bluuebunny/crossref_metadata_2025 huggingface dataset:
Finding Oxford’s medieval Jewry using organic residue analysis, faunal records and historical documents
Authors: Dunne J. , Biddulph E. , Manix P. , Gillard T. , Whelton H. , Teague S. , Champness C. , Broderick L. G. , Nicholson R. , Blinkhorn P. , Craig-Atkins E. , Jervis B. , Madgwick R. , Hodos T. , Cramp L. J. E. , Evershed R. P.
Published: February 2021

Food is often one of the most distinctive expressions of social, religious, cultural or ethnic groups. However, the archaeological identification of specific religious dietary practices, including the Jewish tradition of keepingkosher, associated with ritual food practices and taboos, is very rare. This is arguably one of the oldest known diets across the world and, for an observant Jew, maintaining dietary laws (known as Kashruth) is a fundamental part of everyday life. Recent excavations in the early medieval Oxford Jewish quarter yielded a remarkable assemblage of animal bones, marked by a complete absence of pig specimens and a dominance ofkosher(permitted) birds, domestic fowl and goose. To our knowledge, this is the first identification of a Jewish dietary signature in British zooarchaeology, which contrasted markedly with the previous Saxon phase where pig bones were present in quantity and bird bones were barely seen. Lipid residue analysis of pottery from St Aldates showed that vessels from the possible Jewish houses were solely used to process ruminant carcass products, with an avoidance of pig product processing, correlating well with the faunal data. In contrast, lipid analysis of pottery from comparative assemblages from the previous Saxon phase at the site and a contemporaneous site in the city, The Queen’s College, shows that the majority of these vessels appear to have been used to process mixtures of both ruminant and non-ruminant (pig) products. Here, the combination of organic residue analysis, site excavation and animal and fish bone evidence was consistent with the presence of Jewish houses in eleventh- and twelfth-century St Aldates, Oxford, hitherto only suspected through documentary information. This is the first identification of specific religious dietary practices using lipid residue analysis, verifying that, at least 800 years ago, medieval Jewish Oxford communities practised dietary laws known as Kashruth.
Temperature correction for oil film interferometry with infrared camera in skin friction measurements
Authors: Iijima Hidetoshi , Uchiyama Takahiro , Kato Hiroyuki
Published: February 2021

Graphic abstract
Hom-left-symmetric color dialgebras, Hom-tridendriform color algebras and Yau’s twisting generalizations
Authors: Bakayoko Ibrahima , Silvestrov Sergei
Published: February 2021

The goal of this paper is to introduce and give some constructions and study properties of Hom-left-symmetric color dialgebras and Hom-tridendriform color algebras. Next, we study their connection with Hom-associative color algebras, Hom-post-Lie color algebras and Hom–Poisson color dialgebras. Finally, we generalize Yau’s twisting to a class of color Hom-algebras and use endomorphisms or elements of centroids to produce other color Hom-algebras from given one.
The interactions between habitat, sex, biomass and leaf traits of different willow (Salix) genotypes
Authors: Konatowska Monika , Rutkowski Paweł , Budka Anna , Goliński Piotr , Szentner Kinga , Mleczek Mirosław
Published: February 2021

Knowledge of the impacts of sex on plant mortality and biomass production has scientific and practical importance. In the case of willows, we know relatively little about such effects. The main objective of this study was to evaluate whether the sex of individuals of different willow species determines their biomass and mortality. An additional goal was to determine whether the secondary sex characteristics, such as leaf traits, depend on sex. The experiment was conducted from 2011 to 2014 with 8100 plants comprising 150 willow genotypes, including 8 species, 16 interspecies hybrids, cultivars, and specimens differentiated by sex. Statistical analysis of the leaf traits revealed their relationship to sex. On average, male specimens have longer and wider leaves. They also have longer petioles. Males of the studied Salix genotypes were characterized by higher biomass and showed a greater survival rate than females but only under better site conditions; when the site conditions were poorer, males had higher mortality than females.
Precision agriculture and geospatial techniques for sustainable disease control
Authors: Roberts Daniel P. , Short Nicholas M. , Sill James , Lakshman Dilip K. , Hu Xiaojia , Buser Michael
Published: February 2021

The agricultural community is confronted with dual challenges; increasing production of nutritionally dense food and decreasing the impacts of these crop production systems on the land, water, and climate. Control of plant pathogens will figure prominently in meeting these challenges as plant diseases cause significant yield and economic losses to crops responsible for feeding a large portion of the world population. New approaches and technologies to enhance sustainability of crop production systems and, importantly, plant disease control need to be developed and adopted. By leveraging advanced geoinformatic techniques, advances in computing and sensing infrastructure (e.g., cloud-based, big data-driven applications) will aid in the monitoring and management of pesticides and biologicals, such as cover crops and beneficial microbes, to reduce the impact of plant disease control and cropping systems on the environment. This includes geospatial tools being developed to aid the farmer in managing cropping system and disease management strategies that are more sustainable but increasingly complex. Geoinformatics and cloud-based, big data-driven applications are also being enlisted to speed up crop germplasm improvement; crop germplasm that has enhanced tolerance to pathogens and abiotic stress and is in tune with different cropping systems and environmental conditions is needed. Finally, advanced geoinformatic techniques and advances in computing infrastructure allow a more collaborative framework amongst scientists, policymakers, and the agricultural community to speed the development, transfer, and adoption of these sustainable technologies.
Soft X‐ray and ENA Imaging of the Earth's Dayside Magnetosphere
Authors: Connor H. K. , Sibeck D. G. , Collier M. R. , Baliukin I. I. , Branduardi‐Raymont G. , Brandt P. C. , Buzulukova N. Y. , Collado‐Vega Y. M. , Escoubet C. P. , Fok M.‐C. , Hsieh S.‐Y. , Jung J. , Kameda S. , Kuntz K. D. , Porter F. S. , Sembay S. , Sun T. , Walsh B. M. , Zoennchen J. H.
Published: February 2021

The LEXI and SMILE missions will provide soft X‐ray images of the Earth's magnetosheath and cusps after their anticipated launch in 2023 and 2024, respectively. The IBEX mission showed the potential of an Energetic Neutral Atom (ENA) instrument to image dayside magnetosheath and cusps, albeit over the long hours required to raster an image with a single pixel imager. Thus, it is timely to discuss the two imaging techniques and relevant science topics. We simulate soft X‐ray and low‐ENA images that might be observed by a virtual spacecraft during two interesting solar wind scenarios: a southward turning of the interplanetary magnetic field and a sudden enhancement of the solar wind dynamic pressure. We employ the OpenGGCM global magnetohydrodynamics model and a simple exospheric neutral density model for these calculations. Both the magnetosheath and the cusps generate strong soft X‐rays and ENA signals that can be used to extract the locations and motions of the bow shock and magnetopause. Magnetopause erosion corresponds closely to the enhancement of dayside reconnection rate obtained from the OpenGGCM model, indicating that images can be used to understand global‐scale magnetopause reconnection. When dayside imagers are installed with high‐ENA inner‐magnetosphere and FUV/UV aurora imagers, we can trace the solar wind energy flow from the bow shock to the magnetosphere and then to the ionosphere in a self‐standing manner without relying upon other observatories. Soft X‐ray and/or ENA imagers can also unveil the dayside exosphere density structure and its response to space weather.
Response of Mars's Topside Ionosphere to Changing Solar Activity and Comparisons to Venus
Authors: Hensley K. , Withers P.
Published: February 2021

Studying how planetary ionospheres respond to changes in solar irradiance can inform our understanding of how planetary atmospheres have reacted to our changing Sun over the course of solar system history. The response of Mars's main ionospheric peak to changing solar irradiance has been well‐studied. Less well understood are the altitudes above the main peak. We use radio occultation observations by Mars Global Surveyor and ground‐based solar radio flux measurements to quantify the response of Mars's electron densities to changing solar irradiance at these altitudes. This analysis shows that the electron densities respond modestly at and just above the main peak, with the response increasing above or below the peak. We use a one‐dimensional photochemical equilibrium model to reproduce the observed electron densities and investigate the influence of minor ions, changing electron temperatures, and changing neutral densities and composition on the resultant electron density. We find that the neutral atmosphere is primarily responsible for the observed behavior. We also make comparisons to Venus, which shows a more dramatic increase in its ionospheric response as a function of altitude. We show that while the ionospheric responses of Mars and Venus as a function of altitude are markedly different, recasting the analysis in terms of number of scale heights above the main peak brings the two planets into closer agreement, especially at the main peak. The agreement is worse at higher altitudes and this is attributed to Venus's larger proportion of atomic oxygen.
Multiscale Superposition and Decomposition of Field‐Measured Suspended Sediment Concentrations: Implications for Extending 1DV Models to Coastal Oceans With Advected Fine Sediments
Authors: Zhang Shaotong , Nielsen Peter , Perrochet Pierre , Jia Yonggang
Published: February 2021

One‐dimensional vertical (1DV) diffusion‐settling models are practical tools for sediment transport analysis of sands, which is mostly a local process. However, for fine sediments, the observed concentrations C(t) can be mixed via horizontal advection (HA) due to the lower settling velocity, which makes the C(t) not necessarily a local process, thus making 1DV models invalid. It is important to determine the qualitative significance of HA or quantitatively separate HA signals when applying 1DV models to environments with advected fine sediments. Here, novel methods are combined to (1) qualitatively identify the physical mechanisms underlying C(t) variations and determine whether HA is significant via multiscale frequency superposition and (2) quantitatively decompose C(t) components according to their physical mechanisms via spectral filter decomposition. In situ observational data of C(t) and concurrent hydrodynamics in the subaqueous Yellow River Delta is employed to analyze the methods' performance. The decomposed signals are reasonable because they can be interpreted in light of other observed physical processes. The results indicated that M2 tidal advection contributed 8.30% by carrying sediments from 1.6 km upstream of the flood tides, M4 and M6 + M8 tidal resuspension contributed 4.16% and 3.96%, respectively, by periodically resuspending a “fluffy layer.” Waves resuspended sediments from an erosion center 5 km upstream of the flood tides and contributed to 76.49% of the elevated C(t). The proposed methods can exclude HA signals from the measured C(t) to increase the applicability of 1DV models to environments with advected fines when C(t) and hydrodynamics are measured.
The South Asia Monsoon Break Promotes Grass Growth on the Tibetan Plateau
Authors: Ren Yanghang , Yang Kun , Wang Han , Zhao Long , Chen Yingying , Zhou Xu , La Zhu
Published: February 2021

As a region that is highly sensitive to global climate change, the Tibetan Plateau (TP) experiences an intra‐seasonal soil water deficient due to the reduced precipitation during the South Asia monsoon (SAM) breaks. Few studies have investigated the impact of SAM breaks on TP ecological processes, although a number of studies have explored the effects of inter‐annual and decadal climate variability. In this study, the response of vegetation activity to SAM breaks was investigated. The data used are: (1) soil moisture from in situ, satellite remote sensing and data assimilation; and (2) the normalized difference vegetation index (NDVI) and solar‐induced chlorophyll fluorescence (SIF). We found that in the SAM break‐impacted region, which is distributed in the central‐eastern part of TP, photosynthesis become more active during SAM breaks. And temporal variability in the photosynthesis of this region is controlled mainly by solar radiation variability and has little sensitivity to soil moisture. We adopted a diagnostic process‐based modeling approach to examine the causes of enhanced plant activity during SAM breaks on the central‐eastern TP. Our analysis indicates that more carbon assimilated by photosynthesis in the reduced precipitation is stimulated by increases in solar radiation absorbed and temperature. This study highlights the importance of sub‐seasonal climate variability for characterizing the relationship between vegetation and climate.
An Innovative Approach for Investigating Subduction Slip Budgets
Authors: Shultz David
Published: February 2021

A new 3D model offers a state-of-the-art look at the full spectrum of slip behaviors in the Nankai subduction zone off Japan.
Exposure to ambient particulate matter and biomass burning during pregnancy: associations with birth weight in Thailand
Authors: Mueller William , Tantrakarnapa Kraichat , Johnston Helinor Jane , Loh Miranda , Steinle Susanne , Vardoulakis Sotiris , Cherrie John W.
Published: February 2021

Background

There is a growing evidence that exposure to ambient particulate air pollution during pregnancy is associated with adverse birth outcomes, including reduced birth weight (BW). The objective of this study was to quantify associations between BW and exposure to particulate matter (PM) and biomass burning during pregnancy in Thailand.

Methods

We collected hourly ambient air pollutant data from ground-based monitors (PM with diameter of <10 µm [PM10], Ozone [O3], and nitrogen dioxide [NO2]), biomass burning from satellite remote sensing data, and individual birth weight data during 2015–2018. We performed a semi-ecological analysis to evaluate the association between mean trimester exposure to air pollutants and biomass burning with BW and low-birth weight (LBW) (<2500 g), adjusting for gestation age, sex, previous pregnancies, mother’s age, heat index, season, year, gaseous pollutant concentrations, and province. We examined potential effect modification of PM10and biomass burning exposures by sex.

Results

There were 83,931 eligible births with a mean pregnancy PM10exposure of 39.7 µg/m3(standard deviation [SD] = 7.7). The entire pregnancy exposure was associated with reduced BW both for PM10(−6.81 g per 10 µg/m3increase in PM10[95% CI = −12.52 to −1.10]) and biomass burning (−6.34 g per 1 SD increase in fires/km2[95% CI = −11.35 to −1.34]) only after adjustment for NO2. In contrast with these findings, a reduced odds ratio (OR) of LBW was associated with PM10exposure only in trimesters one and two, with no relationship across the entire pregnancy period. Associations with biomass burning were limited to increased ORs of LBW with exposure in trimester three, but only for male births.

Conclusion

Based on our results, we encourage further investigation of air pollution, biomass burning and BW in Thailand and other low-income and middle-income countries.
A dynamical approach to generate chaos in a micromechanical resonator
Authors: Defoort Martial , Rufer Libor , Fesquet Laurent , Basrour Skandar
Published: February 2021

Chaotic systems, presenting complex and nonreproducible dynamics, may be found in nature, from the interaction between planets to the evolution of weather, but can also be tailored using current technologies for advanced signal processing. However, the realization of chaotic signal generators remains challenging due to the involved dynamics of the underlying physics. In this paper, we experimentally and numerically present a disruptive approach to generate a chaotic signal from a micromechanical resonator. This technique overcomes the long-established complexity of controlling the buckling in micro/nanomechanical structures by modulating either the amplitude or the frequency of the driving force applied to the resonator in the nonlinear regime. The experimental characteristic parameters of the chaotic regime, namely, the Poincaré sections and Lyapunov exponents, are directly comparable to simulations for different configurations. These results confirm that this dynamical approach is transposable to any kind of micro/nanomechanical resonator, from accelerometers to microphones. We demonstrate a direct application exploiting the mixing properties of the chaotic regime by transforming an off-the-shelf microdiaphragm into a true random number generator conforming to the National Institute of Standards and Technology specifications. The versatility of this original method opens new paths to combine the unique properties of chaos with the exceptional sensitivity of microstructures, leading to emergent microsystems.
HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner
Authors: Turgu Busra , Zhang Fan , El-Naggar Amal , Negri Gian Luca , Kogler Melanie , Tortola Luigi , Johnson Fraser , Ng Tony , Li Amy , Yapp Donald , Lockwood William , Martinez Daniel , Maris John M. , Daugaard Mads , Penninger Josef M. , Hughes Christopher S. , Sorensen Poul H.
Published: February 2021

Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated. In this report, we establish a link between HACE1 and the major stress factor, hypoxia-inducible factor 1 alpha (HIF1α). We find that HACE1 blocks the accumulation of HIF1α during cellular hypoxia through decreased protein stability. This property is dependent on HACE1 E3 ligase activity and loss of Ras-related C3 botulinum toxin substrate 1 (RAC1), an established target of HACE1 mediated ubiquitinylation and degradation. In vivo, genetic deletion of Rac1 reversed the increased HIF1α expression observed in Hace1–/– mice in murine KRasG12D-driven lung tumors. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner.
Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA
Authors: Niu Guanglin , Hellmuth Isabel , Flisikowska Tatiana , Pausch Hubert , Rieblinger Beate , Carrapeiro Alexander , Schade Benjamin , Böhm Brigitte , Kappe Eva , Fischer Konrad , Klinger Bernhard , Steiger Katja , Burgkart Reiner , Bourdon Jean-Christophe , Saur Dieter , Kind Alexander , Schnieke Angelika , Flisikowski Krzysztof
Published: February 2021

Recent years have seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modified TP53 allele that carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutation TP53R167H (orthologous to human TP53R175H) in exon 5. Pigs with the unrecombined mutant allele (flTP53R167H) develop mainly osteosarcoma but also nephroblastomas and lymphomas. This observation suggested that TP53 gene dysfunction is itself the key initiator of bone tumorigenesis, but raises the question which aspects of the TP53 regulation lead to the development of such a narrow tumour spectrum. Molecular analysis of p53 revealed the presence of two internal TP53 promoters (Pint and P2) equivalent to those found in human. Consequently, both pig and human express TP53 isoforms. Data presented here strongly suggest that P2-driven expression of the mutant R167H-Δ152p53 isoform (equivalent to the human R175H-Δ160p53 isoform) and its circular counterpart circTP53 determine the tumour spectrum and play a critical role in the malignant transformation in flTP53R167H pigs. The detection of Δ152p53 isoform mRNA in serum is indicative of tumorigenesis. Furthermore, we showed a tissue-specific p53-dependent deregulation of the p63 and p73 isoforms in these tumours. This study highlights important species-specific differences in the transcriptional regulation of TP53. Considering the similarities of TP53 regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novel circTP53 in both the pig model and human patients.
Treating the patient and not just the cancer: therapeutic burden in prostate cancer
Authors: Spratt Daniel E. , Shore Neal , Sartor Oliver , Rathkopf Dana , Olivier Kara
Published: February 2021

Background

Prostate cancer (PC) is a leading cause of death in older men. Androgen deprivation therapy (ADT) is considered the standard-of-care for men with locally advanced disease. However, continuous androgen ablation is associated with acute and long-term adverse effects and most patients will eventually develop castration-resistant PC (CRPC). The recent approval of three, second-generation androgen receptor inhibitors (ARIs), apalutamide, enzalutamide, and darolutamide, has transformed the treatment landscape of PC. Treatment with these second-generation ARIs have produced positive trends in metastasis-free survival, progression-free survival, and overall survival. For patients with non-metastatic CRPC, who are mainly asymptomatic from their disease, maintaining quality of life is a major objective when prescribing therapy. Polypharmacy for age-related comorbidities also is common in this population and may increase the potential for drug–drug interactions (DDIs).

Method

This review summarizes the multiple factors that may contribute to the therapeutic burden of patients with CRPC, including the interplay between age, comorbidities, concomitant medications, the use of ARIs, and financial distress.

Conclusions

As the treatment landscape in PC continues to rapidly evolve, consideration must be given to the balance between therapeutic benefits and potential treatment-emergent adverse events that may be further complicated by DDIs with concomitant medications. Patient-centered communication is a crucial aspect of alleviating this burden, and healthcare professionals (HCPs) may benefit from training in effective patient communication. HCPs should closely and frequently monitor patient treatment responses, in order to better understand symptom onset and exacerbation. Patients also should be encouraged to participate in exercise programs, and health information and support groups, which may assist them in preventing or mitigating certain determinants of the therapeutic burden associated with PC and its management.
Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy
Authors: Tang Tianyu , Huang Xing , Zhang Gang , Hong Zhengtao , Bai Xueli , Liang Tingbo
Published: February 2021

Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.
Assessment of neuropathic pain after spinal cord injury using quantitative pain drawings
Authors: Rosner Jan , Lütolf Robin , Hostettler Pascal , Villiger Michael , Clijsen Ron , Hohenauer Erich , Barbero Marco , Curt Armin , Hubli Michèle
Published: February 2021

Study design

Clinimetric cross-sectional cohort study in adults with paraplegic spinal cord injury (SCI) and neuropathic pain (NP).

Objective

To assess the reliability of standardized quantitative pain drawings in patients with NP following SCI.

Setting

Hospital-based research facility at the Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.

Methods

Twenty individuals with chronic thoracic spinal cord injury and neuropathic pain were recruited from a national and local SCI registry. A thorough clinical examination and pain assessments were performed. Pain drawings were acquired at subsequent timepoints, 13 days (IQR 7.8–14.8) apart, in order to assess test-retest reliability.

Results

The average extent [%] and intensity [NRS 0–10] of spontaneous NP were 11.3% (IQR 4.9–35.8) and 5 (IQR 3–7), respectively. Pain extent showed excellent inter-session reliability (intraclass correlation coefficient 0.96). Sensory loss quantified by light touch and pinprick sensation was associated with larger pain extent (rpinprick = −0.47, p = 0.04; rlight touch = −0.64, p < 0.01).

Conclusion

Assessing pain extent using quantitative pain drawings is readily feasible and reliable in human SCI. Relating information of sensory deficits to the presence of pain may provide distinct insights into the interaction of sensory deafferentation and the development of neuropathic pain after SCI.
Lifestyle of sponge symbiont phages by host prediction and correlative microscopy
Authors: Jahn M T , Lachnit T , Markert S M , Stigloher C , Pita L , Ribes M , Dutilh B E , Hentschel U
Published: February 2021

Bacteriophages (phages) are ubiquitous elements in nature, but their ecology and role in animals remains little understood. Sponges represent the oldest known extant animal-microbe symbiosis and are associated with dense and diverse microbial consortia. Here we investigate the tripartite interaction between phages, bacterial symbionts, and the sponge host. We combined imaging and bioinformatics to tackle important questions on who the phage hosts are and what the replication mode and spatial distribution within the animal is. This approach led to the discovery of distinct phage-microbe infection networks in sponge versus seawater microbiomes. A new correlative in situ imaging approach (‘PhageFISH-CLEM‘) localised phages within bacterial symbiont cells, but also within phagocytotically active sponge cells. We postulate that the phagocytosis of free virions by sponge cells modulates phage-bacteria ratios and ultimately controls infection dynamics. Prediction of phage replication strategies indicated a distinct pattern, where lysogeny dominates the sponge microbiome, likely fostered by sponge host-mediated virion clearance, while lysis dominates in seawater. Collectively, this work provides new insights into phage ecology within sponges, highlighting the importance of tripartite animal-phage-bacterium interplay in holobiont functioning. We anticipate that our imaging approach will be instrumental to further understanding of viral distribution and cellular association in animal hosts.
A systematic review and meta-analysis of genotype-based and individualized data analysis of SLCO1B1 gene and statin-induced myopathy
Authors: Turongkaravee Saowalak , Jittikoon Jiraphun , Lukkunaprasit Thitiya , Sangroongruangsri Sermsiri , Chaikledkaew Usa , Thakkinstian Ammarin
Published: February 2021

This meta-analysis was conducted to determine the genotypic effects of rs4149056 and rs2306283 polymorphism in SLCO1B1 gene on myopathy in patients with statin. Studies were searched using multiple databases and selected following inclusion criteria. Two reviewers independently performed data extraction and assessments for risk of bias. Fixed-or-random-effect was applied to pool allele frequency/effects. Mixed-effect logit model was used to pool genotypic effects using individual patient data. Heterogeneity and publication bias were explored. Fourteen studies were pooled for rs4149056; the minor C allele frequency were 15% in Caucasians and 14% in Asians. Six studies were pooled for rs2306283; the minor G allele frequency was 34% in Caucasian and 75% in Asians. Genotypic effects of rs4149056 polymorphism in Caucasians indicated that statin users who carried CC and TC genotypes had a significantly higher risk of myopathy than those who carried TT genotype, with a pooled odds ratio (OR) of 2.9 (95% confidence interval, 1.59, 5.34) and 1.6 (1.20, 2.16), respectively. For subgroup analysis, CC and TC genotypes also suggested a higher risk of myopathy in simvastatin users [OR = 2.8 (1.17, 6.77) and OR = 1.8 (1.15, 2.77), respectively] and in atorvastatin users [OR = 4.0 (1.23, 12.63) and OR = 2.0 (1.11, 3.52), respectively] than those who carried TT genotype. There was no significant association between rs2306283 polymorphism and myopathy in Caucasians and Asians. There was no evidence of publication bias for both polymorphisms.
Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress
Authors: Zhang Weijie , Qu Wan , Wang Hua , Yan He
Published: February 2021

Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota–gut–brain axis. But the impact of antidepressants on gut microbiota function and composition remains poorly understood. Thus this study assessed the effect of serotonin reuptake inhibitor antidepressant fluoxetine (Flu) and tricyclic antidepressant amitriptyline (Ami) administration on gut microbiota composition, diversity, and species abundance, along with microbial function in a chronic unpredictable mild stress (CUMS)-induced depression rat model. Oral administration of Ami and Flu significantly altered the overall gut microbiota profile of CUMS-induced rats, as assessed using the permutational multivariate analysis of variance test. At the phylum level, 6-week of antidepressant treatment led to a decreased Firmicutes/Bacteroidetes ratio due to an enhanced Bacteroidetes and reduced Firmicutes relative abundance. Flu was more potent than Ami at altering the Firmicutes and Bacteroidetes levels in the CUMS rats. At the family level, both antidepressants significantly increased the abundance of Porphyromonadaceae. However, an increased Bacteroidaceae level was significantly associated with Ami, not Flu treatment. Furthermore, at the genus level, an increase in the relative abundance of Parabacteroides, Butyricimonas, and Alistipes was observed following Ami and Flu treatment. Subsequent metagenomics and bioinformatics analysis further indicated that Ami and Flu likely also modulated metabolic pathways, such as those involved in carbohydrate metabolism, membrane transport, and signal transduction. Additionally, both antidepressants affected antibiotic resistome, such as for aminoglycoside (aph3iiiA), multidrug (mdtK, mdtP, mdtH, mdtG, acrA), and tetracycline (tetM) resistance in CUMS rats. These data clearly illustrated the direct impact of oral administration of Flu and Ami on the gut microbiome, thus set up the foundation to reveal more insights on the therapeutic function of the antidepressants and their overall contribution to host health.
Acute psychological impact on COVID-19 patients in Hubei: a multicenter observational study
Authors: Wang Minghuan , Hu Caihong , Zhao Qian , Feng Renjie , Wang Qing , Cai Hongbin , Guo Zhenli , Xu Kang , Luo Wenjing , Guo Canshou , Zhang Sheng , Chen Chunfa , Zhu Chunli , Wang Hongmin , Chen Yu , Ma Li , Zhan Peiyan , Cao Jie , Huang Shanshan , Yang Mia Jiming , Fang Yuxin , Zhu Suiqiang , Yang Yuan
Published: February 2021

We conducted a multicentre cross-sectional survey of COVID-19 patients to evaluate the acute psychological impact on the patients with coronavirus disease 2019 (COVID-19) during isolation treatment based on online questionnaires from 2 February to 5 March 2020. A total of 460 COVID-19 patients from 13 medical centers in Hubei province were investigated for their mental health status using online questionnaires (including Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Patient Health Questionnaire-15, and Insomnia Severity Index scales). Among all 460 COVID-19 patients, 187 (40.65%) of them were healthcare workers (HCWs). 297 (64.57%) of them were females. The most common psychological problems were somatization symptoms (66.09%, n = 304), followed by depression (53.48%, n = 246), anxiety (46.30%, n = 213), problems of insomnia (42.01%, n = 171), and then self-mutilating or suicidal thoughts (23.26%, n = 107). Of all the patients, 15.65% (n = 72) had severe somatization symptoms, and 2.83% (n = 13) had severe (almost every day) self-mutilating or suicidal thoughts. The most common psychological problems for HCWs were somatization symptoms (67.84%, n = 125), followed by depression (51.87%, n = 97), anxiety (44.92%, n = 84), problems of insomnia (36.18%, n = 55), and then self-mutilating or suicidal thoughts (20.86%, n = 39). Patients with lower education levels were found to be associated with higher incidence of self-mutilating or suicidal thoughts (odds ratio [OR], 2.68, 95% confidence interval [95% CI], 1.66–4.33 [P < 0.001]). Patients with abnormal body temperature were found to be associated with higher incidence of self-mutilating or suicidal thoughts (OR, 3.97, 95% CI, 2.07–7.63 [P < 0.001]), somatic symptoms (OR, 2.06, 95% CI, 1.20–3.55 [P = 0.009]) and insomnia (OR, 1.66, 95% CI, 1.04–2.65 [P = 0.033]). Those with suspected infected family members displayed a higher prevalence of anxiety than those without infected family members (OR, 1.61, 95% CI, 1.1–2.37 [P = 0.015]). Patients at the age of 18–44 years old had fewer somatic symptoms than those aged over 45 years old (OR, 1.91, 95% CI, 1.3–2.81 [P = 0.001]). In conclusion, COVID-19 patients tended to have a high prevalence of adverse psychological events. Early identification and intervention should be conducted to avoid extreme events such as self-mutilating or suicidal impulsivity for COVID-19 patients, especially for those with low education levels and females who have undergone divorce or bereavement.
Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling
Authors: Tseng Wei Chou , Reinhart Veronica , Lanz Thomas A. , Weber Mark L. , Pang Jincheng , Le Kevin Xuong Vinh , Bell Robert D. , O’Donnell Patricio , Buhl Derek L.
Published: February 2021

Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1β protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.
Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment
Authors: van der Horst Hilma J. , de Jonge A. Vera , Hiemstra Ida H. , Gelderloos Anne T. , Berry Daniella R. A. I. , Hijmering Nathalie J. , van Essen Hendrik F. , de Jong Daphne , Chamuleau Martine E. D. , Zweegman Sonja , Breij Esther C. W. , Roemer Margaretha G. M. , Mutis Tuna
Published: February 2021

Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20+ tumor cells. Here, we assessed the preclinical efficacy of epcoritamab against primary tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.
Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life
Authors: Terpos Evangelos , Mikhael Joseph , Hajek Roman , Chari Ajai , Zweegman Sonja , Lee Hans C. , Mateos María-Victoria , Larocca Alessandra , Ramasamy Karthik , Kaiser Martin , Cook Gordon , Weisel Katja C. , Costello Caitlin L. , Elliott Jennifer , Palumbo Antonio , Usmani Saad Z.
Published: February 2021

Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the ‘efficacy’ of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual’s composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic stem cell transplantation for thalassemia major: incidence, management, and outcome
Authors: Lai Xiaoxuan , Liu Lianjin , Zhang Zhongming , Shi Lingling , Yang Gaohui , Wu Meiqing , Huang Rui , Liu Rongrong , Lai Yongrong , Li Qiaochuan
Published: February 2021

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present prospective study, we aimed to investigate the incidence, management, and outcome of VOD/SOS in patients with thalassemia major (TM) who received allo-HSCT. VOD/SOS was diagnosed and classified based on the modified Seattle criteria. The prophylactic regimen for VOD/SOS was a combination treatment of dalteparin and lipo-PGE1. VOD/SOS was managed through an approach consisting of adequate supportive measures, short-term withdrawal of calcineurin inhibitors (CNIs), and the use of methylprednisolone and basiliximab for graft-versus-host disease prophylaxis. VOD/SOS was found in 54 of 521 patients (10.4%) at a median time of 12 days after allo-HSCT. The cumulative incidence of all-grade and moderate VOD/SOS was 10.4% and 4.2%, respectively. Among the 54 VOD/SOS patients, no patient developed severe grade and died from VOD/SOS. Besides, the cumulative incidence of transplant-related mortality on day 100 for patients with or without VOD/SOS was 0% vs. 4.0% (P = 0.187), respectively, and the 3-year overall survival rates were 94.3% vs. 93.2% (P = 0.707), respectively. Collectively, we concluded that appropriate symptomatic therapy and short-term withdrawal of CNIs safely mitigated the mortality of VOD/SOS in TM patients who underwent allo-HSCT.
c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia–reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway
Authors: Liu Dajun , Liu Ying , Zheng Xiaotong , Liu Naiquan
Published: February 2021

Ischemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin–eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/β-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/β-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/β-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future.
Syngeneic leukemia models using lentiviral transgenics
Authors: Keinan Nurit , Scharff Ye’ela , Goldstein Oron , Chamo Michael , Ilic Stefan , Gazit Roi
Published: February 2021

Animal models are necessary to study cancer and develop treatments. After decades of intensive research, effective treatments are available for only a few types of leukemia, while others are currently incurable. Our goal was to generate novel leukemia models in immunocompetent mice. We had achieved abilities for overexpression of multiple driving oncogenes simultaneously in normal primary cells, which can be transplanted and followed in vivo. Our experiments demonstrated the induction of primary malignant growth. Leukemia lines that model various types of leukemia, such as acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), were passaged robustly in congenic wild-type immunocompetent mice. These novel leukemia lines, which may complement previous models, offer the flexibility to generate tailored models of defined oncogenes of interest. The characterization of our leukemia models in immunocompetent animals can uncover the mechanisms of malignancy progression and offer a unique opportunity to stringently test anti-cancer chemotherapies.
Deletion of FGF9 in GABAergic neurons causes epilepsy
Authors: Guo Moran , Cui Can , Song Xueqin , Jia Lijing , Li Duan , Wang Xiuli , Dong Hui , Ma Yanqin , Liu Yaling , Cui Zhiqiang , Yi Le , Li Zhongyao , Bi Yue , Li Yuanyuan , Liu Yakun , Duan Weisong , Li Chunyan
Published: February 2021

Fibroblast growth factor 9 (FGF9) has long been assumed to modulate multiple biological processes, yet very little is known about the impact of FGF9 on neurodevelopment. Herein, we found that loss of Fgf9 in olig1 progenitor cells induced epilepsy in mice, with pathological changes in the cortex. Then depleting Fgf9 in different neural populations revealed that epilepsy was associated with GABAergic neurons. Fgf9 CKO in GABAergic neuron (CKOVGAT) mice exhibited not only the most severe seizures, but also the most severe growth retardation and highest mortality. Fgf9 deletion in CKOVGAT mice caused neuronal apoptosis and decreased GABA expression, leading to a GABA/Glu imbalance and epilepsy. The adenylate cyclase/cyclic AMP and ERK signaling pathways were activated in this process. Recombinant FGF9 proteoliposomes could significantly decrease the number of seizures. Furthermore, the decrease of FGF9 was commonly observed in serum of epileptic patients, especially those with focal seizures. Thus, FGF9 plays essential roles in GABAergic neuron survival and epilepsy pathology, which could serve as a new target for the treatment of epilepsy.