bluuebunny/crossref_metadata_2025 huggingface dataset:
The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill
Authors: Knight Jennifer M. , Costanzo Erin S. , Singh Suraj , Yin Ziyan , Szabo Aniko , Pawar Deepa S. , Hillard Cecilia J. , Rizzo J. Douglas , D’Souza Anita , Pasquini Marcelo , Coe Christopher L. , Irwin Michael R. , Raison Charles L. , Drobyski William R.
Published: January 2021

Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II–IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more—not less—depressive symptoms.
Lower functional hippocampal redundancy in mild cognitive impairment
Authors: Langella Stephanie , Sadiq Muhammad Usman , Mucha Peter J. , Giovanello Kelly S. , Dayan Eran ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2021

With an increasing prevalence of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in response to an aging population, it is critical to identify and understand neuroprotective mechanisms against cognitive decline. One potential mechanism is redundancy: the existence of duplicate elements within a system that provide alternative functionality in case of failure. As the hippocampus is one of the earliest sites affected by AD pathology, we hypothesized that functional hippocampal redundancy is protective against cognitive decline. We compared hippocampal functional redundancy derived from resting-state functional MRI networks in cognitively normal older adults, with individuals with early and late MCI, as well as the relationship between redundancy and cognition. Posterior hippocampal redundancy was reduced between cognitively normal and MCI groups, plateauing across early and late MCI. Higher hippocampal redundancy was related to better memory performance only for cognitively normal individuals. Critically, functional hippocampal redundancy did not come at the expense of network efficiency. Our results provide support that hippocampal redundancy protects against cognitive decline in aging.
The placenta protects the fetal circulation from anxiety-driven elevations in maternal serum levels of brain-derived neurotrophic factor
Authors: Dingsdale Hayley , Nan Xinsheng , Garay Samantha M. , Mueller Annett , Sumption Lorna A. , Chacón-Fernández Pedro , Martinez-Garay Isabel , Ghevaert Cedric , Barde Yves-Alain , John Rosalind M.
Published: January 2021

Brain-derived neurotrophic factor (BDNF) plays crucial roles in brain function. Numerous studies report alterations in BDNF levels in human serum in various neurological conditions, including mood disorders such as depression. However, little is known about BDNF levels in the blood during pregnancy. We asked whether maternal depression and/or anxiety during pregnancy were associated with altered serum BDNF levels in mothers (n = 251) and their new-born infants (n = 212). As prenatal exposure to maternal mood disorders significantly increases the risk of neurological conditions in later life, we also examined the possibility of placental BDNF transfer by developing a new mouse model. We found no association between maternal symptoms of depression and either maternal or infant cord blood serum BDNF. However, maternal symptoms of anxiety correlated with significantly raised maternal serum BDNF exclusively in mothers of boys (r = 0.281; P = 0.005; n = 99). Serum BDNF was significantly lower in male infants than female infants but neither correlated with maternal anxiety symptoms. Consistent with this observation, we found no evidence for BDNF transfer across the placenta. We conclude that the placenta protects the developing fetus from maternal changes in serum BDNF that could otherwise have adverse consequences for fetal development.
MEDAG enhances breast cancer progression and reduces epirubicin sensitivity through the AKT/AMPK/mTOR pathway
Authors: Li Zhiyu , Li Chenyuan , Wu Qi , Tu Yi , Wang Changhua , Yu Xin , Li Bei , Wang Zhong , Sun Si , Sun Shengrong
Published: January 2021

Breast cancer (BC) is the most common malignancy among women. Mesenteric estrogen-dependent adipogenesis gene (MEDAG) was first reported as a novel adipogenic gene, and its involvement and mechanism in visceral adiposity were analyzed. However, the role of MEDAG in BC is unclear. The biological roles and corresponding mechanisms were investigated in vitro and in vivo. We found that MEDAG was highly expressed in BC samples and that a high MEDAG expression was correlated with clinicopathological characteristics and poor survival in BC patients. MEDAG knockdown inhibited cell proliferation, invasion, and migration; triggered epithelial-to-mesenchymal transition (EMT); and enhanced epirubicin sensitivity in vitro. The opposite results were observed in MEDAG-overexpressing cells. The inhibition of MEDAG suppressed tumor growth and metastasis in vivo. Mechanistically, MEDAG knockdown led to decreased phosphorylation levels of AKT, increased levels of p-AMPK, and reduced levels of p-mTOR, while the overexpression of MEDAG had the opposite effects. Moreover, the activation of p-AKT and inhibition of p-AMPK restored the effect of MEDAG on EMT and chemosensitivity in BC cell lines, indicating that MEDAG functions as an oncogene by regulating the AKT/AMPK/mTOR pathway. MEDAG regulates BC progression and EMT via the AKT/AMPK/mTOR pathway and reduces chemosensitivity in BC cells. Therefore, MEDAG is a promising target for BC.
Wnt5a promotes renal tubular inflammation in diabetic nephropathy by binding to CD146 through noncanonical Wnt signaling
Authors: Li Xiaomei , Wen Jiejun , Dong Yang , Zhang Qunzi , Guan Jian , Liu Feng , Zhou Ting , Li Ze , Fan Ying , Wang Niansong
Published: January 2021

Immune and inflammatory factors have emerged as key pathophysiological mechanisms in the progression of diabetic renal injury. Noncanonical Wnt5a signaling plays an essential role in obesity- or diabetes-induced metabolic dysfunction and inflammation, but its explicit molecular mechanisms and biological function in diabetic nephropathy (DN) remain unknown. In this study, we found that the expression of Wnt5a and CD146 in the kidney and the level of soluble form of CD146 (sCD146) in serum and urine samples were upregulated in DN patients compared to controls, and this alteration was correlated with the inflammatory process and progression of renal impairment. Blocking the activation of Wnt5a signaling with the Wnt5a antagonist Box5 prevented JNK phosphorylation and high glucose-induced inflammatory responses in db/db mice and high glucose-treated HK-2 cells. Similar effects were observed by silencing Wnt5a with small-interfering RNA (siRNA) in cultured HK-2 cells. Knockdown of CD146 blocked Wnt5a-induced expression of proinflammatory cytokines and activation of JNK, which suggests that CD146 is essential for the activation of the Wnt5a pathway. Finally, we confirmed that Wnt5a directly interacted with CD146 to activate noncanonical Wnt signaling in HK-2 cells. Taken together, our findings suggest that by directly binding to CD146, Wnt5a-induced noncanonical signaling is a contributing mechanism for renal tubular inflammation in diabetic nephropathy. The concentration of sCD146 in serum and urine could be a potential biomarker to predict renal outcomes in DN patients.
M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
Authors: Bai Li , Kong Ming , Duan Zhongping , Liu Shuang , Zheng Sujun , Chen Yu
Published: January 2021

Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis.
miR-541-3p enhances the radiosensitivity of prostate cancer cells by inhibiting HSP27 expression and downregulating β-catenin
Authors: He Zhenhua , Shen Fuhui , Qi Ping , Zhai Zhenxing , Wang Zhiping
Published: January 2021

Heat shock protein 27 (HSP27), a regulator of cell survival, can enhance the resistance of cancer cells to radiotherapy. As microRNA-541-3p (miR-541-3p) was recently predicted to be a putative upstream modulator of HSP27, the present study was designed to investigate the function and mechanism underlying how miR-541-3p modulates the radiosensitivity of prostate cancer (PCa) cells by regulating HSP27. Through quantitative PCR, miR-541-3p was determined to be poorly expressed in PCa tissues relative to normal controls, whereas its expression was enhanced after radiotherapy. Consistently, miR-541-3p expression levels in PCa cells were elevated after radiation. Cell viability and proliferation and apoptosis under radiation were subsequently evaluated in response to loss-of-function of miR-541-3p. It was found that inhibition of miR-541-3p facilitated the viability and proliferation of PCa cells and promoted their apoptosis post radiation, hence reducing the radiosensitivity of LNCaP cells. Dual-luciferase reporter assay identified that miR-541-3p negatively regulated the HSP27 mRNA expression by targeting its 3′-UTR. Meanwhile, miR-541-3p overexpression inhibited the β-catenin expression by targeting HSP27. Furthermore, HSP27 or β-catenin overexpression was noted to significantly reverse the miR-541-3p-mediated changes in the biological functions of PCa cells post radiation, suggesting that HSP27-dependent activation of β-catenin might be the mechanism responsible for the promotive effect of miR-541-3p on radiosensitivity. Collectively, this study suggests that miR-541-3p specifically inhibits the HSP27 expression and downregulates β-catenin, thereby enhancing the radiosensitivity of PCa cells. Our findings highlight the underlying mechanism of the miR-541-3p/HSP27/Wnt/β-catenin axis regarding radiotherapy for PCa.
Observation and control of the weak topological insulator state in ZrTe5
Authors: Zhang Peng , Noguchi Ryo , Kuroda Kenta , Lin Chun , Kawaguchi Kaishu , Yaji Koichiro , Harasawa Ayumi , Lippmaa Mikk , Nie Simin , Weng Hongming , Kandyba V. , Giampietri A. , Barinov A. , Li Qiang , Gu G. D. , Shin Shik , Kondo Takeshi
Published: January 2021

A quantum spin Hall (QSH) insulator hosts topological states at the one-dimensional (1D) edge, along which backscattering by nonmagnetic impurities is strictly prohibited. Its 3D analogue, a weak topological insulator (WTI), possesses similar quasi-1D topological states confined at side surfaces. The enhanced confinement could provide a route for dissipationless current and better advantages for applications relative to strong topological insulators (STIs). However, the topological side surface is usually not cleavable and is thus hard to observe. Here, we visualize the topological states of the WTI candidate ZrTe5 by spin and angle-resolved photoemission spectroscopy (ARPES): a quasi-1D band with spin-momentum locking was revealed on the side surface. We further demonstrate that the bulk band gap is controlled by external strain, realizing a more stable WTI state or an ideal Dirac semimetal (DS) state. The highly directional spin-current and the tunable band gap in ZrTe5 will provide an excellent platform for applications.
Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis
Authors: Li Mingsen , Huang Huaxing , Li Lingyu , He Chenxi , Zhu Liqiong , Guo Huizhen , Wang Li , Liu Jiafeng , Wu Siqi , Liu Jingxin , Xu Tao , Mao Zhen , Cao Nan , Zhang Kang , Lan Fei , Ding Junjun , Yuan Jin , Liu Yizhi , Ouyang Hong
Published: January 2021

Adult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis-regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis.
A database framework for rapid screening of structure-function relationships in PFAS chemistry
Authors: Su An , Rajan Krishna
Published: January 2021

This paper describes a database framework that enables one to rapidly explore systematics in structure-function relationships associated with new and emerging PFAS chemistries. The data framework maps high dimensional information associated with the SMILES approach of encoding molecular structure with functionality data including bioactivity and physicochemical property. This ‘PFAS-Map’ is a 3-dimensional unsupervised visualization tool that can automatically classify new PFAS chemistries based on current PFAS classification criteria. We provide examples on how the PFAS-Map can be utilized, including the prediction and estimation of yet unmeasured fundamental physical properties of PFAS chemistries, uncovering hierarchical characteristics in existing classification schemes, and the fusion of data from diverse sources.
Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach
Authors: Wang Yafei , Brodin Erik , Nishii Kenichiro , Frieboes Hermann B. , Mumenthaler Shannon M. , Sparks Jessica L. , Macklin Paul
Published: January 2021

Colorectal cancer and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could “reawaken” after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer.
A shift towards early-age desexing of cats under veterinary care in Australia
Authors: Mazeau Loic , Wylie Claire , Boland Lara , Beatty Julia A.
Published: January 2021

The global problem of unowned domestic cats, driven by their phenomenal reproductive success, carries significant economic, animal welfare and biodiversity costs. Desexing owned cats prior to puberty prevents unwanted litters that contribute to unowned cat populations. The prevalence and predictors of desexing, and the age at which surgery was carried out were investigated using anonymized electronic patient records in the VetCompass Australia database of cats presented to veterinary practices. Of 52,941 cats born between 2010 and 2017, 83.6% were desexed. Among 7463 desexed females, 21.5% had been desexed by 4 months of age, 59.8% by 6 months and 85.4% by 1 year. Sex, breed, location and socioeconomic indices significantly influenced desexing status and age at surgery. Cats born between 2010 and 2017 had greater odds of being desexed than cats born between 1995and 2009 at each age cut-off (≤ 4 months [OR 1.76, CI951.58–1.97], ≤ 6 months [OR 1.50, CI951.38–1.62] and ≤ 1 year [OR 2.33, CI952.11–2.57]p < 0.001). Most cats presented to veterinarians in Australia are desexed. Compared with cats born before 2010, cats born later are significantly younger at desexing but, even so, many cats would have reached sexual maturity before surgery. These findings will inform the design of front-line strategies promoting prepubertal desexing and they demonstrate, for the first time, a shift towards desexing younger cats.
A comparative study to evaluate CT-based semantic and radiomic features in preoperative diagnosis of invasive pulmonary adenocarcinomas manifesting as subsolid nodules
Authors: Wu Yun-Ju , Liu Yung-Chi , Liao Chien-Yang , Tang En-Kuei , Wu Fu-Zong
Published: January 2021

This study aims to predict the histological invasiveness of pulmonary adenocarcinoma spectrum manifesting with subsolid nodules ≦ 3 cm using the preoperative CT-based radiomic approach. A total of 186 patients with 203 SSNs confirmed with surgically pathologic proof were retrospectively reviewed from February 2016 to March 2020 for training cohort modeling. The validation cohort included 50 subjects with 57 SSNs confirmed with surgically pathologic proof from April 2020 to August 2020. CT-based radiomic features were extracted using an open-source software with 3D nodular volume segmentation manually. The association between CT-based conventional features/selected radiomic features and histological invasiveness of pulmonary adenocarcinoma status were analyzed. Diagnostic models were built using conventional CT features, selected radiomic CT features and experienced radiologists. In addition, we compared diagnostic performance between radiomic CT feature, conventional CT features and experienced radiologists. In the training cohort of 203 SSNs, there were 106 invasive lesions and 97 pre-invasive lesions. Logistic analysis identified that a selected radiomic feature named GLCM_Entropy_log10 was the predictor for histological invasiveness of pulmonary adenocarcinoma spectrum (OR: 38.081, 95% CI 2.735–530.309, p = 0.007). The sensitivity and specificity for predicting histological invasiveness of pulmonary adenocarcinoma spectrum using the cutoff value of CT-based radiomic parameter (GLCM_Entropy_log10) were 84.8% and 79.2% respectively (area under curve, 0.878). The diagnostic model of CT-based radiomic feature was compared to those of conventional CT feature (morphologic and quantitative) and three experienced radiologists. The diagnostic performance of radiomic feature was similar to those of the quantitative CT feature (nodular size and solid component, both lung and mediastinal window) in prediction invasive pulmonary adenocarcinoma (IPA). The AUC value of CT radiomic feature was higher than those of conventional CT morphologic feature and three experienced radiologists. The c-statistic of the training cohort model was 0.878 (95% CI 0.831–0.925) and 0.923 (0.854–0.991) in the validation cohort. Calibration was good in both cohorts. The diagnostic performance of CT-based radiomic feature is not inferior to solid component (lung and mediastinal window) and nodular size for predicting invasiveness. CT-based radiomic feature and nomogram could help to differentiate IPA lesions from preinvasive lesions in the both independent training and validation cohorts. The nomogram may help clinicians with decision making in the management of subsolid nodules.
Effects of symmetry-breaking on electromagnetic backscattering
Authors: Abdelrahman Mohamed Ismail , Slivina Evgeniia , Rockstuhl Carsten , Fernandez-Corbaton Ivan
Published: January 2021

Systems with a discrete rotational symmetry $$2\pi /n$$

2
π
/
n

where $$n\ge 3$$

n
≥
3

that also have electromagnetic duality symmetry exhibit zero backscattering. The impact of breaking one of the two symmetries on the emerging backscattering has not yet been systematically studied. Here, we investigate the effect that perturbatively breaking each of the two symmetries has on the backscattering off individual objects and 2D arrays. We find that the backscattering off electromagnetically-small prisms increases with the parameters that determine the symmetry breaking, and that the increase of the backscattering due to the progressive breaking of one of the symmetries can be related to the other symmetry. Further exploration of the interplay between the two symmetries reveals that, in systems lacking enough rotational symmetry, the backscattering can be almost-entirely suppressed for a given linear polarization by deliberately breaking the duality symmetry. This duality breaking can be interpreted as an effective increase of the electromagnetic degree of rotational symmetry for that linear polarization.
Dietary patterns, food groups and nutrients in Crohn’s disease: associations with gut and systemic inflammation
Authors: Naqvi S. Ali , Taylor Lorian M. , Panaccione Remo , Ghosh Subrata , Barkema Herman W. , Hotte Naomi , Shommu Nusrat , Kaur Sandeep , Reimer Raylene A. , Madsen Karen L. , Raman Maitreyi
Published: January 2021

This study examined associations between dietary intake and gut and systemic inflammation assessed by fecal calprotectin ≤ or > 100 μg/mg (FCP), C-reactive protein ≤ or > 5 mg/L (CRP) and serum cytokine profiles in Crohn’s disease (CD) patients in clinical remission. A 3-month observational study was conducted at the University of Calgary in Calgary, Alberta, Canada between 2016 and 2018 in 66 outpatients with CD in clinical remission. FCP was obtained from stool samples at baseline and 3-months and serum CRP and serum cytokines were assessed at 3-months only (n = 41). Dietary intakes were collected using 3-day food records at baseline and 3-months and categorized as: PREDIMED Mediterranean diet scores (pMDS) total and individual components, the dietary inflammatory index (DII), food groups, and common micro- and macro-nutrients. Statistical models were developed to identify relationships between dietary factors and FCP, CRP and cytokine levels. Daily intake of leafy green vegetables was associated with FCP ≤ 100 μg/mg (p < 0.05). Increasing omega 6:3 ratio was associated with CRP ≤ 5 mg/L (p = 0.02). Different cytokines were significantly associated with various dietary variables. Future studies in patients with greater disease activity should be undertaken to explore these relationships.
Dynamics of neuronal oscillations underlying nociceptive response in the mouse primary somatosensory cortex
Authors: Iwamoto Shosuke , Tamura Makoto , Sasaki Atsushi , Nawano Masao
Published: January 2021

Pain is caused by tissue injury, inflammatory disease, pathogen invasion, or neuropathy. The perception of pain is attributed to the neuronal activity in the brain. However, the dynamics of neuronal activity underlying pain perception are not fully known. Herein, we examined theta-oscillation dynamics of local field potentials in the primary somatosensory cortex of a mouse model of formalin-induced pain, which usually shows a bimodal behavioral response interposed between pain-free periods. We found that formalin injection exerted a reversible shift in the theta-peak frequency toward a slower frequency. This shift was observed during nociceptive phases but not during the pain-free period and was inversely correlated with instantaneous pain intensity. Furthermore, instantaneous oscillatory analysis indicated that the probability of slow theta oscillations increased during nociceptive phases with an association of augmented slow theta power. Finally, cross-frequency coupling between theta and gamma oscillations indicated that the coupling peak frequency of theta oscillations was also shifted toward slower oscillations without affecting coupling strength or gamma power. Together, these results suggest that the dynamic changes in theta oscillations in the mouse primary somatosensory cortex represent the ongoing status of pain sensation.
Hsa-miR-494-3p attenuates gene HtrA3 transcription to increase inflammatory response in hypoxia/reoxygenation HK2 Cells
Authors: Gong Qian , Shen Zhi-ming , Sheng Zhe , Jiang Shi , Ge Sheng-lin
Published: January 2021

The occurrence of cardiac surgery-associated acute kidney injury (CSA-AKI) increases hospital stay and mortality. MicroRNAs has a crucial role in AKI. This objective of the current study is to explore the function of hsa-miR-494-3p in inflammatory response in human kidney tubular epithelial (HK2) cells with hypoxia/reoxygenation. According to KDIGO standard, patients after cardiac surgery with cardiopulmonary bypass were divided into two groups: AKI (n = 10) and non-AKI patients (n = 8). HK2 were raised in the normal and hypoxia/reoxygenation circumstances and mainly treated by overexpression ofmiR-494-3p and HtrA3. The relationship between miR-494-3p and HtrA3 was determined by dual-luciferase reporter assay. Our result showed that Hsa-miR-494-3p was elevated in the serum of patients with CSA-AKI, and also induced in hypoxic reoxygenated HK2 cells. Hsa-miR-494-3p also increased a hypoxia-reoxygenation induced inflammatory response in HK2 cells. Moreover, as a target gene of miR-494-3p, overexpression of HtrA3 downregulated the hypoxia-reoxygenation induced inflammatory response in HK2 cells. Overexpression of hsa-miR-494-3p-induced inflammatory response was inhibited by overexpression of HtrA3. Collectively, we identified that hsa-miR-494-3p, a miRNA induced in both circulation of AKI patients and hypoxia-reoxygenation-treated HK2 cells, enhanced renal inflammation by targeting HtrA3, which may suggest a possible role as a new therapeutic target for CSA-AKI.
Variable- and person-centered approaches to affect-biased attention in infancy reveal unique relations with infant negative affect and maternal anxiety
Authors: Vallorani Alicia , Fu Xiaoxue , Morales Santiago , LoBue Vanessa , Buss Kristin A. , Pérez-Edgar Koraly
Published: January 2021

Affect-biased attention is an automatic process that prioritizes emotionally or motivationally salient stimuli. Several models of affect-biased attention and its development suggest that it comprises an individual’s ability to both engage with and disengage from emotional stimuli. Researchers typically rely on singular tasks to measure affect-biased attention, which may lead to inconsistent results across studies. Here we examined affect-biased attention across three tasks in a unique sample of 193 infants, using both variable-centered (factor analysis; FA) and person-centered (latent profile analysis; LPA) approaches. Using exploratory FA, we found evidence for two factors of affect-biased attention: an Engagement factor and a Disengagement factor, where greater maternal anxiety was related to less engagement with faces. Using LPA, we found two groups of infants with different patterns of affect-biased attention: a Vigilant group and an Avoidant group. A significant interaction noted that infants higher in negative affect who also had more anxious mothers were most likely to be in the Vigilant group. Overall, these results suggest that both FA and LPA are viable approaches for studying distinct questions related to the development of affect-biased attention, and set the stage for future longitudinal work examining the role of infant negative affect and maternal anxiety in the emergence of affect-biased attention.
Soil microbial properties of subalpine steppe soils at different grazing intensities in the Chinese Altai Mountains
Authors: Goenster-Jordan Sven , Ingold Mariko , Jannoura Ramia , Buerkert Andreas , Joergensen Rainer Georg
Published: January 2021

Long-term provision of ecosystem services by grasslands is threatened by increasing stocking densities. The functions of grassland ecosystems depend on a mutual relationship between aboveground and belowground biota. While the effects of increasing stocking density on plant biomass are well studied, little is known about its impact on soil microbial properties. To fill this knowledge gap a grazing experiment was conducted on a summer pasture in the Chinese Altai Mountains during the summers of 2014 and 2015 using a randomized block design with stocking densities of 0, 8, 16, and 24 sheep ha−1 replicated four times. After two summer grazing periods (each 56 days), topsoil samples (1–7 cm) were taken in September 2015 and analyzed for major physical, chemical, and microbial soil properties. Except for the metabolic quotient (qCO2; p < 0.05), the examined soil properties remained unaffected by the increasing stocking densities, likely due to high spatial variability. The qCO2 declined from 13.5 mg CO2–C g−1 microbial biomass C d−1 at zero grazing to 12.2 mg CO2–C g−1 microbial biomass C d−1 at a stocking density of 24 sheep ha−1. Low values of qCO2 indicate an aged and dormant microbial community that diverts less soil organic carbon (SOC) to catabolic processes within their cells, characteristic for C limiting conditions. The aboveground biomass affected by grazing intensity correlated positively with SOC (rs = 0.60, p = 0.015) and ergosterol (rs = 0.76, p = 0.001) pointing indirectly to the effect of stocking density. Additionally to the relatively high values of qCO2, highest values of SOC (39.2 mg g−1 soil), ergosterol (6.01 µg g−1 soil), and basal respiration (10.7 µg g−1 soil d−1) were observed at a stocking density of 8 sheep ha−1 indicating that a low grazing intensity is recommendable to avoid soil degradation.
A numerical study of fish adaption behaviors in complex environments with a deep reinforcement learning and immersed boundary–lattice Boltzmann method
Authors: Zhu Yi , Tian Fang-Bao , Young John , Liao James C. , Lai Joseph C. S.
Published: January 2021

Fish adaption behaviors in complex environments are of great importance in improving the performance of underwater vehicles. This work presents a numerical study of the adaption behaviors of self-propelled fish in complex environments by developing a numerical framework of deep learning and immersed boundary–lattice Boltzmann method (IB–LBM). In this framework, the fish swimming in a viscous incompressible flow is simulated with an IB–LBM which is validated by conducting two benchmark problems including a uniform flow over a stationary cylinder and a self-propelled anguilliform swimming in a quiescent flow. Furthermore, a deep recurrent Q-network (DRQN) is incorporated with the IB–LBM to train the fish model to adapt its motion to optimally achieve a specific task, such as prey capture, rheotaxis and Kármán gaiting. Compared to existing learning models for fish, this work incorporates the fish position, velocity and acceleration into the state space in the DRQN; and it considers the amplitude and frequency action spaces as well as the historical effects. This framework makes use of the high computational efficiency of the IB–LBM which is of crucial importance for the effective coupling with learning algorithms. Applications of the proposed numerical framework in point-to-point swimming in quiescent flow and position holding both in a uniform stream and a Kármán vortex street demonstrate the strategies used to adapt to different situations.
Super-resolution time-resolved imaging using computational sensor fusion
Authors: Callenberg C. , Lyons A. , Brok D. den , Fatima A. , Turpin A. , Zickus V. , Machesky L. , Whitelaw J. , Faccio D. , Hullin M. B.
Published: January 2021

Imaging across both the full transverse spatial and temporal dimensions of a scene with high precision in all three coordinates is key to applications ranging from LIDAR to fluorescence lifetime imaging. However, compromises that sacrifice, for example, spatial resolution at the expense of temporal resolution are often required, in particular when the full 3-dimensional data cube is required in short acquisition times. We introduce a sensor fusion approach that combines data having low-spatial resolution but high temporal precision gathered with a single-photon-avalanche-diode (SPAD) array with data that has high spatial but no temporal resolution, such as that acquired with a standard CMOS camera. Our method, based on blurring the image on the SPAD array and computational sensor fusion, reconstructs time-resolved images at significantly higher spatial resolution than the SPAD input, upsampling numerical data by a factor $$12 \times 12$$

12
×
12

, and demonstrating up to $$4 \times 4$$

4
×
4

upsampling of experimental data. We demonstrate the technique for both LIDAR applications and FLIM of fluorescent cancer cells. This technique paves the way to high spatial resolution SPAD imaging or, equivalently, FLIM imaging with conventional microscopes at frame rates accelerated by more than an order of magnitude.
Multi-faceted enhancement of full-thickness skin wound healing by treatment with autologous micro skin tissue columns
Authors: Fuchs Christiane , Pham Linh , Henderson Jermaine , Stalnaker Katherine J. , Anderson R. Rox , Tam Joshua
Published: January 2021

Impaired wound healing is an immense medical challenge, and while autologous skin grafting remains the “gold-standard” therapeutic option for repairing wounds that cannot be closed by primary or secondary intention, it is limited by substantial donor site morbidity. We previously developed the alternative approach of harvesting full-thickness skin tissue in the form of “micro skin tissue columns” (MSTCs), without causing scarring or any other long-term morbidity. In this study we investigated how MSTC treatment affects the different cellular processes involved in wound healing. We found that MSTC-derived cells were able to remodel and repopulate the wound volume, and positively impact multiple aspects of the wound healing process, including accelerating re-epithelialization by providing multiple cell sources throughout the wound area, increasing collagen deposition, enhancing dermal remodeling, and attenuating the inflammatory response. These effects combined to enhance both epidermal and dermal wound healing. This MSTC treatment approach was designed for practical clinical use, could convey many benefits of autologous skin grafting, and avoids the major drawback of donor site morbidity.
Endogenous zebrafish proneural Cre drivers generated by CRISPR/Cas9 short homology directed targeted integration
Authors: Almeida Maira P. , Welker Jordan M. , Siddiqui Sahiba , Luiken Jon , Ekker Stephen C. , Clark Karl J. , Essner Jeffrey J. , McGrail Maura
Published: January 2021

We previously reported efficient precision targeted integration of reporter DNA in zebrafish and human cells using CRISPR/Cas9 and short regions of homology. Here, we apply this strategy to isolate zebrafish Cre recombinase drivers whose spatial and temporal restricted expression mimics endogenous genes. A 2A-Cre recombinase transgene with 48 bp homology arms was targeted into proneural genes ascl1b, olig2 and neurod1. We observed high rates of germline transmission ranging from 10 to 100% (2/20 olig2; 1/5 neurod1; 3/3 ascl1b). The transgenic lines Tg(ascl1b-2A-Cre)is75, Tg(olig2-2A-Cre)is76, and Tg(neurod1-2A-Cre)is77 expressed functional Cre recombinase in the expected proneural cell populations. Somatic targeting of 2A-CreERT2 into neurod1 resulted in tamoxifen responsive recombination in the nervous system. The results demonstrate Cre recombinase expression is driven by the native promoter and regulatory elements of the targeted genes. This approach provides a straightforward, efficient, and cost-effective method to generate cell type specific zebrafish Cre and CreERT2 drivers, overcoming challenges associated with promoter-BAC and transposon mediated transgenics.
Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques
Authors: Gillis Richard B. , Solomon Hodaya V. , Govada Lata , Oldham Neil J. , Dinu Vlad , Jiwani Shahwar Imran , Gyasi-Antwi Philemon , Coffey Frank , Meal Andy , Morgan Paul S. , Harding Stephen E. , Helliwell John R. , Chayen Naomi E. , Adams Gary G.
Published: January 2021

This study concerns glulisine, a rapid-acting insulin analogue that plays a fundamental role in diabetes management. We have applied a combination of methods namely X-ray crystallography, and biophysical characterisation to provide a detailed insight into the structure and function of glulisine. X-ray data provided structural information to a resolution of 1.26 Å. Crystals belonged to the H3 space group with hexagonal (centred trigonal) cell dimensions a = b = 82.44 and c = 33.65 Å with two molecules in the asymmetric unit. A unique position of D21Glu, not present in other fast-acting analogues, pointing inwards rather than to the outside surface was observed. This reduces interactions with neighbouring molecules thereby increasing preference of the dimer form. Sedimentation velocity/equilibrium studies revealed a trinary system of dimers and hexamers/dihexamers in dynamic equilibrium. This new information may lead to better understanding of the pharmacokinetic and pharmacodynamic behaviour of glulisine which might aid in improving formulation regarding its fast-acting role and reducing side effects of this drug.
Analysis of global human gut metagenomes shows that metabolic resilience potential for short-chain fatty acid production is strongly influenced by lifestyle
Authors: Jacobson David K. , Honap Tanvi P. , Ozga Andrew T. , Meda Nicolas , Kagoné Thérèse S. , Carabin Hélène , Spicer Paul , Tito Raul Y. , Obregon-Tito Alexandra J. , Reyes Luis Marin , Troncoso-Corzo Luzmila , Guija-Poma Emilio , Sankaranarayanan Krithivasan , Lewis Cecil M.
Published: January 2021

High taxonomic diversity in non-industrial human gut microbiomes is often interpreted as beneficial; however, it is unclear if taxonomic diversity engenders ecological resilience (i.e. community stability and metabolic continuity). We estimate resilience through genus and species-level richness, phylogenetic diversity, and evenness in short-chain fatty acid (SCFA) production among a global gut metagenome panel of 12 populations (n = 451) representing industrial and non-industrial lifestyles, including novel metagenomic data from Burkina Faso (n = 90). We observe significantly higher genus-level resilience in non-industrial populations, while SCFA production in industrial populations is driven by a few phylogenetically closely related species (belonging to Bacteroides and Clostridium), meaning industrial microbiomes have low resilience potential. Additionally, database bias obfuscates resilience estimates, as we were 2–5 times more likely to identify SCFA-encoding species in industrial microbiomes compared to non-industrial. Overall, we find high phylogenetic diversity, richness, and evenness of bacteria encoding SCFAs in non-industrial gut microbiomes, signaling high potential for resilience in SCFA production, despite database biases that limit metagenomic analysis of non-industrial populations.
Effects of social distancing on the spreading of COVID-19 inferred from mobile phone data
Authors: Khataee Hamid , Scheuring Istvan , Czirok Andras , Neufeld Zoltan
Published: January 2021

A better understanding of how the COVID-19 pandemic responds to social distancing efforts is required for the control of future outbreaks and to calibrate partial lock-downs. We present quantitative relationships between key parameters characterizing the COVID-19 epidemiology and social distancing efforts of nine selected European countries. Epidemiological parameters were extracted from the number of daily deaths data, while mitigation efforts are estimated from mobile phone tracking data. The decrease of the basic reproductive number ($$R_0$$

R
0

) as well as the duration of the initial exponential expansion phase of the epidemic strongly correlates with the magnitude of mobility reduction. Utilizing these relationships we decipher the relative impact of the timing and the extent of social distancing on the total death burden of the pandemic.
Usability assessment of drug-linking laboratory data listed on prescriptions for outpatients of chiba university hospital
Authors: Yokoyama Iichiro , Yamaguchi Hiroki , Yamazaki Kaori , Sekiya Misato , Arai Sayaka , Nakamura Takako , Suzuki Takaaki , Ishii Itsuko
Published: January 2021

To evaluate the impact of pharmacotherapy on efficacy and safety by providing laboratory data information linked to medicines on outpatient prescriptions from the hospital to the community pharmacy. Beginning on October 28, 2014, standardized laboratory data and drug-linking laboratory data were included with outpatient prescriptions at our hospital. We have created a database of drug-linking laboratory data for all drugs that can be prescribed in Japan. We counted the number of prescription inquiries related to laboratory data from community pharmacies, including those leading to prescription changes. Before laboratory data were listed on outpatient prescriptions, 4 prescription inquiries from community pharmacies per year were related to laboratory data. After our hospital started to list laboratory data, this number rose to 643, 576, 563, and 847 in the first, second, third, and fourth year (P < .05). Of these, 132, 143, 152, and 224 inquiries resulted in prescription changes. Listing laboratory data on outpatient prescriptions avoided 153 contraindications and 84 exacerbations of adverse drug reactions in four years by a prescription inquiry that had never been done before. The efficacy and safety of pharmacotherapy can be improved by listing relevant laboratory data on outpatient prescriptions.
Genome analysis of a halophilic bacterium Halomonas malpeensis YU-PRIM-29T reveals its exopolysaccharide and pigment producing capabilities
Authors: Athmika  , Ghate Sudeep D. , Arun A. B. , Rao Sneha S. , Kumar S. T. Arun , Kandiyil Mrudula Kinarulla , Saptami Kanekar , Rekha P. D.
Published: January 2021

Halomonas malpeensis strain YU-PRIM-29T is a yellow pigmented, exopolysaccharide (EPS) producing halophilic bacterium isolated from the coastal region. To understand the biosynthesis pathways involved in the EPS and pigment production, whole genome analysis was performed. The complete genome sequencing and the de novo assembly were carried out using Illumina sequencing and SPAdes genome assembler (ver 3.11.1) respectively followed by detailed genome annotation. The genome consists of 3,607,821 bp distributed in 18 contigs with 3337 protein coding genes and 53% of the annotated CDS are having putative functions. Gene annotation disclosed the presence of genes involved in ABC transporter-dependent pathway of EPS biosynthesis. As the ABC transporter-dependent pathway is also implicated in the capsular polysaccharide (CPS) biosynthesis, we employed extraction protocols for both EPS (from the culture supernatants) and CPS (from the cells) and found that the secreted polysaccharide i.e., EPS was predominant. The EPS showed good emulsifying activities against the petroleum hydrocarbons and its production was dependent on the carbon source supplied. The genome analysis also revealed genes involved in industrially important metabolites such as zeaxanthin pigment, ectoine and polyhydroxyalkanoate (PHA) biosynthesis. To confirm the genome data, we extracted these metabolites from the cultures and successfully identified them. The pigment extracted from the cells showed the distinct UV–Vis spectra having characteristic absorption peak of zeaxanthin (λmax 448 nm) with potent antioxidant activities. The ability of H. malpeensis strain YU-PRIM-29T to produce important biomolecules makes it an industrially important bacterium.