bluuebunny/crossref_metadata_2025 huggingface dataset:
Views and experiences of family physicians about Syrian refugee patients in Turkey: a qualitative research
Authors: Ayhan Baser Duygu , Mıhcı Özge , Direk Meltem Tugce , Cankurtaran Mustafa
Published: May 2021

Aim:

The aim of this study was to describe the attitudes, views and solution proposals of family physicians (FPs) about primary healthcare problems of Syrian refugee patients. This study would be the very first study for Turkey that evaluates the attitudes, views and solution proposals of FPs about primary healthcare problems of Syrian refugee patients.

Background:

Following the anti-regime demonstrations that started in March 2011, the developments in Syria created one of the biggest humanitarian crises in the world and the largest number of asylum seekers continue to be hosted in Turkey. There are some studies evaluating asylum seekers’ access to healthcare services in Europe, and the common result is that refugees have free access to primary healthcare services in most countries; however, they face many obstacles when accessing primary healthcare services. While there are studies in the literature evaluating the situation of access to primary healthcare services from the perspective of asylum seekers; there are few studies evaluating the opinions/views of FPs.

Methods:

A qualitative methodology informed by the grounded theory was used to guide the research. A total of 20 FPs were interviewed face to face through semi-structured interviews, using 12 questions about their lived experience and views caring of refugee population. Interviews were analysed thematically.

Finding:

The following themes were revealed: Benefiting from Primary Health Care Services, Benefiting from Rights, Differences Between the Approach/Attitudes of Turkish Citizens and Refugees, Barriers to Healthcare Delivery, Training Needs of Physicians, Solution proposals. FPs reported that there is a need for support in primary care and a need for training them and refugees in this regard and they specified refugee healthcare centres are the best healthcare centres for refugees; however, the number of these and provided services should be increased.
A referral aid for smoking cessation interventions in primary care: study protocol for a randomized controlled trial
Authors: Zijlstra Daniëlle N. , Muris Jean W.M. , Bolman Catherine , Elling J. Mathis , Knapen Vera E.R.A. , de Vries Hein
Published: May 2021

Background:

To expedite the use of evidence-based smoking cessation interventions (EBSCIs) in primary care and to thereby increase the number of successful quit attempts, a referral aid was developed. This aid aims to optimize the referral to and use of EBSCIs in primary care and to increase adherence to Dutch guidelines for smoking cessation.

Methods:

Practice nurses (PNs) will be randomly allocated to an experimental condition or control condition, and will then recruit smoking patients who show a willingness to quit smoking within six months. PNs allocated to the experimental condition will provide smoking cessation guidance in accordance with the referral aid. Patients from both conditions will receive questionnaires at baseline and after six months. Cessation effectiveness will be tested via multilevel logistic regression analyses. Multiple imputations as well as intention to treat analysis will be performed. Intervention appreciation and level of informed decision-making will be compared using analysis of (co)variance. Predictors for appreciation and informed decision-making will be assessed using multiple linear regression analysis and/or structural equation modeling. Finally, a cost-effectiveness study will be conducted.

Discussion:

This paper describes the study design for the development and evaluation of an information and decision tool to support PNs in their guidance of smoking patients and their referral to EBSCIs. The study aims to provide insight into the (cost) effectiveness of an intervention aimed at expediting the use of EBSCIs in primary care.
Transcriptome analysis of aTriticum aestivumlandrace (Roshan) in response to salt stress conditions
Authors: Azimian Jamshid , Hervan Eslam Majidi , Azadi Amin , Bakhtiarizadeh Mohammad Reza , Azizinezhad Reza
Published: May 2021

In order to better understand the molecular mechanisms associated with salinity tolerance, transcriptome analysis of a local salt-tolerant wheat landrace (i.e. Roshan) was performed under salt stress. Transcriptome sequencing yielded 137,508,542 clean reads using the Illumina HiSeq 2000 platform. The results of two alignment programs, i.e. STAR and HISAT2, were used separately to perform the analysis of differentially expressed genes (DEGs) using DESeq2. Finally, a total of 17,897 DEGs were identified by DESeq2. Moreover, gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses identified 108 GO terms and 62 significant KEGG pathways, of which ‘metabolic process’ and ‘metabolic pathways’ were the most abundant enriched term and pathway, respectively. Additionally, key salinity-tolerant genes, including asparagine synthetase, were also identified in the present study. Out of 87 identified families of transcription factors, GAI‐RGA ‐ and ‐SCR (GRAS) was one of the most important, which participates in signal transduction, and meristem maintenance and development. Eventually, to validate the gene expression levels, six DEGs were selected for a quantitative real-time polymerase chain reaction, and the results were in line with those of RNA-Seq. The findings of the current study can guide future genetic and molecular studies and allow a better understanding and improvement of salt tolerance in wheat.
Low-profile, wideband dual-polarized 1 × 2 MIMO antenna with FSS decoupling technique
Authors: Anudeep B. , Krishnamoorthy K. , Rao P. H.
Published: May 2021

A low-profile, wideband dual-polarized 1 × 2 multiple-input-multiple-output (MIMO) antenna with frequency selective surface (FSS) decoupling technique is presented. Low profile is realized with two different artificial magnetic conductor (AMC) cells out of which one operates at 3.5 GHz and other with dual band at 3.1 and 4.5 GHz. The proposed antenna height is maintained at 0.125λ0 which is significantly reduced when compared with the conventional perfect electric conductor (PEC) ground plane. Wideband dual polarization is enabled by two pairs of bow-tie antenna elements surrounded by a square ring placed in the orthogonal orientation. To mitigate the near-field coupling in 1 × 2 MIMO an FSS wall is constructed with wide band stop characteristics from 2.85 to 4.75 GHz. Measured results show by inserting FSS wall vertically, coupling reduction is improved by 27 dB over the existing coupling and the antenna exhibits a bandwidth of 57.14% (2.95–4.95 GHz) for VSWR<2 with port isolation of more than 25 dB for entire band of operation.
Mind the Gap!
Authors: Theobald Maria , Bellhäuser Henrik
Published: May 2021

Abstract. The goal of this study was to investigate the dynamic interplay of affect and time investment during exam preparation using daily learning diaries. University students ( N = 56) reported a simultaneous increase in negative affect as well as intended and actual time investment over the course of the survey period (30 days). Cramming of study time partially accounted for the increase in negative affect. More planning strategies were associated with lower negative and more positive affect. Unmet time schedules predicted higher negative and lower positive affect. Results further revealed compensatory feedback loops: Higher negative affect in the evening predicted higher intended time investment on the next morning, but without improvements in planning strategies. Results suggest that unmet time schedules could contribute to the increase in negative affect during exam preparation. Interventions should promote students’ planning to reduce the difference between intended and actual time investment.
Slab Transport of Fluids to Deep Focus Earthquake Depths—Thermal Modeling Constraints and Evidence From Diamonds
Authors: Shirey Steven B. , Wagner Lara S. , Walter Michael J. , Pearson D. Graham , van Keken Peter E.
Published: May 2021

The nature and cause of deep earthquakes remain enduring unknowns in the field of seismology. We present new models of thermal structures of subducted slabs traced to mantle transition zone depths that permit a detailed comparison between slab pressure/temperature (P/T) paths and hydrated/carbonated mineral phase relations. We find a remarkable correlation between slabs capable of transporting water to transition zone depths in dense hydrous magnesium silicates with slabs that produce seismicity below ∼300‐km depth, primarily between 500 and 700 km. This depth range also coincides with the P/T conditions at which oceanic crustal lithologies in cold slabs are predicted to intersect the carbonate‐bearing basalt solidus to produce carbonatitic melts. Both forms of fluid evolution are well represented by sublithospheric diamonds whose inclusions record the existence of melts, fluids, or supercritical liquids derived from hydrated or carbonate‐bearing slabs at depths (∼300–700 km) generally coincident with deep‐focus earthquakes. We propose that the hydrous and carbonated fluids released from subducted slabs at these depths lead to fluid‐triggered seismicity, fluid migration, diamond precipitation, and inclusion crystallization. Deep focus earthquake hypocenters could track the general region of deep fluid release, migration, and diamond formation in the mantle. The thermal modeling of slabs in the mantle and the correlation between sublithospheric diamonds, deep focus earthquakes, and slabs at depth demonstrate a deep subduction pathway to the mantle transition zone for carbon and volatiles that bypasses shallower decarbonation and dehydration processes.
Migration of Arc Magmatism Above Mantle Wedge Diapirs With Variable Sediment Contribution in the Aegean
Authors: Schaarschmidt A. , Haase K. M. , Voudouris P. C. , Melfos V. , Klemd R.
Published: May 2021

Compiled data show the age progression of magmatic centers along the two approximately linear profiles from NE Greece and NW Turkey to the South Aegean Volcanic Arc. The age progression reveals the southwestward migration of arc magmatic activity from Oligocene to present, perpendicular to the Hellenic Trench. This is in accordance with the migration of the Aegean subduction zone due to the collision of oceanic and continental blocks, trench retreat, mantle flow, and coeval extension. We suggest that the subduction of large volumes of sediments and their contribution to the sub‐arc magma source controlled the composition of calc‐alkaline to high‐K calc‐alkaline and shoshonitic arc magmas during the past 30 Ma. The magma geochemistry and the approximately linear age‐progressive migration of magmatic activity suggest focused ascent of mixed material from the subducted slab into the mantle wedge, most likely in the form of mélange diapirs. Geochemical data along the profile reveals increasing Sr and decreasing Nd isotopes during Upper Miocene in agreement with the ongoing subduction of continental blocks, low subduction rates, and development of an accretionary wedge. The different K‐rich arc magmas reflect the variable subduction of sediments, whereas crustal assimilation often plays a minor role. Magmas with variable 87Sr/86Sr, P/Nd, and Ba/La indicate a variable contribution of clastic, phosphate‐bearing, and barite‐bearing sediments. Low‐degree partial melting in sediment‐dominated mélange diapirs causes the formation of shoshonitic magmas with high Sr and P2O5 contents and high La/Yb in the northern Aegean.
Nonmonotonic Change of the Arctic Ocean Freshwater Storage Capability in a Warming Climate
Authors: Wang Shizhu , Wang Qiang , Shu Qi , Song Zhenya , Lohmann Gerrit , Danilov Sergey , Qiao Fangli
Published: May 2021

Freshwater in the Arctic Ocean is one of the key climate components. It is not well understood how the capability of the Arctic Ocean to store freshwater will develop when freshwater supplies increase in a warming climate. By using numerical experiments, we find that this capability varies with the Arctic sea ice decline nonmonotonically, with the largest capability at intermediate strength of sea ice decline. Through enhancing the ocean surface stress, sea ice decline not only accumulates freshwater toward the Amerasian Basin but also tends to reduce the amount of freshwater in both the Eurasian and Amerasian basins by increasing the occupation of Atlantic‐origin water in the upper ocean. An increase in river runoff modulates the counterbalance of the two competing effects, leading to the nonmonotonic changes of the Arctic freshwater storage capability in a warming climate.
Winter Limnology: How do Hydrodynamics and Biogeochemistry Shape Ecosystems Under Ice?
Authors: Jansen Joachim , MacIntyre Sally , Barrett David C. , Chin Yu‐Ping , Cortés Alicia , Forrest Alexander L. , Hrycik Allison R. , Martin Rosemary , McMeans Bailey C. , Rautio Milla , Schwefel Robert
Published: May 2021

The ice‐cover period in lakes is increasingly recognized for its distinct combination of physical and biological phenomena and ecological relevance. Knowledge gaps exist where research areas of hydrodynamics, biogeochemistry and biology intersect. For example, density‐driven circulation under ice coincides with an expansion of the anoxic zone, but abiotic and biotic controls on oxygen depletion have not been disentangled, and while heterotrophic microorganisms and migrating phytoplankton often thrive at the oxycline, the extent to which physical processes induce fluxes of heat and substrates that support under‐ice food webs is uncertain. Similarly, increased irradiance in spring can promote growth of motile phytoplankton or, if radiatively driven convection occurs, more nutritious diatoms, but links between functional trait selection, trophic transfer to zooplankton and fish, and the prevalence of microbial versus classical food webs in seasonally ice‐covered lakes remain unclear. Under‐ice processes cascade into and from the ice‐free season, and are relevant to annual cycling of energy and carbon through aquatic food webs. Understanding the coupling between state transitions and the reorganization of trophic hierarchies is essential for predicting complex ecosystem responses to climate change. In this interdisciplinary review we describe existing knowledge of physical processes in lakes in winter and the parallel developments in under‐ice biogeochemistry and ecology. We then illustrate interactions between these processes, identify extant knowledge gaps and present (novel) methods to address outstanding questions.
Gradually Cooling of the Yellow Sea Warm Current Driven by Tropical Pacific Subsurface Water Temperature Changes Over the Past 5 kyr
Authors: Li Da‐Wei , Yu Meng , Jia Yonghao , Steinke Stephan , Li Li , Xiang Rong , Zhao Meixun
Published: May 2021

The integrated effects of ocean‐atmosphere dynamics on the temperature evolution in the western North Pacific marginal seas have remained elusive. In order to study mechanisms controlling southern Yellow Sea (YS) temperature changes, bottom water temperature (BWT) changes were reconstructed for the last 8.8 kyr by using the TEXL86 index, which archives temperature signal of the winter season Yellow Sea Warm Current. Our results reveal a series of abrupt multi‐centennial to millennial scale BWT changes (∼1°C), superimposed on a gradual long‐term cooling (>3°C) trend starting from ∼5 ka to the present. The YS BWT changes are positively correlated with subsurface water temperature changes in the Western Pacific Warm Pool (WPWP). The Western Pacific Warm Pool subsurface water cooling signal was most likely transmitted by the Kuroshio Current into the southern YS, highlighting the role of WPWP in influencing thermodynamics of the extratropical regions during the Holocene.
Towards integrated photonic interposers for processing octave-spanning microresonator frequency combs
Authors: Rao Ashutosh , Moille Gregory , Lu Xiyuan , Westly Daron A. , Sacchetto Davide , Geiselmann Michael , Zervas Michael , Papp Scott B. , Bowers John , Srinivasan Kartik
Published: May 2021

Microcombs—optical frequency combs generated in microresonators—have advanced tremendously in the past decade, and are advantageous for applications in frequency metrology, navigation, spectroscopy, telecommunications, and microwave photonics. Crucially, microcombs promise fully integrated miniaturized optical systems with unprecedented reductions in cost, size, weight, and power. However, the use of bulk free-space and fiber-optic components to process microcombs has restricted form factors to the table-top. Taking microcomb-based optical frequency synthesis around 1550 nm as our target application, here, we address this challenge by proposing an integrated photonics interposer architecture to replace discrete components by collecting, routing, and interfacing octave-wide microcomb-based optical signals between photonic chiplets and heterogeneously integrated devices. Experimentally, we confirm the requisite performance of the individual passive elements of the proposed interposer—octave-wide dichroics, multimode interferometers, and tunable ring filters, and implement the octave-spanning spectral filtering of a microcomb, central to the interposer, using silicon nitride photonics. Moreover, we show that the thick silicon nitride needed for bright dissipative Kerr soliton generation can be integrated with the comparatively thin silicon nitride interposer layer through octave-bandwidth adiabatic evanescent coupling, indicating a path towards future system-level consolidation. Finally, we numerically confirm the feasibility of operating the proposed interposer synthesizer as a fully assembled system. Our interposer architecture addresses the immediate need for on-chip microcomb processing to successfully miniaturize microcomb systems and can be readily adapted to other metrology-grade applications based on optical atomic clocks and high-precision navigation and spectroscopy.
Early-life oxytocin attenuates the social deficits induced by caesarean-section delivery in the mouse
Authors: Morais Livia H. , Golubeva Anna V. , Casey Sophie , Scott Karen A. , Ramos Costa Ana Paula , Moloney Gerard M. , Dinan Timothy G. , Cryan John F.
Published: May 2021

The oxytocin (OXT) system has been strongly implicated in the regulation of social behaviour and anxiety, potentially contributing to the aetiology of a wide range of neuropathologies. Birth by Caesarean-section (C-section) results in alterations in microbiota diversity in early-life, alterations in brain development and has recently been associated with long-term social and anxiety-like behaviour deficits. In this study, we assessed whether OXT intervention in the early postnatal period could reverse C-section-mediated effects on behaviour, and physiology in early life and adulthood. Following C-section or per vaginum birth, pups were administered with OXT (0.2 or 2 μg/20 μl; s.c.) or saline daily from postnatal days 1–5. We demonstrate that early postnatal OXT treatment has long-lasting effects reversing many of the effects of C-section on mouse behaviour and physiology. In early-life, high-dose OXT administration attenuated C-section-mediated maternal attachment impairments. In adulthood, low-dose OXT restored social memory deficits, some aspects of anxiety-like behaviour, and improved gastrointestinal transit. Furthermore, as a consequence of OXT intervention in early life, OXT plasma levels were increased in adulthood, and dysregulation of the immune response in C-section animals was attenuated by both doses of OXT treatment. These findings indicate that there is an early developmental window sensitive to manipulations of the OXT system that can prevent lifelong behavioural and physiological impairments associated with mode of birth.
Onset and recurrence of psychiatric disorders associated with anti-hypertensive drug classes
Authors: Colbourne Lucy , Luciano Sierra , Harrison Paul J.
Published: May 2021

The major anti-hypertensive (AHT) drug classes have been associated with differential risks of psychiatric disorders. However, existing data are limited largely to depression, and confounding variables have not always been controlled for. We sought to fill the evidence gap, using TriNetX Analytics, an electronic health records network. Amongst 58.6 million patients aged 18–90 years, patients prescribed a calcium channel blocker (CCB) were compared with those taking a diuretic, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or β-blocker. Cohorts were propensity score-matched for age, sex, race, and blood pressure. Over a 2-year exposure period, we measured the incidence and risk ratio of a first diagnosis (ICD-10 codes), or a recurrence, of psychotic, affective, and anxiety disorders, as well as substance use disorders and sleep disorders. Cohort sizes ranged from 33,734 to 322,814. CCBs were associated with a lower incidence of psychotic, affective, and anxiety disorders than β-blockers (risk ratios 0.69–0.99) and a higher incidence than ARBs (risk ratios 1.04–2.23) for both first and recurrent diagnoses. Comparisons of CCBs with ACEIs or diuretics showed smaller risk ratios that varied between disorders, and between first episode and recurrence. AHT classes were also associated with the incidence of substance use and sleep disorders. Results remained largely unchanged after more extensive cohort matching for additional potential confounders. In a secondary analysis, a comparison between ARBs and ACEIs showed lower rates of psychotic, affective, and substance use disorders with ARBs, but higher risks of anxiety and sleep disorders. In conclusion, AHT classes are differentially associated with the incidence of psychiatric disorders. ARBs show the most advantageous profile and β-blockers the least. The apparent beneficial effects of ARBs merit further study.
Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma
Authors: Ma Xiaohong , Zhao Tianyi , Yan Hong , Guo Kui , Liu Zhiming , Wei Lina , Lu Wei , Qiu Chunping , Jiang Jie
Published: May 2021

Progesterone resistance can significantly restrict the efficacy of conservative treatment for patients with endometrial cancer who wish to preserve their fertility or those who suffer from advanced and recurrent cancer. SREBP1 is known to be involved in the occurrence and progression of endometrial cancer, although the precise mechanism involved remains unclear. In the present study, we carried out microarray analysis in progesterone-sensitive and progesterone-resistant cell lines and demonstrated that SREBP1 is related to progesterone resistance. Furthermore, we verified that SREBP1 is over-expressed in both drug-resistant tissues and cells. Functional studies further demonstrated that the inhibition of SREBP1 restored the sensitivity of endometrial cancer to progesterone both in vitro and in vivo, and that the over-expression of SREBP1 promoted resistance to progesterone. With regards to the mechanism involved, we found that SREBP1 promoted the proliferation of endometrial cancer cells and inhibited their apoptosis by activating the NF-κB pathway. To solve the problem of clinical application, we found that Fatostatin, an inhibitor of SREBP1, could increase the sensitivity of endometrial cancer to progesterone and reverse progesterone resistance by inhibiting SREBP1 both in vitro and in vivo. Our results highlight the important role of SREBP1 in progesterone resistance and suggest that the use of Fatostatin to target SREBP1 may represent a new method to solve progesterone resistance in patients with endometrial cancer.
Roles of tRNA metabolism in aging and lifespan
Authors: Zhou Zheng , Sun Bao , Yu Dongsheng , Bian Meng
Published: May 2021

Transfer RNAs (tRNAs) mainly function as adapter molecules that decode messenger RNAs (mRNAs) during protein translation by delivering amino acids to the ribosome. Traditionally, tRNAs are considered as housekeepers without additional functions. Nevertheless, it has become apparent from biological research that tRNAs are involved in various physiological and pathological processes. Aging is a form of gradual decline in physiological function that ultimately leads to increased vulnerability to multiple chronic diseases and death. Interestingly, tRNA metabolism is closely associated with aging and lifespan. In this review, we summarize the emerging roles of tRNA-associated metabolism, such as tRNA transcription, tRNA molecules, tRNA modifications, tRNA aminoacylation, and tRNA derivatives, in aging and lifespan, aiming to provide new ideas for developing therapeutics and ultimately extending lifespan in humans.
Synthesized soliton crystals
Authors: Lu Zhizhou , Chen Hao-Jing , Wang Weiqiang , Yao Lu , Wang Yang , Yu Yan , Little B. E. , Chu S. T. , Gong Qihuang , Zhao Wei , Yi Xu , Xiao Yun-Feng , Zhang Wenfu
Published: May 2021

Dissipative Kerr soliton (DKS) featuring broadband coherent frequency comb with compact size and low power consumption, provides an unparalleled tool for nonlinear physics investigation and precise measurement applications. However, the complex nonlinear dynamics generally leads to stochastic soliton formation process and makes it highly challenging to manipulate soliton number and temporal distribution in the microcavity. Here, synthesized and reconfigurable soliton crystals (SCs) are demonstrated by constructing a periodic intra-cavity potential field, which allows deterministic SCs synthesis with soliton numbers from 1 to 32 in a monolithic integrated microcavity. The ordered temporal distribution coherently enhanced the soliton crystal comb lines power up to 3 orders of magnitude in comparison to the single-soliton state. The interaction between the traveling potential field and the soliton crystals creates periodic forces on soliton and results in forced soliton oscillation. Our work paves the way to effectively manipulate cavity solitons. The demonstrated synthesized SCs offer reconfigurable temporal and spectral profiles, which provide compelling advantages for practical applications such as photonic radar, satellite communication and radio-frequency filter.
The quantitative metabolome is shaped by abiotic constraints
Authors: Akbari Amir , Yurkovich James T. , Zielinski Daniel C. , Palsson Bernhard O.
Published: May 2021

Living systems formed and evolved under constraints that govern their interactions with the inorganic world. These interactions are definable using basic physico-chemical principles. Here, we formulate a comprehensive set of ten governing abiotic constraints that define possible quantitative metabolomes. We apply these constraints to a metabolic network ofEscherichia colithat represents 90% of its metabolome. We show that the quantitative metabolomes allowed by the abiotic constraints are consistent with metabolomic and isotope-labeling data. We find that: (i) abiotic constraints drive the evolution of high-affinity phosphate transporters; (ii) Charge-, hydrogen- and magnesium-related constraints underlie transcriptional regulatory responses to osmotic stress; and (iii) hydrogen-ion and charge imbalance underlie transcriptional regulatory responses to acid stress. Thus, quantifying the constraints that the inorganic world imposes on living systems provides insights into their key characteristics, helps understand the outcomes of evolutionary adaptation, and should be considered as a fundamental part of theoretical biology and for understanding the constraints on evolution.
TAPBPR promotes antigen loading on MHC-I molecules using a peptide trap
Authors: McShan Andrew C. , Devlin Christine A. , Morozov Giora I. , Overall Sarah A. , Moschidi Danai , Akella Neha , Procko Erik , Sgourakis Nikolaos G.
Published: May 2021

Chaperones Tapasin and TAP-binding protein related (TAPBPR) perform the important functions of stabilizing nascent MHC-I molecules (chaperoning) and selecting high-affinity peptides in the MHC-I groove (editing). While X-ray and cryo-EM snapshots of MHC-I in complex with TAPBPR and Tapasin, respectively, have provided important insights into the peptide-deficient MHC-I groove structure, the molecular mechanism through which these chaperones influence the selection of specific amino acid sequences remains incompletely characterized. Based on structural and functional data, a loop sequence of variable lengths has been proposed to stabilize empty MHC-I molecules through direct interactions with the floor of the groove. Using deep mutagenesis on two complementary expression systems, we find that important residues for the Tapasin/TAPBPR chaperoning activity are located on a large scaffolding surface, excluding the loop. Conversely, loop mutations influence TAPBPR interactions with properly conformed MHC-I molecules, relevant for peptide editing. Detailed biophysical characterization by solution NMR, ITC and FP-based assays shows that the loop hovers above the MHC-I groove to promote the capture of incoming peptides. Our results suggest that the longer loop of TAPBPR lowers the affinity requirements for peptide selection to facilitate peptide loading under conditions and subcellular compartments of reduced ligand concentration, and to prevent disassembly of high-affinity peptide-MHC-I complexes that are transiently interrogated by TAPBPR during editing.
Reversible modulation of circadian time with chronophotopharmacology
Authors: Kolarski Dušan , Miró-Vinyals Carla , Sugiyama Akiko , Srivastava Ashutosh , Ono Daisuke , Nagai Yoshiko , Iida Mui , Itami Kenichiro , Tama Florence , Szymanski Wiktor , Hirota Tsuyoshi , Feringa Ben L.
Published: May 2021

The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology.
Structure-based protein function prediction using graph convolutional networks
Authors: Gligorijević Vladimir , Renfrew P. Douglas , Kosciolek Tomasz , Leman Julia Koehler , Berenberg Daniel , Vatanen Tommi , Chandler Chris , Taylor Bryn C. , Fisk Ian M. , Vlamakis Hera , Xavier Ramnik J. , Knight Rob , Cho Kyunghyun , Bonneau Richard
Published: May 2021

The rapid increase in the number of proteins in sequence databases and the diversity of their functions challenge computational approaches for automated function prediction. Here, we introduce DeepFRI, a Graph Convolutional Network for predicting protein functions by leveraging sequence features extracted from a protein language model and protein structures. It outperforms current leading methods and sequence-based Convolutional Neural Networks and scales to the size of current sequence repositories. Augmenting the training set of experimental structures with homology models allows us to significantly expand the number of predictable functions. DeepFRI has significant de-noising capability, with only a minor drop in performance when experimental structures are replaced by protein models. Class activation mapping allows function predictions at an unprecedented resolution, allowing site-specific annotations at the residue-level in an automated manner. We show the utility and high performance of our method by annotating structures from the PDB and SWISS-MODEL, making several new confident function predictions. DeepFRI is available as a webserver at https://beta.deepfri.flatironinstitute.org/.
Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells
Authors: Funakoshi Shunsuke , Fernandes Ian , Mastikhina Olya , Wilkinson Dan , Tran Thinh , Dhahri Wahiba , Mazine Amine , Yang Donghe , Burnett Benjamin , Lee Jeehoon , Protze Stephanie , Bader Gary D. , Nunes Sara S. , Laflamme Michael , Keller Gordon
Published: May 2021

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.
Interplay of spin–orbit coupling and Coulomb interaction in ZnO-based electron system
Authors: Maryenko D. , Kawamura M. , Ernst A. , Dugaev V. K. , Sherman E. Ya. , Kriener M. , Bahramy M. S. , Kozuka Y. , Kawasaki M.
Published: May 2021

Spin–orbit coupling (SOC) is pivotal for various fundamental spin-dependent phenomena in solids and their technological applications. In semiconductors, these phenomena have been so far studied in relatively weak electron–electron interaction regimes, where the single electron picture holds. However, SOC can profoundly compete against Coulomb interaction, which could lead to the emergence of unconventional electronic phases. Since SOC depends on the electric field in the crystal including contributions of itinerant electrons, electron–electron interactions can modify this coupling. Here we demonstrate the emergence of the SOC effect in a high-mobility two-dimensional electron system in a simple band structure MgZnO/ZnO semiconductor. This electron system also features strong electron–electron interaction effects. By changing the carrier density with Mg-content, we tune the SOC strength and achieve its interplay with electron–electron interaction. These systems pave a way to emergent spintronic phenomena in strong electron correlation regimes and to the formation of quasiparticles with the electron spin strongly coupled to the density.
Dual-atom Pt heterogeneous catalyst with excellent catalytic performances for the selective hydrogenation and epoxidation
Authors: Tian Shubo , Wang Bingxue , Gong Wanbing , He Zizhan , Xu Qi , Chen Wenxing , Zhang Qinghua , Zhu Youqi , Yang Jiarui , Fu Qiang , Chen Chun , Bu Yuxiang , Gu Lin , Sun Xiaoming , Zhao Huijun , Wang Dingsheng , Li Yadong
Published: May 2021

Atomically monodispersed heterogeneous catalysts with uniform active sites and high atom utilization efficiency are ideal heterogeneous catalytic materials. Designing such type of catalysts, however, remains a formidable challenge. Herein, using a wet-chemical method, we successfully achieved a mesoporous graphitic carbon nitride (mpg-C3N4) supported dual-atom Pt2 catalyst, which exhibited excellent catalytic performance for the highly selective hydrogenation of nitrobenzene to aniline. The conversion of ˃99% is significantly superior to the corresponding values of mpg-C3N4-supported single Pt atoms and ultra-small Pt nanoparticles (~2 nm). First-principles calculations revealed that the excellent and unique catalytic performance of the Pt2 species originates from the facile H2 dissociation induced by the diatomic characteristics of Pt and the easy desorption of the aniline product. The produced Pt2/mpg-C3N4 samples are versatile and can be applied in catalyzing other important reactions, such as the selective hydrogenation of benzaldehyde and the epoxidation of styrene.
CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution
Authors: Wang Qinchuan , Hernández-Ochoa Erick O. , Viswanathan Meera C. , Blum Ian D. , Do Danh C. , Granger Jonathan M. , Murphy Kevin R. , Wei An-Chi , Aja Susan , Liu Naili , Antonescu Corina M. , Florea Liliana D. , Talbot C. Conover , Mohr David , Wagner Kathryn R. , Regot Sergi , Lovering Richard M. , Gao Peisong , Bianchet Mario A. , Wu Mark N. , Cammarato Anthony , Schneider Martin F. , Bever Gabriel S. , Anderson Mark E.
Published: May 2021

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.
The SUN1-SPDYA interaction plays an essential role in meiosis prophase I
Authors: Chen Yanyan , Wang Yan , Chen Juan , Zuo Wu , Fan Yong , Huang Sijia , Liu Yongmei , Chen Guangming , Li Qing , Li Jinsong , Wu Jian , Bian Qian , Huang Chenhui , Lei Ming
Published: May 2021

Chromosomes pair and synapse with their homologous partners to segregate correctly at the first meiotic division. Association of telomeres with the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex composed of SUN1 and KASH5 enables telomere-led chromosome movements and telomere bouquet formation, facilitating precise pairwise alignment of homologs. Here, we identify a direct interaction between SUN1 and Speedy A (SPDYA) and determine the crystal structure of human SUN1-SPDYA-CDK2 ternary complex. Analysis of meiosis prophase I process in SPDYA-binding-deficient SUN1 mutant mice reveals that the SUN1-SPDYA interaction is required for the telomere-LINC complex connection and the assembly of a ring-shaped telomere supramolecular architecture at the nuclear envelope, which is critical for efficient homologous pairing and synapsis. Overall, our results provide structural insights into meiotic telomere structure that is essential for meiotic prophase I progression.
Cell morphology-based machine learning models for human cell state classification
Authors: Li Yi , Nowak Chance M. , Pham Uyen , Nguyen Khai , Bleris Leonidas
Published: May 2021

Herein, we implement and access machine learning architectures to ascertain models that differentiate healthy from apoptotic cells using exclusively forward (FSC) and side (SSC) scatter flow cytometry information. To generate training data, colorectal cancer HCT116 cells were subjected to miR-34a treatment and then classified using a conventional Annexin V/propidium iodide (PI)-staining assay. The apoptotic cells were defined as Annexin V-positive cells, which include early and late apoptotic cells, necrotic cells, as well as other dying or dead cells. In addition to fluorescent signal, we collected cell size and granularity information from the FSC and SSC parameters. Both parameters are subdivided into area, height, and width, thus providing a total of six numerical features that informed and trained our models. A collection of logistical regression, random forest, k-nearest neighbor, multilayer perceptron, and support vector machine was trained and tested for classification performance in predicting cell states using only the six aforementioned numerical features. Out of 1046 candidate models, a multilayer perceptron was chosen with 0.91 live precision, 0.93 live recall, 0.92 live f value and 0.97 live area under the ROC curve when applied on standardized data. We discuss and highlight differences in classifier performance and compare the results to the standard practice of forward and side scatter gating, typically performed to select cells based on size and/or complexity. We demonstrate that our model, a ready-to-use module for any flow cytometry-based analysis, can provide automated, reliable, and stain-free classification of healthy and apoptotic cells using exclusively size and granularity information.
Heat impact during laser ablation extraction of mineralised tissue micropillars
Authors: McPhee Samuel , Groetsch Alexander , Shephard Jonathan D. , Wolfram Uwe
Published: May 2021

The underlying constraint of ultrashort pulsed laser ablation in both the clinical and micromachining setting is the uncertainty regarding the impact on the composition of material surrounding the ablated region. A heat model representing the laser-tissue interaction was implemented into a finite element suite to assess the cumulative temperature response of bone during ultrashort pulsed laser ablation. As an example, we focus on the extraction of mineralised collagen fibre micropillars. Laser induced heating can cause denaturation of the collagen, resulting in ultrastructural loss which could affect mechanical testing results. Laser parameters were taken from a used micropillar extraction protocol. The laser scanning pattern consisted of 4085 pulses, with a final radial pass being 22 $$\upmu {\text {m}}$$μmaway from the micropillar. The micropillar temperature was elevated to 70.58 $$^{\circ }{\text {C}}$$∘C, remaining 79.42 $$^{\circ }{\text {C}}$$∘Clower than that of which we interpret as an onset for denaturation. We verified the results by means of Raman microscopy and Energy Dispersive X-ray Microanalysis and found the laser-material interaction had no effect on the collagen molecules or mineral nanocrystals that constitute the micropillars. We, thus, show that ultrashort pulsed laser ablation is a safe and viable tool to fabricate bone specimens for mechanical testing at the micro- and nanoscale and we provide a computational model to efficiently assess this.
PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma
Authors: Vidarsdottir Linda , Azimi Alireza , Das Ishani , Sigvaldadottir Ingibjorg , Suryo Rahmanto Aldwin , Petri Andreas , Kauppinen Sakari , Ingvar Christian , Jönsson Göran , Olsson Håkan , Frostvik Stolt Marianne , Tuominen Rainer , Sangfelt Olle , Pokrovskaja Tamm Katja , Hansson Johan , Grandér Dan , Egyházi Brage Suzanne , Johnsson Per
Published: May 2021

BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.
Leaky and waveguide modes in biperiodic holograms
Authors: Keshmiri Hamid , Armin Fahimeh , Elsayad Kareem , Schreiber Frank , Moreno Mauricio
Published: May 2021

This study details a theoretical analysis of leaky and waveguide modes in biperiodic all-dielectric holograms. By tuning diffraction orders and subsequently confining local density of optical states at two distinct resonance wavelengths, we present a new class of highly sensitive refractive index biosensing platforms that are capable of resolving 35.5 to 41.3 nm/RIU of spectral shift for two separate biological analytes.
Environmental DNA detection of an invasive ant species (Linepithema humile) from soil samples
Authors: Yasashimoto Tetsu , Sakata Masayuki K. , Sakita Tomoya , Nakajima Satoko , Ozaki Mamiko , Minamoto Toshifumi
Published: May 2021

Alien ant species (Formicidae, Hymenoptera) cause serious damage worldwide. Early detection of invasion and rapid management are significant for controlling these species. However, these attempts are sometimes hindered by the need for direct detection techniques, such as capture, visual observation, or morphological identification. In this study, we demonstrated that environmental DNA (eDNA) analysis can be used as a monitoring tool for alien ants using Linepithema humile (Argentine ant), one of the most invasive ants, as a model species. We designed a new real-time PCR assay specific to L. humile and successfully detected eDNA from the surface soil. The reliability of eDNA analysis was substantiated by comparing eDNA detection results with traditional survey results. Additionally, we examined the relationship between eDNA concentration and distance from nests and trails. Our results support the effectiveness of eDNA for alien ant monitoring and suggest that this new method could improve our ability to detect invasive ant species.
Ndufs4 ablation decreases synaptophysin expression in hippocampus
Authors: Shil Subrata Kumar , Kagawa Yoshiteru , Umaru Banlanjo Abdulaziz , Nanto-Hara Fumika , Miyazaki Hirofumi , Yamamoto Yui , Kobayashi Shuhei , Suzuki Chitose , Abe Takaaki , Owada Yuji
Published: May 2021

Altered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.