Focusing on possible implicated factors on development and predisposition of SLE, diet is feasibly one of the most important factors since it is linked directly to epigenetic alterations and these epigenetic changes may augment or diminish the risk of SLE. Nevertheless, several studies have suggested that dietary therapy could be promising to SLE patients via prophylactic actions deprived of side effects of pharmacology, decreasing co-morbidities and improving lifestyle of SLE sufferers. Herein, we review and discuss the cross-link between epigenetic mechanisms on SLE predisposition and development, as well as the influence of dietary factors on regulation of epigenetic modifications that may eventually make a positive impact on SLE patients.
Conscription, rural populations and the dynamics of war and revolution in Ireland (1914–18)
Authors: Destenay Emmanuel
Published: August 2021

Drawing on secret witness reports from Intelligence Officers of the Royal Irish Constabulary, and diplomatic correspondence from France’s representatives to Dublin and London, this article seeks to complement recent historiography and qualify our understanding of the period 1914–18 by engaging fully with the issue of compulsory military service from the outbreak of the conflict. It contemplates how fears of conscription contributed to the radicalisation of rural communities and demonstrates that opposition to conscription formed a solid political foundation for Sinn Féin. Britain’s determination to implement conscription to Ireland frightened civilian populations, gave rise to nationwide discontent, and attracted towards Sinn Féin populations likely to be drafted into the British Army. That study seeks to be a re-examination of the dynamics between the Irish revolution and the conscription scares and maintains that fears of compulsory service in Ireland significantly contributed to the victory of Sinn Féin candidates during the four electoral contests in 1917.
Last suppers at Sardis
Authors: Rautman Marcus
Published: August 2021

The realia of shared meals provide a key index for social behavior in Late Antiquity. Much attention has been paid to the architecture and ceramics of dining, but usually separately and from unrelated contexts. Three excavated rooms at Sardis present an opportunity to extend this discussion to the furnishings that once stood at the center of domestic hospitality. Nearly complete marble tabletops recovered from their places of intended use show differing approaches to the physical and social arrangements of convivial dining, with implications for interpreting reception areas in Late Roman houses. Circumstances of preservation indicate that all three rooms were leveled, probably by earthquakes, in the early 7th c. CE.
Reanalysis Surface Mass Balance of the Greenland Ice Sheet Along K‐Transect (2000–2014)
Authors: Navari Mahdi , Margulis Steven A. , Tedesco Marco , Fettweis Xavier , van de Wal Roderik S. W.
Published: August 2021

Accurate estimates of surface mass balance over the Greenland ice sheet (GrIS) would contribute to understanding the cause of recent changes and would help to better estimate the future contribution of the GrIS to sea‐level rise. Given the limitations of in‐situ measurements, modeling, and remote sensing, it is critical to explore the opportunity to merge the available data to better characterize the spatial and temporal variation of the GrIS surface mass balance (SMB). This work utilizes a particle batch smoother data assimilation technique that yields SMB estimates that benefit from the snow model Crocus and a 16‐day albedo product derived from satellite remote sensing data. Comparison of the results against in‐situ SMB measurements shows that the assimilation of the albedo product reduces the root mean square error of the posterior estimates of SMB by 51% and reduces bias by 95%.
A Framework for Assessing Concentration‐Discharge Catchment Behavior From Low‐Frequency Water Quality Data
Authors: Pohle Ina , Baggaley Nikki , Palarea‐Albaladejo Javier , Stutter Marc , Glendell Miriam
Published: August 2021

Effective nutrient pollution mitigation measures require in‐depth understanding of spatio‐temporal controls on water quality which can be obtained by analyzing export regime and hysteresis patterns in concentration‐discharge () relationships. Such analyses require high‐frequency data (hourly or higher resolution), hampering the assessment of hysteresis patterns in widely available low‐frequency (monthly, biweekly) regulatory water quality data. We propose a reproducible classification of relationships considering export regime (dilution, constancy, enrichment) and long‐term average hysteresis pattern (clockwise, no hysteresis, anticlockwise) applicable to low‐frequency water quality data. The classification is based on power‐law models with separate parametrization for low and high discharge and rising and falling hydrograph limb, enabling a better representation of dynamics. The classification has been applied to a 30‐years record of daily streamflow and monthly spot samples of solute concentrations in 45 Scottish catchments with contrasting characteristics in terms of topography, climate, soil and land cover. We found that classification is solute‐ and catchment‐specific and linked to upland versus lowland catchments and streamflow variability. However as the relationship between solute behavior and catchment characteristics is variable, we propose that future typologies should integrate both water quality response, that is, classification, and catchment characteristics. The data‐driven classification allows us to increase the information content of low‐frequency water quality data and thus inform mitigation measures, monitoring strategies, and modeling approaches. Such approaches open up an ability to characterize processes and best management for a wider number of catchments, subject to regulatory surveillance and outside of research catchments.
Bayesian Inversion of Multi‐Gaussian Log‐Conductivity Fields With Uncertain Hyperparameters: An Extension of Preconditioned Crank‐Nicolson Markov Chain Monte Carlo With Parallel Tempering
Authors: Xiao Sinan , Xu Teng , Reuschen Sebastian , Nowak Wolfgang , Hendricks Franssen Harrie‐Jan
Published: August 2021

In conventional Bayesian geostatistical inversion, specific values of hyperparameters characterizing the prior distribution of random fields are required. However, these hyperparameters are typically very uncertain in practice. Thus, it is more appropriate to consider the uncertainty of hyperparameters as well. The preconditioned Crank‐Nicolson Markov chain Monte Carlo with parallel tempering (pCN‐PT) has been used to efficiently solve the conventional Bayesian inversion of high‐dimensional multi‐Gaussian random fields. In this study, we extend pCN‐PT to Bayesian inversion with uncertain hyperparameters of multi‐Gaussian fields. To utilize the dimension robustness of the preconditioned Crank‐Nicolson algorithm, we reconstruct the problem by decomposing the random field into hyperparameters and white noise. Then, we apply pCN‐PT with a Gibbs split to this “new” problem to obtain the posterior samples of hyperparameters and white noise, and further recover the posterior samples of spatially distributed model parameters. Finally, we apply the extended pCN‐PT method for estimating a finely resolved multi‐Gaussian log‐hydraulic conductivity field from direct data and from head data to show its effectiveness. Results indicate that the estimation of hyperparameters with hydraulic head data is very challenging and the posterior distributions of hyperparameters are only slightly narrower than the prior distributions. Direct measurements of hydraulic conductivity are needed to narrow more the posterior distribution of hyperparameters. To the best of our knowledge, this is a first accurate and fully linearization free solution to Bayesian multi‐Gaussian geostatistical inversion with uncertain hyperparameters.
Development of a Telepsychology Program for Parents of Pediatric Patients
Authors: Goertz Mackenzie T. , Brosig Cheryl , Bice-Urbach Brittany , Malkoff Anne , Kroll Kristin
Published: August 2021

Objective: Telepsychology represents a promising approach to treatment for individuals and families encountering barriers to traditional face-to-face health care, especially in the challenging context of the 2019 coronavirus disease (COVID-19). Implementing the necessary infrastructure to sustain telepsychology programs within health care institutions requires detailed attention to a variety of domains. Despite the growing use of telepsychology, logistical considerations for the development of such programs are often unclear. Method: In order to clarify considerations regarding the use of telepsychology within partnering health care institutions, we describe the process of developing a telepsychology group intervention with parents of pediatric patients. Results: The development of a telepsychology program for parents at a large children’s health care institution is discussed across four developmental phases: (a) curriculum development, (b) clinical framework, (c) program logistics, and (d) protocol and training infrastructure. Conclusion: Due to the growing need for telepsychological interventions for parents, both practitioners and health care institutions are tasked with collaborating to develop well-designed programs that are aligned with clinical best practices.

Implications for Impact Statement

This article provides a reference guide for the development of a telepsychology group intervention with parents of pediatric patients. Increasing telepsychology interventions is one avenue to promote health equity by increasing greater access to care.
Road-to-Recovery-TBI: Pilot Trial of an eHealth Intervention for Caregivers After Pediatric Brain Injury
Authors: Raj Stacey P. , Schmidt Matthew M. , Moscato Emily L. , Guzman-Gomez Amalia , Rodriguez Beatriz , Seid Claire S. , Wade Shari L.
Published: August 2021

Objective: Traumatic brain injury (TBI) is a leading cause of acquired disability in childhood, impacting long-term health and functioning. Caregivers of children with TBI report worsening psychological health—and caregiver functioning and behaviors directly impact child recovery and outcomes. We developed and pilot tested road-to-recovery-TBI (R2R-TBI), a self-guided, eHealth intervention to support caregivers during the acute phase following pediatric TBI and equip families with skills to promote a positive path to recovery. Method: Caregivers of children hospitalized for moderate-to-severe TBI were recruited within 3 months postinjury. Twenty primary caregivers completed measures assessing caregiver psychological functioning, family functioning, and child behavior prior to accessing the intervention and at follow-up 1 month later. Caregivers also completed postintervention satisfaction and usability surveys. Results: Thirty of 42 eligible caregivers consented to participate. Caregivers were diverse with regard to race/ethnicity (45% non-White), income (65% receiving public assistance), and child age (1 month to 15 years). All caregivers rated the intervention as helpful and 90% reported making positive changes. While average scores were in the nonclinical range at baseline and follow-up, percentages of caregivers reporting clinically elevated challenges across all measures (15% to 50%) were higher than instrument norms. There were no significant changes in caregiver, family, or child outcomes from baseline to follow-up. Conclusions: Given challenges that caregivers experience accessing in-office interventions that target their well-being and/or parenting, the R2R-TBI program may be a cost-effective and accessible approach to supporting families during a challenging phase of recovery. Further research is needed to examine the efficacy of the intervention.

Implications for Impact Statement

We developed and pilot tested road-to-recovery-traumatic brain injury (R2R-TBI), a self-guided, eHealh intervention to support caregivers during the stressful and challenging acute phase following pediatric TBI and equip families with skills to promote a positive path to recovery. Caregivers in this pilot trial reported good satisfaction with intervention, though no overall changes in caregiver, family, or child functioning were noted between baseline and 1-month follow-up. With further efficacy trials, the R2R-TBI intervention may have promise as a form of preventative behavioral health care for children and families in the acute phase of pediatric TBI.
The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing
Authors: Tsatsanis Andrew , McCorkindale Andrew N. , Wong Bruce X. , Patrick Ellis , Ryan Tim M. , Evans Robert W. , Bush Ashley I. , Sutherland Greg T. , Sivaprasadarao Asipu , Guennewig Boris , Duce James A.
Published: August 2021

Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.
Radiation therapy dose and androgen deprivation therapy in localized prostate cancer: a meta-regression of 5-year outcomes in phase III randomized controlled trials
Authors: Jiang Tommy , Markovic Daniela , Patel Jay , Juarez Jesus E. , Ma Ting Martin , Shabsovich David , Nickols Nicholas G. , Reiter Robert E. , Elashoff David , Rettig Matthew B. , Zaorsky Nicholas G. , Spratt Daniel E. , Kishan Amar U.
Published: August 2021

Background

While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer.

Methods

Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial.

Results

Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22–0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20–0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41–0.75, p < 0.001).

Conclusion

While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.
Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs
Authors: Gan Yibo , He Jian , Zhu Jun , Xu Zhengyang , Wang Zhong , Yan Jing , Hu Ou , Bai Zhijie , Chen Lin , Xie Yangli , Jin Min , Huang Shuo , Liu Bing , Liu Peng
Published: August 2021

A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development, homeostasis, and disease of human intervertebral disks (IVDs) remains challenging. Here, the transcriptomic landscape of 108 108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs, including the nucleus pulposus (NP), annulus fibrosus, and cartilage endplate (CEP). The chondrocyte subclusters were classified based on their potential regulatory, homeostatic, and effector functions in extracellular matrix (ECM) homeostasis. Notably, in the NP, a PROCR+ resident progenitor population showed enriched colony-forming unit-fibroblast (CFU-F) activity and trilineage differentiation capacity. Finally, intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-β cascades are important cues in the NP microenvironment. In conclusion, a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.
Long-term exhaustion of the inbreeding load in Drosophila melanogaster
Authors: Pérez-Pereira Noelia , Pouso Ramón , Rus Ana , Vilas Ana , López-Cortegano Eugenio , García-Dorado Aurora , Quesada Humberto , Caballero Armando
Published: August 2021

Inbreeding depression, the decline in fitness of inbred individuals, is a ubiquitous phenomenon of great relevance in evolutionary biology and in the fields of animal and plant breeding and conservation. Inbreeding depression is due to the expression of recessive deleterious alleles that are concealed in heterozygous state in noninbred individuals, the so-called inbreeding load. Genetic purging reduces inbreeding depression by removing these alleles when expressed in homozygosis due to inbreeding. It is generally thought that fast inbreeding (such as that generated by full-sib mating lines) removes only highly deleterious recessive alleles, while slow inbreeding can also remove mildly deleterious ones. However, a question remains regarding which proportion of the inbreeding load can be removed by purging under slow inbreeding in moderately large populations. We report results of two long-term slow inbreeding Drosophila experiments (125–234 generations), each using a large population and a number of derived lines with effective sizes about 1000 and 50, respectively. The inbreeding load was virtually exhausted after more than one hundred generations in large populations and between a few tens and over one hundred generations in the lines. This result is not expected from genetic drift alone, and is in agreement with the theoretical purging predictions. Computer simulations suggest that these results are consistent with a model of relatively few deleterious mutations of large homozygous effects and partially recessive gene action.
Structural descriptor for enhanced spin-splitting in 2D hybrid perovskites
Authors: Jana Manoj K. , Song Ruyi , Xie Yi , Zhao Rundong , Sercel Peter C. , Blum Volker , Mitzi David B.
Published: August 2021

Two-dimensional (2D) hybrid metal halide perovskites have emerged as outstanding optoelectronic materials and are potential hosts of Rashba/Dresselhaus spin-splitting for spin-selective transport and spin-orbitronics. However, a quantitative microscopic understanding of what controls the spin-splitting magnitude is generally lacking. Through crystallographic and first-principles studies on a broad array of chiral and achiral 2D perovskites, we demonstrate that a specific bond angle disparity connected with asymmetric tilting distortions of the metal halide octahedra breaks local inversion symmetry and strongly correlates with computed spin-splitting. This distortion metric can serve as a crystallographic descriptor for rapid discovery of potential candidate materials with strong spin-splitting. Our work establishes that, rather than the global space group, local inorganic layer distortions induced via appropriate organic cations provide a key design objective to achieve strong spin-splitting in perovskites. New chiral perovskites reported here couple a sizeable spin-splitting with chiral degrees of freedom and offer a unique paradigm of potential interest for spintronics.
Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern
Authors: Skelly Donal T. , Harding Adam C. , Gilbert-Jaramillo Javier , Knight Michael L. , Longet Stephanie , Brown Anthony , Adele Sandra , Adland Emily , Brown Helen ,   Medawar Laboratory Team, Chinnakannan Senthil , Donnison Timothy , Ali Mohammad , Rongkard Patpong , Pace Matthew , Zacharopoulou Peny , Robinson Nicola , Csala Anna , De Lara Cathy , Hutchings Claire L. , Mehta Hema , Lee Lian Ni , Edmans Matthew , Hackstein Carl-Philipp , Phalora Prabhjeet , Li Wenqin , Phillips Eloise , Malone Tom , Ogbe Ane , Jay Cecilia , Tipoe Timothy , Tipton Tom , Stafford Lizzie , Mentzer Alexander J. , Johnson Síle A. , Amini Ali ,   OPTIC (Oxford Protective T cell Immunology for COVID-19) Clinical Group, Marjot Thomas , Dimitriadis Stavros , Simmons Beatrice , Deeks Alexandra , Kerneis Sven , Abuelgasim Hibatullah , Wilson Robert , Thomas Sarah R. , Watson Adam , Alhussni Ahmed , Cutteridge Joseph , Weeks Esme , Denly Lucy , Lillie Katy , Holmes Jennifer , Matthews Philppa C. , O’Donnell Denise , Tan Tiong Kit , Schimanski Lisa , Huang Kuan-Ying A. , Rijal Pramila ,   PITCH (Protective Immunity T cells in Health Care Worker) Study Group, Turtle Lance , de Silva Thushan , Richter Alex , Duncan Christopher J. A. , Payne Rebecca P. , Moore Shona C. ,   C-MORE/PHOSP-C Group, Knight Julian C. , Cassar Mark Philip , Raman Betty , Neubauer Stefan , Fries Anastasia , Talbot Nick P. , Petousi Nayia , Ho Ling-Pei , Peng Yanchun , Dong Tao , Camara Susana , Marinou Spyridoula , Linder Aline , Adlou Syed , Kasanyinga Mwila , Bridges-Webb Alice , Hill Jennifer , Silva-Reyes Laura , Blackwell Luke , Frater John , Goulder Philip , Conlon Christopher P. , Jeffery Katie , Dold Christina , Pollard Andrew J. , Sigal Alex , de Oliveira Tulio , Townsend Alain R. , Klenerman Paul , Dunachie Susanna J. , Barnes Eleanor , Carroll Miles W. , James William S.
Published: August 2021

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.
High COVID-19 transmission potential associated with re-opening universities can be mitigated with layered interventions
Authors: Brooks-Pollock Ellen , Christensen Hannah , Trickey Adam , Hemani Gibran , Nixon Emily , Thomas Amy C. , Turner Katy , Finn Adam , Hickman Matt , Relton Caroline , Danon Leon
Published: August 2021

Controlling COVID-19 transmission in universities poses challenges due to the complex social networks and potential for asymptomatic spread. We developed a stochastic transmission model based on realistic mixing patterns and evaluated alternative mitigation strategies. We predict, for plausible model parameters, that if asymptomatic cases are half as infectious as symptomatic cases, then 15% (98% Prediction Interval: 6–35%) of students could be infected during the first term without additional control measures. First year students are the main drivers of transmission with the highest infection rates, largely due to communal residences. In isolation, reducing face-to-face teaching is the most effective intervention considered, however layering multiple interventions could reduce infection rates by 75%. Fortnightly or more frequent mass testing is required to impact transmission and was not the most effective option considered. Our findings suggest that additional outbreak control measures should be considered for university settings.
High-harmonic generation in metallic titanium nitride
Authors: Korobenko A. , Saha S. , Godfrey A. T. K. , Gertsvolf M. , Naumov A. Yu. , Villeneuve D. M. , Boltasseva A. , Shalaev V. M. , Corkum P. B.
Published: August 2021

High-harmonic generation is a cornerstone of nonlinear optics. It has been demonstrated in dielectrics, semiconductors, semi-metals, plasmas, and gases, but, until now, not in metals. Here we report high harmonics of 800-nm-wavelength light irradiating metallic titanium nitride film. Titanium nitride is a refractory metal known for its high melting temperature and large laser damage threshold. We show that it can withstand few-cycle light pulses with peak intensities as high as 13 TW/cm2, enabling high-harmonics generation up to photon energies of 11 eV. We measure the emitted vacuum ultraviolet radiation as a function of the crystal orientation with respect to the laser polarization and show that it is consistent with the anisotropic conduction band structure of titanium nitride. The generation of high harmonics from metals opens a link between solid and plasma harmonics. In addition, titanium nitride is a promising material for refractory plasmonic devices and could enable compact vacuum ultraviolet frequency combs.
Dual metal nanoparticles within multicompartmentalized mesoporous organosilicas for efficient sequential hydrogenation
Authors: Zou Houbing , Dai Jinyu , Suo Jinquan , Ettelaie Rammile , Li Yuan , Xue Nan , Wang Runwei , Yang Hengquan
Published: August 2021

Controlling localization of multiple metal nanoparticles on a single support is at the cutting edge of designing cascade catalysts, but is still a scientific and technological challenge because of the lack of nanostructured materials that can not only host metal nanoparticles in different sub-compartments but also enable efficient molecular transport between different metals. Herein we report a multicompartmentalized mesoporous organosilica with spatially separated sub-compartments that are connected by short nanochannels. Such a unique structure allows co-localization of Ru and Pd nanoparticles in a nanoscale proximal fashion. The so designed cascade catalyst exhibits an order of magnitude activity enhancement in the sequential hydrogenation of nitroarenes to cyclohexylamines compared with its mono/bi-metallic counterparts. Crucially, an interesting phenomenon of neighboring metal-assisted hydrogenation via hydrogen spillover is observed, contributing to the significant enhancement in catalytic efficiency. The multicompartmentalized architectures along with the revealed mechanism of accelerated hydrogenation provide vast opportunity for designing efficient cascade catalysts.
Direct deoxygenative borylation of carboxylic acids
Authors: Li Jianbin , Huang Chia-Yu , Ataya Mohamad , Khaliullin Rustam Z. , Li Chao-Jun
Published: August 2021

Carboxylic acids are readily available, structurally diverse and shelf-stable; therefore, converting them to the isoelectronic boronic acids, which play pivotal roles in different settings, would be highly enabling. In contrast to the well-recognised decarboxylative borylation, the chemical space of carboxylic-to-boronic acid transformation via deoxygenation remains underexplored due to the thermodynamic and kinetic inertness of carboxylic C-O bonds. Herein, we report a deoxygenative borylation reaction of free carboxylic acids or their sodium salts to synthesise alkylboronates under metal-free conditions. Promoted by a uniquely Lewis acidic and strongly reducing diboron reagent, bis(catecholato)diboron (B2cat2), a library of aromatic carboxylic acids are converted to the benzylboronates. By leveraging the same borylative manifold, a facile triboration process with aliphatic carboxylic acids is also realised, diversifying the pool of available 1,1,2-alkyl(trisboronates) that were otherwise difficult to access. Detailed mechanistic studies reveal a stepwise C-O cleavage profile, which could inspire and encourage future endeavours on more appealing reductive functionalisation of oxygenated feedstocks.
Genome-scale target identification in Escherichia coli for high-titer production of free fatty acids
Authors: Fang Lixia , Fan Jie , Luo Shulei , Chen Yaru , Wang Congya , Cao Yingxiu , Song Hao
Published: August 2021

To construct a superior microbial cell factory for chemical synthesis, a major challenge is to fully exploit cellular potential by identifying and engineering beneficial gene targets in sophisticated metabolic networks. Here, we take advantage of CRISPR interference (CRISPRi) and omics analyses to systematically identify beneficial genes that can be engineered to promote free fatty acids (FFAs) production in Escherichia coli. CRISPRi-mediated genetic perturbation enables the identification of 30 beneficial genes from 108 targets related to FFA metabolism. Then, omics analyses of the FFAs-overproducing strains and a control strain enable the identification of another 26 beneficial genes that are seemingly irrelevant to FFA metabolism. Combinatorial perturbation of four beneficial genes involving cellular stress responses results in a recombinant strain ihfAL−-aidB+-ryfAM−-gadAH−, producing 30.0 g L−1 FFAs in fed-batch fermentation, the maximum titer in E. coli reported to date. Our findings are of help in rewiring cellular metabolism and interwoven intracellular processes to facilitate high-titer production of biochemicals.
Revealing the chirality origin and homochirality crystallization of Ag14 nanocluster at the molecular level
Authors: Liang Xiao-Qian , Li Ying-Zhou , Wang Zhi , Zhang Shan-Shan , Liu Yi-Cheng , Cao Zhao-Zhen , Feng Lei , Gao Zhi-Yong , Xue Qing-Wang , Tung Chen-Ho , Sun Di
Published: August 2021

Although chirality is an ever-present characteristic in biology and some artificial molecules, controlling the chirality and demystifying the chirality origin of complex assemblies remain challenging. Herein, we report two homochiral Ag14 nanoclusters with inherent chirality originated from identical rotation of six square faces on a Ag8 cube driven by intra-cluster π···π stacking interaction between pntp− (Hpntp = p-nitrothiophenol) ligands. The spontaneous resolution of the racemic (SD/rac-Ag14a) to homochiral nanoclusters (SD/L-Ag14 and SD/R-Ag14) can be realized by re-crystallizing SD/rac-Ag14a in acetonitrile, which promotes the homochiral crystallization in solid state by forming C–H···O/N hydrogen bonds with nitro oxygen atoms in pntp− or aromatic hydrogen atoms in dpph (dpph = 1,6-bis(diphenylphosphino)hexane) on Ag14 nanocluster. This work not only provides strategic guidance for the syntheses of chiral silver nanoclusters in an all-achiral environment, but also deciphers the origin of chirality at molecular level by identifying the special effects of intra- and inter-cluster supramolecular interactions.
Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures
Authors: Barski Michal S. , Vanzo Teresa , Zhao Xue Zhi , Smith Steven J. , Ballandras-Colas Allison , Cronin Nora B. , Pye Valerie E. , Hughes Stephen H. , Burke Terrence R. , Cherepanov Peter , Maertens Goedele N.
Published: August 2021

Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.
Difluorocarbene enables to access 2-fluoroindoles from ortho-vinylanilines
Authors: Su Jianke , Hu Xinyuan , Huang Hua , Guo Yu , Song Qiuling
Published: August 2021

2-Fluoroindoles as an important structural scaffold are widely existing in many bioactive or therapeutic agents. Despite their potential usefulness, efficient constructions of 2-fluoroindole derivatives are very sparce. The development of straightforward synthetic approaches to access 2-fluoroindoles is highly desirable for studying their fundamental properties and applications. Herein, we report an efficient and general strategy for the construction of 2-fluoroindoles in which a wide variety of 2-fluoroindoles were accessed with high efficiency and chemoselectivity. Instead of starting from indole skeletons, our strategy constructs indole scaffolds alongside the incorporation of fluorine atom on C2 position in a formal [4+1] cyclization from readily accessible ortho-vinylanilines and difluorocarbene. In our protocol, commercially accessible halodifluoroalkylative reagents provide one carbon and one fluorine atom by cleaving one C-N tertiary bond and forming one C-N bond and one C-C double bond with ortho-vinylanilines. Downstream transformations on 2-fluoroindoles lead to various valuable bioactive molecules which demonstrated significant synthetic advantages over previous reports. And mechanistic studies suggest that the reaction undergoes a cascade difluorocarbene-trapping and intramolecular Michael addition reaction followed by Csp3-F bond cleavage.
Circulating cell-free DNA-based methylation patterns for breast cancer diagnosis
Authors: Zhang Xianyu , Zhao Dezhi , Yin Yanling , Yang Ting , You Zilong , Li Dalin , Chen Yanbo , Jiang Yongdong , Xu Shouping , Geng Jingshu , Zhao Yashuang , Wang Jun , Li Hui , Tao Jinsheng , Lei Shan , Jiang Zeyu , Chen Zhiwei , Yu Shihui , Fan Jian-Bing , Pang Da
Published: August 2021

Mammography is used to detect breast cancer (BC), but its sensitivity is limited, especially for dense breasts. Circulating cell-free DNA (cfDNA) methylation tests is expected to compensate for the deficiency of mammography. We derived a specific panel of markers based on computational analysis of the DNA methylation profiles from The Cancer Genome Atlas (TCGA). Through training (n = 160) and validation set (n = 69), we developed a diagnostic prediction model with 26 markers, which yielded a sensitivity of 89.37% and a specificity of 100% for differentiating malignant disease from normal lesions [AUROC = 0.9816 (95% CI: 96.09-100%), and AUPRC = 0.9704 (95% CI: 94.54–99.46%)]. A simplified 4-marker model including cg23035715, cg16304215, cg20072171, and cg21501525 had a similar diagnostic power [AUROC = 0.9796 (95% CI: 95.56–100%), and AUPRC = 0.9220 (95% CI: 91.02–94.37%)]. We found that a single cfDNA methylation marker, cg23035715, has a high diagnostic power [AUROC = 0.9395 (95% CI: 89.72–99.27%), and AUPRC = 0.9111 (95% CI: 88.45–93.76%)], with a sensitivity of 84.90% and a specificity of 93.88%. In an independent testing dataset (n = 104), the obtained diagnostic prediction model discriminated BC patients from normal controls with high accuracy [AUROC = 0.9449 (95% CI: 90.07–98.91%), and AUPRC = 0.8640 (95% CI: 82.82–89.98%)]. We compared the diagnostic power of cfDNA methylation and mammography. Our model yielded a sensitivity of 94.79% (95% CI: 78.72–97.87%) and a specificity of 98.70% (95% CI: 86.36–100%) for differentiating malignant disease from normal lesions [AUROC = 0.9815 (95% CI: 96.75–99.55%), and AUPRC = 0.9800 (95% CI: 96.6–99.4%)], with better diagnostic power and had better diagnostic power than that of using mammography [AUROC = 0.9315 (95% CI: 89.95–96.34%), and AUPRC = 0.9490 (95% CI: 91.7–98.1%)]. In addition, hypermethylation profiling provided insights into lymph node metastasis stratifications (p < 0.05). In conclusion, we developed and tested a cfDNA methylation model for BC diagnosis with better performance than mammography.
Emergent properties at oxide interfaces controlled by ferroelectric polarization
Authors: Ye Fan , Zhang Yi , Addiego Christopher , Xu Mingjie , Huyan Huaixun , Ren Xiaobing , Pan Xiaoqing
Published: August 2021

Ferroelectric materials are characterized by the spontaneous polarization switchable by the applied fields, which can act as a “gate” to control various properties of ferroelectric/insulator interfaces. Here we review the recent studies on the modulation of oxide hetero-/homo-interfaces by ferroelectric polarization. We discuss the potential applications of recently developed four-dimensional scanning transmission electron microscopy and how it can provide insights into the fundamental understanding of ferroelectric polarization-induced phenomena and stimulate future computational studies. Finally, we give the outlook for the potentials, the challenges, and the opportunities for the contribution of materials computation to future progress in the area.
Metformin treatment for 8 days impacts multiple intestinal parameters in high-fat high-sucrose fed mice
Authors: Bravard Amélie , Gérard Céline , Defois Clémence , Benoit Bérengère , Makki Kassem , Meugnier Emmanuelle , Rainteau Dominique , Rieusset Jennifer , Godet Murielle , Vidal Hubert
Published: August 2021

Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, it is well accepted that the gut plays an important role. To gain more insights into the mechanisms occurring in the different regions of the intestine, adult male mice were fed a high-fat-high sucrose (HFS) diet for 8 days and treated with metformin by gavage (300 mg/day/kg body weight) during the HFS diet. Metformin counteracted HFS diet-induced overexpression of a network of genes involved in the transport of glucose and fatty acids in the different regions of the small intestine. It also induced beneficial modification of secondary bile acid profile in the caecum, with a reduction of deoxycholic acid and lithocholic acid levels and increased abundance of ursodeoxycholic acid and tauroursodeoxycholic acid, potentially leading to FRX inhibition. In parallel, metformin treatment was associated with specific changes of the microbiota composition in the lumen of the different regions of the intestine. Metformin induced a marked increase in the abundance of Akkermansia muciniphila in the lumen all along the gut and counteracted the effects of HFS diet on the abundances of some bacterial groups generally associated with metabolic disturbances (f-Lachnospiraceae, f-Petostreptococcaceae, g-Clostidium). Therefore, the present work clearly emphasises the role of all the regions of the intestinal tract in the beneficial action of the antidiabetic drug metformin in a prediabetic mouse model.
The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium
Authors: Tóth Noémi , Szlovák Jozefina , Kohajda Zsófia , Bitay Gergő , Veress Roland , Horváth Balázs , Papp Julius Gy. , Varró András , Nagy Norbert
Published: August 2021

Cardiac alternans have crucial importance in the onset of ventricular fibrillation. The early explanation for alternans development was the voltage-driven mechanism, where the action potential (AP) restitution steepness was considered as crucial determining factor. Recent results suggest that restitution slope is an inadequate predictor for alternans development, but several studies still claim the role of membrane potential as underlying mechanism of alternans. These controversial data indicate that the relationship of restitution and alternans development is not completely understood. APs were measured by conventional microelectrode technique from canine right ventricular papillary muscles. Ionic currents combined with fluorescent measurements were recorded by patch-clamp technique. APs combined with fluorescent measurements were monitored by sharp microelectrodes. Rapid pacing evoked restitution-independent AP duration (APD) alternans. When non-alternating AP voltage command was used, Ca2+i-transient (CaT) alternans were not observed. When alternating rectangular voltage pulses were applied, CaT alternans were proportional to ICaL amplitude alternans. Selective ICaL inhibition did not influence the fast phase of APD restitution. In this study we found that ICaL has minor contribution in shaping the fast phase of restitution curve suggesting that ICaL—if it plays important role in the alternans mechanism—could be an additional factor that attenuates the reliability of APD restitution slope to predict alternans.
Successful artificial reefs depend on getting the context right due to complex socio-bio-economic interactions
Authors: Brochier Timothée , Brehmer Patrice , Mbaye Adama , Diop Mamadou , Watanuki Naohiko , Terashima Hiroaki , Kaplan David , Auger Pierre
Published: August 2021

Artificial reefs (ARs) are one of the most popular means of supporting marine ecosystem conservation and coastal fisheries, particularly in developing countries. However, ARs generate complex socio-bio-economic interactions that require careful evaluation. This is particularly the case for ARs outside no-take zones, where fish might be subject to enhanced exploitation due to easier catchability. Here, we conducted an interdisciplinary study on how ARs impact fish and fishing yields, combining mathematical and sociological approaches. Both approaches converge to confirm that fishery yields decline when ARs are exploited as if they were open access areas. This situation typically occurs in areas with weak governance and/or high levels of illegal fishing activity, both of which are common in many developing countries. To avoid these adverse effects and their associated ecological consequences, we recommend prioritizing the onset of a long-term surveillance system against illegal fishing activities, and adapting design and location of the ARs based on both and local and academic knowledge, before the deployment of ARs.
New loci and neuronal pathways for resilience to heat stress in cattle
Authors: Cheruiyot Evans K. , Haile-Mariam Mekonnen , Cocks Benjamin G. , MacLeod Iona M. , Xiang Ruidong , Pryce Jennie E.
Published: August 2021

While understanding the genetic basis of heat tolerance is crucial in the context of global warming’s effect on humans, livestock, and wildlife, the specific genetic variants and biological features that confer thermotolerance in animals are still not well characterized. We used dairy cows as a model to study heat tolerance because they are lactating, and therefore often prone to thermal stress. The data comprised almost 0.5 million milk records (milk, fat, and proteins) of 29,107 Australian Holsteins, each having around 15 million imputed sequence variants. Dairy animals often reduce their milk production when temperature and humidity rise; thus, the phenotypes used to measure an individual’s heat tolerance were defined as the rate of milk production decline (slope traits) with a rising temperature–humidity index. With these slope traits, we performed a genome-wide association study (GWAS) using different approaches, including conditional analyses, to correct for the relationship between heat tolerance and level of milk production. The results revealed multiple novel loci for heat tolerance, including 61 potential functional variants at sites highly conserved across 100 vertebrate species. Moreover, it was interesting that specific candidate variants and genes are related to the neuronal system (ITPR1, ITPR2, and GRIA4) and neuroactive ligand–receptor interaction functions for heat tolerance (NPFFR2, CALCR, and GHR), providing a novel insight that can help to develop genetic and management approaches to combat heat stress.
Determination of reliable reference genes for gene expression studies in Chinese chive (Allium tuberosum) based on the transcriptome profiling
Authors: Tong Jing , Hu Manman , Han Beibei , Ji Yanhai , Wang Baoju , Liang Hao , Liu Mingchi , Wu Zhanhui , Liu Ning
Published: August 2021

Chinese chive (Allium tuberosum) is widely cultivated around the world for its unique flavor, nutrient, and medicinal values, yet its molecular mechanism on flavor formation and other metabolic pathways remains intangible. The elucidation of these complex processes begins with investigating the expression of the genes of interest, however the appropriate reference genes (RGs) for normalizing the gene expression are still unavailable in A. tuberosum. To fill this lacuna, transcriptome-wide screening was undertaken to identify the most stable genes according to the analysis of their FPKM values. The expression stability of the RGs was further evaluated using geNorm, NormFinder, BestKeeper, and RefFinder algorithms. The comprehensive analysis showed that GLY1 and SKP1, instead of two traditionally used RGs (eIF1α and ACT2), were the most stable genes across diverse A. tuberosum tissues, indicating the necessity to carefully validate the stability of RGs prior to their use for normalizations. As indicated by geNorm, the normalizations with at least two RGs could give more accurate results. qRT-PCR experiments were conducted with randomly selected genes, demonstrating that normalization with a combination of GLY1 and SKP1 resulted in reliable normalization results. Our finding represents the first attempt toward establishing a standardized qRT-PCR analysis in this economically important vegetable.