bluuebunny/crossref_metadata_2025 huggingface dataset:
Ubiquitin proteolysis of a CDK-related kinase regulates titan cell formation and virulence in the fungal pathogen Cryptococcus neoformans
Authors: Cao Chengjun , Wang Keyi , Wang Yina , Liu Tong-Bao , Rivera Amariliz , Xue Chaoyang
Published: October 2022

Fungal pathogens often undergo morphological switches, including cell size changes, to adapt to the host environment and cause disease. The pathogenic yeast Cryptococcus neoformans forms so-called ‘titan cells’ during infection. Titan cells are large, polyploid, display alterations in cell wall and capsule, and are more resistant to phagocytosis and various types of stress. Titan cell formation is regulated by the cAMP/PKA signal pathway, which is stimulated by the protein Gpa1. Here, we show that Gpa1 is activated through phosphorylation by a CDK-related kinase (Crk1), which is targeted for degradation by an E3 ubiquitin ligase (Fbp1). Strains overexpressing CRK1 or an allele lacking a PEST domain exhibit increased production of titan cells similarly to the fbp1∆ mutant. Conversely, CRK1 deletion results in reduced titan cell production, indicating that Crk1 stimulates titan cell formation. Crk1 phosphorylates Gpa1, which then localizes to the plasma membrane and activates the cAMP/PKA signal pathway to induce cell enlargement. Furthermore, titan cell-overproducing strains trigger increased Th1 and Th17 cytokine production in CD4+ T cells and show attenuated virulence in a mouse model of systemic cryptococcosis. Overall, our study provides insights into the regulation of titan cell formation and fungal virulence.
Towards a unified theory of plant photosynthesis and hydraulics
Authors: Joshi Jaideep , Stocker Benjamin D. , Hofhansl Florian , Zhou Shuangxi , Dieckmann Ulf , Prentice Iain Colin
Published: October 2022

The global carbon and water cycles are governed by the coupling of CO2and water vapour exchanges through the leaves of terrestrial plants, controlled by plant adaptations to balance carbon gains and hydraulic risks. We introduce a trait-based optimality theory that unifies the treatment of stomatal responses and biochemical acclimation of plants to environments changing on multiple timescales. Tested with experimental data from 18 species, our model successfully predicts the simultaneous decline in carbon assimilation rate, stomatal conductance and photosynthetic capacity during progressive soil drought. It also correctly predicts the dependencies of gas exchange on atmospheric vapour pressure deficit, temperature and CO2. Model predictions are also consistent with widely observed empirical patterns, such as the distribution of hydraulic strategies. Our unified theory opens new avenues for reliably modelling the interactive effects of drying soil and rising atmospheric CO2on global photosynthesis and transpiration.
Direct cell-to-cell transfer in stressed tumor microenvironment aggravates tumorigenic or metastatic potential in pancreatic cancer
Authors: Jang Giyong , Oh Jaeik , Jun Eunsung , Lee Jieun , Kwon Jee Young , Kim Jaesang , Lee Sang-Hyuk , Kim Song Cheol , Cho Sung-Yup , Lee Charles
Published: October 2022

Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44high/SLC16A1high) were similar to cancer stem cell-like-cells (CSCs) with enhanced anchorage-independent growth or invasiveness and acquired metabolic reprogramming. Furthermore, CD24 was a determinant for transition between the tumorsphere formation or invasive properties. Pancreatic cancer patients with CD44low/SLC16A1low expression exhibited better prognoses compared to other groups. Our results suggest that crosstalk via direct cell-to-cell transfer of cellular components foster chemotherapy-induced tumor evolution and that targeting of CD44 and MCT1(encoded by SLC16A1) may be useful strategy to prevent recurrence of gemcitabine-exposed pancreatic cancers.
Laboratory prognostic factors for the long-term survival of multiple system atrophy
Authors: Shin Jung Hwan , Kim Han-Joon , Lee Chan Young , Chang Hee Jin , Woo Kyung Ah , Jeon Beomseok
Published: October 2022

To elucidate the biomarkers related to survival in multiple system atrophy(MSA), we analyzed the predictability of retrospectively collected blood markers for survival in 650 probable MSA. High absolute neutrophil count, red-cell distribution width, C-reactive protein, erythrocyte sedimentation rate, and low hemoglobin, protein, albumin, and creatinine were correlated with higher mortality in MSA. Systemic alteration in inflammation and nutritional status in the early stage are associated with higher mortality in MSA.
Phase flip code with semiconductor spin qubits
Authors: van Riggelen F. , Lawrie W. I. L. , Russ M. , Hendrickx N. W. , Sammak A. , Rispler M. , Terhal B. M. , Scappucci G. , Veldhorst M.
Published: October 2022

The fault-tolerant operation of logical qubits is an important requirement for realizing a universal quantum computer. Spin qubits based on quantum dots have great potential to be scaled to large numbers because of their compatibility with standard semiconductor manufacturing. Here, we show that a quantum error correction code can be implemented using a four-qubit array in germanium. We demonstrate a resonant SWAP gate and by combining controlled-Z and controlled-S−1 gates we construct a Toffoli-like three-qubit gate. We execute a two-qubit phase flip code and find that we can preserve the state of the data qubit by applying a refocusing pulse to the ancilla qubit. In addition, we implement a phase flip code on three qubits, making use of a Toffoli-like gate for the final correction step. Both the quality and quantity of the qubits will require significant improvement to achieve fault-tolerance. However, the capability to implement quantum error correction codes enables co-design development of quantum hardware and software, where codes tailored to the properties of spin qubits and advances in fabrication and operation can now come together to advance semiconductor quantum technology.
Three-year outcomes and predictors for full recovery in patients with early-stage psychosis
Authors: Li Ling , Rami Fatima Zahra , Lee Bo Mi , Kim Woo-Sung , Kim Sung-Wan , Lee Bong Ju , Yu Je-Chun , Lee Kyu Young , Won Seung-Hee , Lee Seung-Hwan , Kim Seung-Hyun , Kang Shi Hyun , Kim Euitae , Chung Young-Chul
Published: October 2022

In the present study, various outcomes over 3-year period in patients with early stage psychosis including remission, recovery, relapse and medication adherence were investigated. Predictor for full recovery at year 3 was also examined. Three-year follow-up data in 534 patients with schizophrenia spectrum disorders (SSD) and psychotic disorder not otherwise specified (PNOS) were examined for overall outcome trajectories. The data of completers at year 3 (n = 157) were used to identify predictors for recovery using logistic regression. The rates of symptomatic remission and full recovery at 6-, 12-, 24-, and 36-month follow-up were 76.10, 69.20, 79.50, and 79.10%, and 22.80, 26.40, 28.60, and 39.60%, respectively. The rates of drop-out and relapse at 6-, 12-, 24-, and 36-month follow-up were 25.4, 29.5, 38.6, and 51.1%, and 3.7, 8.9, 19.0, and 38.9%, respectively. The rates of good adherence and prescription of Long-Acting Injectable Antipsychotics (LAIA) at 6-, 12-, 24- and 36-month follow-up were 87.8, 88.0, 91.9, and 93.9%, and 18.3, 21.7, 22.0, and 25.5%, respectively. Significant predictors for full recovery were duration of untreated psychosis (DUP), family intimacy and physical activity. We observed similar or better results on remission, recovery, and relapse rates compared to other previous studies. Effective psychosocial intervention should be provided to shorten the gap between remission and recovery rates and to address DUP, family issues, and exercise to enhance recovery.
Sterile protection against relapsing malaria with a single-shot vaccine
Authors: Pasini Erica M. , van der Wel Annemarie Voorberg , Heijmans Nicole , Klop Onny , Zeeman Anne-Marie , Oostermeijer Herman , Nieuwenhuis Ivonne , Garcia Roberto Rodriguez , van der Werff Nicole Onur , Hofman Sam O. , Verreck Frank A. W. , Remarque Edmond J. , Faber Bart W. , Kocken Clemens H. M.
Published: October 2022

Vaccine development for Plasmodium vivax, an important human relapsing malaria, is lagging behind. In the case of the most deadly human malaria P. falciparum, unprecedented high levels of protection have been obtained by immunization with live sporozoites under accompanying chemoprophylaxis, which prevents the onset of blood-stage malaria. Such an approach has not been fully evaluated for relapsing malaria. Here, in the P. cynomolgi-rhesus macaque model for relapsing malaria, we employ the parasites’ natural relapsing phenotype to self-boost the immune response against liver-stage parasites, following a single-shot high-dose live sporozoite vaccination. This approach resulted in sterile protection against homologous sporozoite challenge in three out of four animals in the group that was also exposed for several days to blood stages during primary infection and relapses. One out of four animals in the group that received continuous chemoprophylaxis to abort blood-stage exposure was also protected from sporozoite challenge. Although obtained in a small number of animals as part of a Proof-of-Concept study, these results suggest that limited blood-stage parasite exposure may augment protection in this model. We anticipate our data are a starting point for further research into correlates of protection and extrapolation of the single-shot approach to develop efficacious malaria vaccines against relapsing human malaria.
Electrode potential influences the reversibility of lithium-metal anodes
Authors: Ko Seongjae , Obukata Tomohiro , Shimada Tatau , Takenaka Norio , Nakayama Masanobu , Yamada Atsuo , Yamada Yuki
Published: October 2022

Lithium-metal batteries are a promising technology to address the emerging demand for high-energy-density storage systems. However, their cycling encounters a low Coulombic efficiency (CE) due to the unceasing electrolyte decomposition. Improving the stability of solid electrolyte interphase (SEI) suppresses the decomposition and increases CE. However, SEI morphology and chemistry alone cannot account for CE, and a full explanation is still lacking. Here we report that in diverse electrolytes, the large shift (>0.6 V) in the Li electrode potential and its association with the Li+ coordination structure influence the CE. Machine learning regression analysis and vibrational spectroscopy revealed that the formation of ion pairs is essential for upshifting the Li electrode potential, that is, for weakening the reducing ability of Li, which would lead to a high CE with diminished electrolyte decomposition. Various electrolytes with enhanced ion-pairing solution structure are designed to enable a significantly improved CE (>99%).
Quantitative sequencing using BID-seq uncovers abundant pseudouridines in mammalian mRNA at base resolution
Authors: Dai Qing , Zhang Li-Sheng , Sun Hui-Lung , Pajdzik Kinga , Yang Lei , Ye Chang , Ju Cheng-Wei , Liu Shun , Wang Yuru , Zheng Zhong , Zhang Linda , Harada Bryan T. , Dou Xiaoyang , Irkliyenko Iryna , Feng Xinran , Zhang Wen , Pan Tao , He Chuan
Published: October 2022

Functional characterization of pseudouridine (Ψ) in mammalian mRNA has been hampered by the lack of a quantitative method that maps Ψ in the whole transcriptome. We report bisulfite-induced deletion sequencing (BID-seq), which uses a bisulfite-mediated reaction to convert pseudouridine stoichiometrically into deletion upon reverse transcription without cytosine deamination. BID-seq enables detection of abundant Ψ sites with stoichiometry information in several human cell lines and 12 different mouse tissues using 10–20 ng input RNA. We uncover consensus sequences for Ψ in mammalian mRNA and assign different ‘writer’ proteins to individual Ψ deposition. Our results reveal a transcript stabilization role of Ψ sites installed by TRUB1 in human cancer cells. We also detect the presence of Ψ within stop codons of mammalian mRNA and confirm the role of Ψ in promoting stop codon readthrough in vivo. BID-seq will enable future investigations of the roles of Ψ in diverse biological processes.
Retrospectively modeling the effects of increased global vaccine sharing on the COVID-19 pandemic
Authors: Moore Sam , Hill Edward M. , Dyson Louise , Tildesley Michael J. , Keeling Matt J.
Published: October 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused considerable morbidity and mortality worldwide. The protection provided by vaccines and booster doses offered a method of mitigating severe clinical outcomes and mortality. However, by the end of 2021, the global distribution of vaccines was highly heterogeneous, with some countries gaining over 90% coverage in adults, whereas others reached less than 2%. In this study, we used an age-structured model of SARS-CoV-2 dynamics, matched to national data from 152 countries in 2021, to investigate the global impact of different potential vaccine sharing protocols that attempted to address this inequity. We quantified the effects of implemented vaccine rollout strategies on the spread of SARS-CoV-2, the subsequent global burden of disease and the emergence of novel variants. We found that greater vaccine sharing would have lowered the total global burden of disease, and any associated increases in infections in previously vaccine-rich countries could have been mitigated by reduced relaxation of non-pharmaceutical interventions. Our results reinforce the health message, pertinent to future pandemics, that vaccine distribution proportional to wealth, rather than to need, may be detrimental to all.
Benchmarking emergency department prediction models with machine learning and public electronic health records
Authors: Xie Feng , Zhou Jun , Lee Jin Wee , Tan Mingrui , Li Siqi , Rajnthern Logasan S/O , Chee Marcel Lucas , Chakraborty Bibhas , Wong An-Kwok Ian , Dagan Alon , Ong Marcus Eng Hock , Gao Fei , Liu Nan
Published: October 2022

The demand for emergency department (ED) services is increasing across the globe, particularly during the current COVID-19 pandemic. Clinical triage and risk assessment have become increasingly challenging due to the shortage of medical resources and the strain on hospital infrastructure caused by the pandemic. As a result of the widespread use of electronic health records (EHRs), we now have access to a vast amount of clinical data, which allows us to develop prediction models and decision support systems to address these challenges. To date, there is no widely accepted clinical prediction benchmark related to the ED based on large-scale public EHRs. An open-source benchmark data platform would streamline research workflows by eliminating cumbersome data preprocessing, and facilitate comparisons among different studies and methodologies. Based on the Medical Information Mart for Intensive Care IV Emergency Department (MIMIC-IV-ED) database, we created a benchmark dataset and proposed three clinical prediction benchmarks. This study provides future researchers with insights, suggestions, and protocols for managing data and developing predictive tools for emergency care.
Magneto-hydrothermal triple-convection in a W-shaped porous cavity containing oxytactic bacteria
Authors: Biswas Nirmalendu , Mandal Dipak Kumar , Manna Nirmal K. , Benim Ali Cemal
Published: October 2022

Bioconvective heat and mass transport phenomena have recently been the subject of interest in diverse fields of applications pertaining to the motion of fluids and their thermophysical properties. The transport processes in a system involving triple convective phenomena, irregular geometry, and boundary conditions constitute a complex phenomenon. This work aims to explore the mixed thermo-bioconvection of magnetically susceptible fluid containing copper nanoparticles and oxytactic bacteria in a novel W-shaped porous cavity. The buoyant convention is generated due to the isothermal heating at the wavy bottom wall, whereas the mixed convection is induced due to the shearing motion of the top-cooled sliding wall. Furthermore, the bioconvection is induced due to the manifestation of oxytactic bacteria or organisms. The inclined sidewalls are insulated. The geometry is packed with water based Cu nanoparticle mixed porous structure, which is subjected to a magnetizing field acted horizontally. The complex transport equations are transformed into nondimensional forms, which are then computed using the finite volume-based developed code. The coupled triple-convective flow physics are explored for a wide range of involved controlling parameters, which could provide helpful insight to the system designer for its proper operation. The shape of geometry can be considered one of the important parameters to control the heat and mass transport phenomena. In general, the influence of amplitude (δ) is more compared to the waviness number (m) of the undulations. The magnitude of heat (Nu) and mass (Sh) transfer rate for the W-shaped cavity is high compared to conventional square and trapezoidal-shaped cavities. The output of the analysis could be very helpful for the designer for modeling devices operating on nanotechnology-based bioconvection, microbial fuel cells, and others.
Temporal change in plant communities and its relationship to soil salinity and microtopography on the Caspian Sea coast
Authors: Klink Galya V. , Semenkov Ivan N. , Nukhimovskaya Yulia D. , Gasanova Zarema Ul. , Stepanova Nina Yu. , Konyushkova Maria V.
Published: October 2022

The gradual drying up of saltwater bodies creates habitats that are characterised by changing environmental conditions and might be available only for a subset of plants from the local flora. Using two terrestrial areas with different ages on the Caspian Coast as a chronosequence, we investigated factors including microtopography, ground water level and soil salinity that drive plant community succession after the retreat of the sea. Vegetation of the two key sites appearing after the retreat of the Caspian Sea about 365 and 1412 years ago were compared in terms of both evolutionary and ecological traits of plants. Both edaphic conditions and vegetation differed between the two sites with harsher edaphic conditions and more xerophytes on the elder site. Species that grew only in the ‘early’ site were dispersed across the phylogenetic tree, but their loss on the 'late' site was not random. Species that grew only on the 'late' site were phylogenetically clustered. On the level of microtopography, elevated spots were more densely populated in the ‘early’ site than lowered spots, but on the 'late' site the situation was opposite. The main edaphic factors that drive the difference in vegetation composition between the two sites are likely salinity and moisture. During environmental changes, different plant traits are important to survive and to appear in the community de novo. Microtopography is important for forming plant communities, and its role changes with time.
Syndemics of intimate partner violence among women in HIV endemic South Africa: geospatial analysis of nationally representative data
Authors: Tomita Andrew , Cuadros Diego F. , Gibbs Andrew
Published: October 2022

Despite some improvement in lowering HIV incidence, HIV-related challenges, such as intimate partner violence (IPV), remain unacceptably high among women in South Africa. For decades, researchers and activists have pointed to the complex and intertwined reality of the substance abuse, violence and AIDS (SAVA) syndemic that endangers women. However, more recent systematic review/meta-analysis evidence points to inconclusive association between IPV and alcohol use. Furthermore, much of the evidence is often non-population-based that focuses on the co-occurrence rather than synergistic SAVA interaction. In this study, using the latest data from the South Africa Demographic and Health Survey (SA-DHS), we identified geographic synergistic clustering of IPV associated with HIV and substance abuse in South Africa as a measure of population-level interactions among these factors. The SA-DHS is a nationally representative sample that includes wide-ranging data on health, social challenges and household geo-locations of 5,874 women who participated in the domestic violence module. First, geographical IPV, harmful alcohol use (as the substance abuse measure available in SA-DHS) and HIV clusters were identified using the Kulldorff spatial scan statistic in SaTScan. Second, synergistic interactions related to recent IPV (i.e. recent physical, sexual, emotional violence during the last 12 months) with harmful alcohol use and HIV challenge were measured using RERI [Relative excess risk due to interaction], AP [attributable proportion] and S [Synergy index]. In our results, we spatially identified geographical physical IPV syndemic interactions in parts of the Eastern Cape/Free State Provinces (RERI = 4.42 [95% CI: 2.34–6.51], AP = 0.56 [95% CI: 0.44–0.68], S = 2.77 [95% CI: 2.01–3.84], but not in other forms of IPV. Although IPV, based on decade old concept of SAVA syndemic, was less common/widespread than expected from the national scale population-based data, we identified population-level physical violence syndemic occurring in South Africa. Our study highlights the need to prioritize public health response targeting vulnerable populations residing in these high-risk areas of syndemic mechanisms linking these synergistic epidemics that women face in South Africa.
Liming enhances longevity of wheat seeds produced in acid soils
Authors: da Silva Tiago Alexandre , Crusciol Carlos Alexandre Costa , Batista Thiago Barbosa , Bossolani João William , de Oliveira Gustavo Roberto Fonseca , Basso Denise Puntel , de Almeida Carmeis Filho Antônio Carlos , Bravo Juliana Pereira , da Silva Edvaldo Aparecido Amaral
Published: October 2022

The environment where plants grow, such as acidic soils, interferes with the nutrient concentration and physiological quality of seeds. This hypothesis was tested using wheat seeds as a model crop, grown in a tropical soil with and without lime application for twelve years. Here we show that lime provides remarkable enhancements in soil chemistry and seed composition, without altering the seed’s germination and vigor. Also, it favors the production of seeds with additional molecular mechanisms that extend their longevity. Our results indicate that the application of lime mitigates acidity in tropical soils and ensures the production of seeds with enhanced chemical composition and longer life span.
EEG-based analysis of various sensory stimulation effects to reduce visually induced motion sickness in virtual reality
Authors: Yeo Sang Seok , Kwon Jung Won , Park Seo Yoon
Published: October 2022

The use of virtual reality (VR) is frequently accompanied by motion sickness, and approaches for preventing it are not yet well established. We explored the effects of synchronized presentations of sound and motion on visually induced motion sickness (VIMS) in order to reduce VIMS. A total of 25 participants bicycle riding for 5 min with or without sound and motion synchronization presented on a head-mounted display. As a result, the VIMS scores measured by the fast motion sickness scale and simulator sickness questionnaire were significantly lower in the participants who experienced the riding scene with sound and motion than those who experienced the riding scene with sound only, motion only, or neither. Furthermore, analysis of the EEG signal showed that the higher the VIMS, the significant increase in alpha and theta waves in the parietal and occipital lobes. Therefore, we demonstrate that the simultaneous presentation of sound and motion, closely associated with synchronous and visual flow speed, is effective in reducing VIMS while experiencing simulated bicycle riding in a VR environment.
Prediction of autistic tendencies at 18 months of age via markerless video analysis of spontaneous body movements in 4-month-old infants
Authors: Doi Hirokazu , Iijima Naoya , Furui Akira , Soh Zu , Yonei Rikuya , Shinohara Kazuyuki , Iriguchi Mayuko , Shimatani Koji , Tsuji Toshio
Published: October 2022

Early intervention is now considered the core treatment strategy for autism spectrum disorders (ASD). Thus, it is of significant clinical importance to establish a screening tool for the early detection of ASD in infants. To achieve this goal, in a longitudinal design, we analyzed spontaneous bodily movements of 4-month-old infants from general population and assessed their ASD-like behaviors at 18 months of age. A total of 26 movement features were calculated from video-recorded bodily movements of infants at 4 months of age. Their risk of ASD was assessed at 18 months of age with the Modified Checklist for Autism in Toddlerhood, a widely used screening questionnaire. Infants at high risk for ASD at 18 months of age exhibited less rhythmic and weaker bodily movement patterns at 4 months of age than low-risk infants. When the observed bodily movement patterns were submitted to a machine learning-based analysis, linear and non-linear classifiers successfully predicted ASD-like behavior at 18 months of age based on the bodily movement patterns at 4 months of age, at the level acceptable for practical use. This study analyzed the relationship between spontaneous bodily movements at 4 months of age and the ASD risk at 18 months of age. Experimental results suggested the utility of the proposed method for the early screening of infants at risk for ASD. We revealed that the signs of ASD risk could be detected as early as 4 months after birth, by focusing on the infant’s spontaneous bodily movements.
Proteomic consequences of TDA1 deficiency in Saccharomyces cerevisiae: Protein kinase Tda1 is essential for Hxk1 and Hxk2 serine 15 phosphorylation
Authors: Müller Henry , Lesur Antoine , Dittmar Gunnar , Gentzel Marc , Kettner Karina
Published: October 2022

Hexokinase 2 (Hxk2) ofSaccharomyces cerevisiaeis a dual function hexokinase, acting as a glycolytic enzyme and being involved in the transcriptional regulation of glucose-repressible genes. Relief from glucose repression is accompanied by phosphorylation of Hxk2 at serine 15, which has been attributed to the protein kinase Tda1. To explore the role of Tda1 beyond Hxk2 phosphorylation, the proteomic consequences ofTDA1deficiency were investigated by difference gel electrophoresis (2D-DIGE) comparing a wild type and a Δtda1deletion mutant. To additionally address possible consequences of glucose repression/derepression, both were grown at 2% and 0.1% (w/v) glucose. A total of eight protein spots exhibiting a minimum twofold enhanced or reduced fluorescence uponTDA1deficiency was detected and identified by mass spectrometry. Among the spot identities are—besides the expected Hxk2—two proteoforms of hexokinase 1 (Hxk1). Targeted proteomics analyses in conjunction with 2D-DIGE demonstrated thatTDA1is indispensable for Hxk2 and Hxk1 phosphorylation at serine 15. Thirty-six glucose-concentration-dependent protein spots were identified. A simple method to improve spot quantification, approximating spots as rotationally symmetric solids, is presented along with new data on the quantities of Hxk1 and Hxk2 and their serine 15 phosphorylated forms at high and low glucose growth conditions. The Δtda1deletion mutant exhibited no altered growth under high or low glucose conditions or on alternative carbon sources. Also, invertase activity, serving as a reporter for glucose derepression, was not significantly altered. Instead, an involvement of Tda1 in oxidative stress response is suggested.
Sarcomere dynamics revealed by a myofilament integrated FRET-based biosensor in live skeletal muscle fibers
Authors: Martin Ashley A. , Thompson Brian R. , Davis Jonathan P. , Vang Hluechy , Hahn Dongwoo , Metzger Joseph M.
Published: October 2022

The sarcomere is the functional unit of skeletal muscle, essential for proper contraction. Numerous acquired and inherited myopathies impact sarcomere function causing clinically significant disease. Mechanistic investigations of sarcomere activation have been challenging to undertake in the context of intact, live skeletal muscle fibers during real time physiological twitch contractions. Here, a skeletal muscle specific, intramolecular FRET-based biosensor was designed and engineered into fast skeletal muscle troponin C (TnC) to investigate the dynamics of sarcomere activation. In transgenic animals, the TnC biosensor incorporated into the skeletal muscle fiber sarcomeres by stoichiometric replacement of endogenous TnC and did not alter normal skeletal muscle contractile form or function. In intact single adult skeletal muscle fibers, real time twitch contractile data showed the TnC biosensor transient preceding the peak amplitude of contraction. Importantly, under physiological temperatures, inactivation of the TnC biosensor transient decayed significantly more slowly than the Ca2+ transient and contraction. The uncoupling of the TnC biosensor transient from the Ca2+ transient indicates the biosensor is not functioning as a Ca2+ transient reporter, but rather reports dynamic sarcomere activation/ inactivation that, in turn, is due to the ensemble effects of multiple activating ligands within the myofilaments. Together, these findings provide the foundation for implementing this new biosensor in future physiological studies investigating the mechanism of activation of the skeletal muscle sarcomere in health and disease.
Influence of the pulse repetition rate on the acoustic output of ballistic pressure wave devices
Authors: Reinhardt Nina , Wegenaer Jens , de la Fuente Matías
Published: October 2022

Ballistic devices that generate radial pressure waves are used for the treatment of different therapeutic indications. In order to assess the effectiveness of these devices and to interpret and transfer the results of clinical trials, it is important to know their acoustic output. In this paper, two ballistic devices and their reproducibility at different clinically relevant settings were investigated in the same in-vitro test setup. Pressure curves were measured in water at different intensity levels and pulse repetition rates. The sound field parameters (peak pressures, positive pulse intensity integral) were calculated from the pressure curves. Additionally, the surface velocity of the applicator was determined in air using a vibrometer. Both devices show a good pulse-to-pulse reproducibility. While the peak maximum pressure and the positive pulse intensity integral decrease only slightly (pmax up to 12%, PII+ up to 18.8%) comparing 1 Hz and 25 Hz for one device, they drop sharply (pmax up to 68.4%, PII+ up to 90.2%) for the other device comparing 1 Hz to 21 Hz. The same effect was observed in the vibrometer measurements. The results show that with increasing pulse repetition rate the stability of the parameters varies between different devices. Hence, all sound field parameters should be compared before transferring settings from one device to another.
Evidence for the early Toarcian Carbon Isotope Excursion (T-CIE) from the shallow marine siliciclastic red beds of Arabia
Authors: Alnazghah Mahmoud , Koeshidayatullah Ardiansyah , Al-Hussaini Abdulkarim , Amao Abduljamiu , Song Haijun , Al-Ramadan Khalid
Published: October 2022

The Toarcian Oceanic Anoxic Event (T-OAE) and its corresponding Carbon Isotope Excursion (CIE) have been reported widely across the Tethyan region and globally. In Arabia, and based on ammonite dating, the time window of the T-OAE coincided with the deposition of the reddish siliciclastic unit of the Marrat Formation. However, no evidence of the T-OAE/CIE was ever reported from Arabia because these red beds were previously interpreted as continental deposits. Recently, these red beds have been recognized as shallow marine deposits which opened an opportunity to assess the occurrence and expression of T-OAE–CIE in Arabia. In this study, a multiproxy geochemical characterization was performed on the Toarcian Marrat Formation to infer the chemistry of the paleowater column and identify intervals of possible T-OAE/CIE in Arabia. While the low concentrations of redox-sensitive elements (Mo, U, V, Cr) may indicate a shallow oxic marine settings, the coupled negative δ13Corganic excursion and apparent increase in the chemical weathering suggests that the deposition of Marrat red beds coincided with the development of T-CIE and possibly time-equivalent to the T-OAE globally. The origin of reddening is interpreted to have occurred during the middle Marrat deposition due to the stabilization of unstable hydrous iron oxides to hematite under oxic marine conditions. The proposed model further indicates the possible development of source rocks in the deep, anoxic environment counterpart where the T-OAE may be expressed. Since our study documents the first record of the T-CIE and discuss the origin of shallow marine siliciclastic red beds in the Arabian Plate, this will have significant implications for the overall understanding of the T-CIE globally and for hydrocarbon exploration through realizations of potential new source rocks associated with the OAEs in the Toarcian and other time intervals.
Neuromedin U-deficient rats do not lose body weight or food intake
Authors: Yokogi Kyoka , Goto Yuki , Otsuka Mai , Ojima Fumiya , Kobayashi Tomoe , Tsuchiba Yukina , Takeuchi Yu , Namba Masumi , Kohno Mayumi , Tetsuka Minami , Takeuchi Sakae , Matsuyama Makoto , Aizawa Sayaka
Published: October 2022

Studies in genetically modified mice establish that essential roles of endogenous neuromedin U (NMU) are anorexigenic function and metabolic regulation, indicating that NMU is expected to be a potential target for anti-obesity agents. However, in central administration experiments in rats, inconsistent results have been obtained, and the essential role of NMU energy metabolism in rats remain unclear. This study aims to elucidate the role of endogenous NMU in rats. We generated NMU knockout (KO) rats that unexpectedly showed no difference in body weight, adiposity, circulating metabolic markers, body temperature, locomotor activity, and food consumption in both normal and high fat chow feeding. Furthermore, unlike reported in mice, expressions of Nmu and NMU receptor type 2 (Nmur2) mRNA were hardly detectable in the rat hypothalamic nuclei regulating feeding and energy metabolism, including the arcuate nucleus and paraventricular nucleus, while Nmu was expressed in pars tuberalis and Nmur2 was expressed in the ependymal cell layer of the third ventricle. These results indicate that the species–specific expression pattern of Nmu and Nmur2 may allow NMU to have distinct functions across species, and that endogenous NMU does not function as an anorexigenic hormone in rats.
Quantifying neuro-motor correlations during awake deep brain stimulation surgery using markerless tracking
Authors: Tekriwal Anand , Baker Sunderland , Christensen Elijah , Petersen-Jones Humphrey , Tien Rex N. , Ojemann Steven G. , Kern Drew S. , Kramer Daniel R. , Felsen Gidon , Thompson John A.
Published: October 2022

The expanding application of deep brain stimulation (DBS) therapy both drives and is informed by our growing understanding of disease pathophysiology and innovations in neurosurgical care. Neurophysiological targeting, a mainstay for identifying optimal, motor responsive targets, has remained largely unchanged for decades. Utilizing deep learning-based computer vision and related computational methods, we developed an effective and simple intraoperative approach to objectively correlate neural signals with movements, automating and standardizing the otherwise manual and subjective process of identifying ideal DBS electrode placements. Kinematics are extracted from video recordings of intraoperative motor testing using a trained deep neural network and compared to multi-unit activity recorded from the subthalamic nucleus. Neuro-motor correlations were quantified using dynamic time warping with the strength of a given comparison measured by comparing against a null distribution composed of related neuro-motor correlations. This objective measure was then compared to clinical determinations as recorded in surgical case notes. In seven DBS cases for treatment of Parkinson’s disease, 100 distinct motor testing epochs were extracted for which clear clinical determinations were made. Neuro-motor correlations derived by our automated system compared favorably with expert clinical decision making in post-hoc comparisons, although follow-up studies are necessary to determine if improved correlation detection leads to improved outcomes. By improving the classification of neuro-motor relationships, the automated system we have developed will enable clinicians to maximize the therapeutic impact of DBS while also providing avenues for improving continued care of treated patients.
Genetic causal inference between amblyopia and perinatal factors
Authors: Lee Ju-Yeun , Lee Sangjun , Park Sue K.
Published: October 2022

Amblyopia is a common visual disorder that causes significant vision problems globally. Most non-ocular risk factors for amblyopia are closely related to the intrauterine environment, and are strongly influenced by parent-origin effects. Parent-origin perinatal factors may have a direct causal inference on amblyopia development; therefore, we investigated the causal association between perinatal factors and amblyopia risk using a one-sample Mendelian Randomization (MR) with data from the UK Biobank Cohort Data (UKBB). Four distinct MR methods were employed to analyze the association between three perinatal factors (birth weight [BW], maternal smoking, and breastfeeding) and amblyopia risk, based on the summary statistics of genome-wide association studies in the European population. The inverse variance weighting method showed an inverse causal association between BW and amblyopia risk (odds ratio, 0.48 [95% CI, 0.29–0.80]; p = 0.004). Maternal smoking and breastfeeding were not causally associated with amblyopia risk. Our findings provided a possible evidence of a significant genetic causal association between low BW and increased amblyopia risk. This evidence may highlight the potential of BW as a predictive factor for visual maldevelopment and the need for careful management of amblyopia risk in patients with low BW.
Ecological and evolutionary trends of body size in Pristimantis frogs, the world's most diverse vertebrate genus
Authors: Acevedo Aldemar A. , Palma R. Eduardo , Olalla-Tárraga Miguel Ángel
Published: October 2022

Body size is a key organismal trait. However, the environmental and evolutionary factors that drive body size patterns at the interspecific level remain unclear. Here, we explored these relationships between phenotype-environment using neotropical frogs ofPristimantis, the world’s most diverse vertebrate genus. We analyzed: (a) whether this group follows the Rensch’s rule, a trend of sexual size dimorphism (SSD) to increase with size when males are the larger sex; (b) whether environmental constraints have influenced body size variation; and (c) how the rates of body size evolution have varied over time. Analyses were based on two information sources, the first one including body sizes of ~ 85% (495 species) of known species in the genus, and a second one incorporating molecular phylogenetic information for 257 species. Our results showed that allPristimantisspecies exhibited marked SSD but did not follow Rensch’s rule. We found that the models that best explained body size in males, females, and SSD contained environmental variations in temperature, precipitation, and elevation as predictors. In turn, body size has evolved toward an optimum, with a decelerating rate of evolution differentiated between the largePristimantisclades.
Morphological diversity and molecular phylogeny of five Paramecium bursaria (Alveolata, Ciliophora, Oligohymenophorea) syngens and the identification of their green algal endosymbionts
Authors: Spanner Christian , Darienko Tatyana , Filker Sabine , Sonntag Bettina , Pröschold Thomas
Published: October 2022

Paramecium bursaria is a mixotrophic ciliate species, which is common in stagnant and slow-flowing, nutrient-rich waters. It is usually found living in symbiosis with zoochlorellae (green algae) of the genera Chlorella or Micractinium. We investigated P. bursaria isolates from around the world, some of which have already been extensively studied in various laboratories, but whose morphological and genetic identity has not yet been completely clarified. Phylogenetic analyses of the SSU and ITS rDNA sequences revealed five highly supported lineages, which corresponded to the syngen and most likely to the biological species assignment. These syngens R1–R5 could also be distinguished by unique synapomorphies in the secondary structures of the SSU and the ITS. Considering these synapomorphies, we could clearly assign the existing GenBank entries of P. bursaria to specific syngens. In addition, we discovered synapomorphies at amino acids of the COI gene for the identification of the syngens. Using the metadata of these entries, most syngens showed a worldwide distribution, however, the syngens R1 and R5 were only found in Europe. From morphology, the syngens did not show any significant deviations. The investigated strains had either Chlorella variabilis, Chlorella vulgaris or Micractinium conductrix as endosymbionts.
Quiescent innate and adaptive immune responses maintain the long-term integrity of corneal endothelium reconstituted through allogeneic cell injection therapy
Authors: Toda Munetoyo , Ueno Morio , Yamada Jun , Hiraga Asako , Asada Kazuko , Hamuro Junji , Sotozono Chie , Kinoshita Shigeru
Published: October 2022

This study aims to clarify the immunogenicity in acquired and innate immune responses of cultured human corneal endothelial cells (hCECs) applied for cell injection therapy, a newly established modality for corneal endothelium failures. Thirty-four patients with corneal endothelial failure received injection of allogeneic hCEC suspension into anterior chamber. No sign of immunological rejection was observed in all 34 patients during the 5–8 years postoperative follow-up period. Cell injection therapy was successful in 2 patients treated for endothelial failure after penetrating keratoplasty and one patient with Descemet membrane stripping automated endothelial keratoplasty failure. ELISPOT assays performed in allo-mixed lymphocyte reaction to the alloantigen identical to that on the injected hCECs, elicited sparse IFN-γ-specific spots in the peripheral blood mononuclear cells of patients who received hCEC injection. The therapy generated simple and smooth graft-host junctions without wound stress. The injection of C57BL/6 CECs into the anterior chamber of BALB/c mice, which rejected C57BL/6 corneas 6 weeks ago, induced no sign of inflammatory reactions after the second challenge of alloantigen. Collectively, injection of the hCEC cell suspension in the aqueous humor induces immune tolerance that contributes to the survival of the reconstituted endothelium.
Experimentally increased snow depth affects high Arctic microarthropods inconsistently over two consecutive winters
Authors: Krab Eveline J. , Lundin Erik J. , Coulson Stephen J. , Dorrepaal Ellen , Cooper Elisabeth J.
Published: October 2022

Climate change induced alterations to winter conditions may affect decomposer organisms controlling the vast carbon stores in northern soils. Soil microarthropods are particularly abundant decomposers in Arctic ecosystems. We studied whether increased snow depth affected microarthropods, and if effects were consistent over two consecutive winters. We sampled Collembola and soil mites from a snow accumulation experiment at Svalbard in early summer and used soil microclimatic data to explore to which aspects of winter climate microarthropods are most sensitive. Community densities differed substantially between years and increased snow depth had inconsistent effects. Deeper snow hardly affected microarthropods in 2015, but decreased densities and altered relative abundances of microarthropods and Collembola species after a milder winter in 2016. Although increased snow depth increased soil temperatures by 3.2 °C throughout the snow cover periods, the best microclimatic predictors of microarthropod density changes were spring soil temperature and snowmelt day. Our study shows that extrapolation of observations of decomposer responses to altered winter climate conditions to future scenarios should be avoided when communities are only sampled on a single occasion, since effects of longer-term gradual changes in winter climate may be obscured by inter-annual weather variability and natural variability in population sizes.
Analysis of distributed ledger technologies for industrial manufacturing
Authors: Nguyen Lam Duc , Bröring Arne , Pizzol Massimo , Popovski Petar
Published: October 2022

In recent years, industrial manufacturing has undergone massive technological changes that embrace digitalization and automation towards the vision of intelligent manufacturing plants. With the aim of maximizing efficiency and profitability in production, an important goal is to enable flexible manufacturing, both, for the customer (desiring more individualized products) and for the manufacturer (to adjust to market demands). Manufacturing-as-a-service can support this through manufacturing plants that are used by different tenants who utilize the machines in the plant, which are offered by different providers. To enable such pay-per-use business models, Distributed Ledger Technology (DLT) is a viable option to establish decentralized trust and traceability. Thus, in this paper, we study potential DLT technologies for efficient and intelligent integration of DLT-based solutions in manufacturing environments. We propose a general framework to adapt DLT in manufacturing, and then we introduce the use case of shared manufacturing, which we utilize to study the communication and computation efficiency of selected DLTs in resource-constrained wireless IoT networks.