bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns in Rhizosolenia- and Guinardia-associated Richelia abundances in the tropical marginal seas of the western North Pacific
Authors: Tuo Sing-How , Mulholland Margaret R , Chen Yuh-Ling Lee , Chappell P Dreux , Chen Houng-Yung
Published: March 2021

Richelia is a widespread, heterocystous, N2-fixing cyanobacterium that occurs in oligotrophic seas. It can be symbiotic within rhizosolenoid hosts, including Rhizosolenia (R-R) and Guinardia (G-R), and occasionally occurs as free-living (FL-R) filaments. We investigated the Richelia abundances in the South China (SCS) and Philippine Seas (PS) during the northeast (NEM) and southwest monsoon (SWM) seasons between 2001 and 2016. Field results showed that G-R was most abundant in the SCS during the SWM. Both R-R and FL-R were more abundant in the PS than the SCS and during the SWM versus the NEM. In general, R-R were more abundant than G-R, except at the SCS-SWM stations where abundances were comparable. Multivariate statistical models indicate that as R-R and G-R were abundant in warmer seawaters, nitrate plus nitrite was a key factor negatively controlling R-R abundance while silicate was more positively related to G-R. Positive correlation between G-R and FL-R abundances and microscopic observations imply that like Rhizosolenia-associated Richelia, filaments released from Guinardia hosts can remain viable outside their diatom hosts for time periods on the order of days. Overall, results reveal different distribution patterns between the two rhizosolenoid-Richelia symbioses and both G-R and R-R likely contribute to FL-R in the field.
A peroxisomal β-oxidative pathway contributes to the formation of C6–C1 aromatic volatiles in poplar
Authors: Lackus Nathalie D , Schmidt Axel , Gershenzon Jonathan , Köllner Tobias G
Published: March 2021

Benzenoids (C6–C1 aromatic compounds) play important roles in plant defense and are often produced upon herbivory. Black cottonwood (Populus trichocarpa) produces a variety of volatile and nonvolatile benzenoids involved in various defense responses. However, their biosynthesis in poplar is mainly unresolved. We showed feeding of the poplar leaf beetle (Chrysomela populi) on P. trichocarpa leaves led to increased emission of the benzenoid volatiles benzaldehyde, benzylalcohol, and benzyl benzoate. The accumulation of salicinoids, a group of nonvolatile phenolic defense glycosides composed in part of benzenoid units, was hardly affected by beetle herbivory. In planta labeling experiments revealed that volatile and nonvolatile poplar benzenoids are produced from cinnamic acid (C6–C3). The biosynthesis of C6–C1 aromatic compounds from cinnamic acid has been described in petunia (Petunia hybrida) flowers where the pathway includes a peroxisomal-localized chain shortening sequence, involving cinnamate-CoA ligase (CNL), cinnamoyl-CoA hydratase/dehydrogenase (CHD), and 3-ketoacyl-CoA thiolase (KAT). Sequence and phylogenetic analysis enabled the identification of small CNL, CHD, and KAT gene families in P. trichocarpa. Heterologous expression of the candidate genes in Escherichia coli and characterization of purified proteins in vitro revealed enzymatic activities similar to those described in petunia flowers. RNA interference-mediated knockdown of the CNL subfamily in gray poplar (Populus x canescens) resulted in decreased emission of C6–C1 aromatic volatiles upon herbivory, while constitutively accumulating salicinoids were not affected. This indicates the peroxisomal β-oxidative pathway participates in the formation of volatile benzenoids. The chain shortening steps for salicinoids, however, likely employ an alternative pathway.
Susceptibility factor RTP1 negatively regulates Phytophthora parasitica resistance via modulating UPR regulators bZIP60 and bZIP28
Authors: Qiang Xiaoyu , Liu Xingshao , Wang Xiaoxue , Zheng Qing , Kang Lijuan , Gao Xianxian , Wei Yushu , Wu Wenjie , Zhao Hong , Shan Weixing
Published: March 2021

The unfolded protein response (UPR) is a conserved stress adaptive signaling pathway in eukaryotic organisms activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR can be elicited in the course of plant defense, playing important roles in plant–microbe interactions. The major signaling pathways of plant UPR rely on the transcriptional activity of activated forms of ER membrane-associated stress sensors bZIP60 and bZIP28, which are transcription factors that modulate expression of UPR genes. In this study, we report the plant susceptibility factor Resistance to Phytophthora parasitica 1 (RTP1) is involved in ER stress sensing and rtp1-mediated resistance against P. parasitica is synergistically regulated with UPR, as demonstrated by the simultaneous strong induction of UPR and ER stress-associated immune genes in Arabidopsis thaliana rtp1 mutant plants during the infection by P. parasitica. We further demonstrate RTP1 contributes to stabilization of the ER membrane-associated bZIP60 and bZIP28 through manipulating the bifunctional protein kinase/ribonuclease IRE1-mediated bZIP60 splicing activity and interacting with bZIP28. Consequently, we find rtp1bzip60 and rtp1bzip28 mutant plants exhibit compromised resistance accompanied with attenuated induction of ER stress-responsive immune genes and reduction of callose deposition in response to P. parasitica infection. Taken together, we demonstrate RTP1 may exert negative modulating roles in the activation of key UPR regulators bZIP60 and bZIP28, which are required for rtp1-mediated plant resistance to P. parasitica. This facilitates our understanding of the important roles of stress adaptive UPR and ER stress in plant immunity.
Retention rate and effectiveness of secukinumab vs TNF inhibitor in ankylosing spondylitis patients with prior TNF inhibitor exposure
Authors: Min Hong Ki , Kim Hae-Rim , Lee Sang-Heon , Hong Yeon Sik , Kim Moon-Young , Park Sung-Hwan , Kang Kwi Young
Published: March 2021

Objectives

The choice of second-line biologics for AS patients previously treated with a TNF inhibitor (TNFi) remains unclear. Here, we compared drug retention and clinical efficacy between AS patients who switched biologics to secukinumab and those who switched to a different TNFi.

Methods

AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were included, and patients with non-radiographic axial spondyloarthritis were excluded. Patients with previous TNFi exposure were divided into the secukinumab group and the TNFi switching group. Drug retention and clinical efficacy [BASDAI50, Assessment of Spondylo-Arthritis International Society (ASAS)20, ASAS40, AS disease activity score (ASDAS) <2.1, ASDAS clinically important improvement and ASDAS major improvement] were assessed at the 1 year follow-up. Propensity score (PS)-matched and covariate-adjusted logistic regression analyses were performed.

Results

Two hundred and forty-six had available 1 year follow-up data. Secukinumab as third- or later-line biologic was more frequent than alternative TNFi (54% vs 14%). PS-matched and multiple covariate-adjusted analyses showed that the odds ratio (OR) for drug discontinuation was comparable between the secukinumab and TNFi switching groups [OR 1.136 (95% CI 0.843, 1.531) and 1.000 (95% CI 0.433–2.308), respectively]. The proportion of patients who achieved BASDAI50 was also comparable between the two groups [OR 0.833 (95% CI 0.481, 1.441) in PS-matched analysis]. Other clinical efficacy parameters were also comparable. In the subgroup analysis of AS patients with previous TNFi discontinuation due to ineffectiveness, all clinical efficacy parameters were comparable between the two groups.

Conclusion

In AS patients with previous exposure to a TNFi, switching biologics to secukinumab and switching to an alternative TNFi resulted in comparable drug retention and clinical efficacy.
Structural Covariance of Cortical Gyrification at Illness Onset in Treatment Resistance: A Longitudinal Study of First-Episode Psychoses
Authors: Ajnakina Olesya , Das Tushar , Lally John , Di Forti Marta , Pariante Carmine M , Marques Tiago Reis , Mondelli Valeria , David Anthony S , Murray Robin M , Palaniyappan Lena , Dazzan Paola
Published: March 2021

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject’s contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges’s g = 2.09, P < .001) and a reduced clustering coefficient (Hedges’s g = 1.07, P < .001) with increased length (Hedges’s g = −2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.
Revealing Secrets: Talismans, Healthcare and the Market of the Occult in Early Twentieth-century China
Authors: Bernardi Junqueira Luis Fernando
Published: March 2021

This article analyses the place and value of occult arts in the healthcare market of Republican China (1912–1949). Medical historiography has long neglected the resilience of such occult arts as talismans, astrology and divination in the context of China’s search for modernity. Focusing on the production, trade, and consumption of goods and services related to talismanic healing, I give voice to Chinese occultists by investigating the formation of a ‘market of the occult’ in the Republican era. I adopt a global perspective to clarify the changes that occult healing underwent following the popularisation of new printing technologies, mass media and transnational spiritualism in early twentieth-century China. Erstwhile embraced in secrecy, the occult was now being made public. Cheap manuals, wide-circulation newspapers and book catalogues reveal that in contrast to past studies that herald the disenchantment of the world as the hallmark of Chinese modernity, occult healing did not simply survive but thrived in the face of modern science and technology.
Continuities in State–Society Interactions across Broad Spatio-temporal Realms: Gong Tingxian as Both an Author of Popular Medical Texts and an Imperial Medical Secretary in Early Modern China
Authors: Aricanli Sare
Published: March 2021

Medical popularisation in late-sixteenth and early-seventeenth-century China has been understood within the context of the state’s retreat from medicine. This article points to ongoing state–societal continuities and thus suggests that the process was more complicated than it had been assumed to be. Analyses with more limited spatial or temporal frames tend to underestimate the extent of continuities forged by societal figures such as Gong Tingxian (fl. 1581–1616), an imperial medical doctor and author of popular medical texts. Gong’s self-fashioning illustrates state–society connections that are also apparent in the reception of his work and in his later legacy. These continuities crossed political, linguistic and cultural lines as Gong’s popular texts were translated to Manchu and housed in a state medical library of the ensuing dynasty. Moreover, Gong’s texts were not only transmitted in China, but reached Japan and Korea, and even found a place within a European collection by the early eighteenth century.
Metrics of sleep apnea severity: beyond the apnea-hypopnea index
Authors: Malhotra Atul , Ayappa Indu , Ayas Najib , Collop Nancy , Kirsch Douglas , Mcardle Nigel , Mehra Reena , Pack Allan I , Punjabi Naresh , White David P , Gottlieb Daniel J
Published: March 2021

Obstructive sleep apnea (OSA) is thought to affect almost 1 billion people worldwide. OSA has well established cardiovascular and neurocognitive sequelae, although the optimal metric to assess its severity and/or potential response to therapy remains unclear. The apnea-hypopnea index (AHI) is well established; thus, we review its history and predictive value in various different clinical contexts. Although the AHI is often criticized for its limitations, it remains the best studied metric of OSA severity, albeit imperfect. We further review the potential value of alternative metrics including hypoxic burden, arousal intensity, odds ratio product, and cardiopulmonary coupling. We conclude with possible future directions to capture clinically meaningful OSA endophenotypes including the use of genetics, blood biomarkers, machine/deep learning and wearable technologies. Further research in OSA should be directed towards providing diagnostic and prognostic information to make the OSA diagnosis more accessible and to improving prognostic information regarding OSA consequences, in order to guide patient care and to help in the design of future clinical trials.
Regional brain metabolism differs between narcolepsy type 1 and idiopathic hypersomnia
Authors: Trotti Lynn Marie , Saini Prabhjyot , Crosson Bruce , Meltzer Carolyn C , Rye David B , Nye Jonathon A
Published: March 2021

Study Objectives

Daytime sleepiness is a manifestation of multiple sleep and neurologic disorders. Few studies have assessed patterns of regional brain metabolism across different disorders of excessive daytime sleepiness. One such disorder, idiopathic hypersomnia (IH), is particularly understudied.

Methods

People with IH, narcolepsy (NT1), and non-sleepy controls underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) with electroencephalography (EEG). Participants were instructed to resist sleep and were awoken if sleep occurred. Voxel-wise parametric analysis identified clusters that significantly differed between each pair of groups, with a minimum cluster size of 100 voxels at a cluster detection threshold of p < 0.005. Correlations between glucose metabolism and sleep characteristics were evaluated.

Results

Participants (77% women) had IH (n = 16), NT1 (n = 14), or were non-sleepy controls (n = 9), whose average age was 33.8 (±10.7) years. Compared to controls, NT1 participants demonstrated hypermetabolism in fusiform gyrus, middle occipital gyrus, superior and middle temporal gyri, insula, cuneus, precuneus, pre- and post-central gyri, and culmen. Compared to controls, IH participants also demonstrated hypermetabolism in precuneus, inferior parietal lobule, superior and middle temporal gyri, and culmen. Additionally, IH participants demonstrated altered metabolism of the posterior cingulate. Most participants fell asleep. Minutes of N1 during uptake was significantly negatively correlated with metabolism of the middle temporal gyrus.

Conclusion

NT1 and IH demonstrate somewhat overlapping, but distinct, patterns of regional metabolism.
A New Method for Integrating Ecological Niche Modeling with Phylogenetics to Estimate Ancestral Distributions
Authors: Guillory Wilson X , Brown Jason L
Published: March 2021

Ancestral range estimation and projection of niche models into the past have both become common in evolutionary studies where the ancient distributions of organisms are in question. However, these methods are hampered by complementary hurdles: discrete characterization of areas in ancestral range estimation can be overly coarse, especially at shallow timescales, and niche model projection neglects evolution. Phylogenetic niche modeling accounts for both of these issues by incorporating knowledge of evolutionary relationships into a characterization of environmental tolerances. We present a new method for phylogenetic niche modeling, implemented in R. Given past and present climate data, taxon occurrence data, and a time-calibrated phylogeny, our method constructs niche models for each extant taxon, uses ancestral character estimation to reconstruct ancestral niche models, and projects these models into paleoclimate data to provide a historical estimate of the geographic range of a lineage. Models either at nodes or along branches of the phylogeny can be estimated. We demonstrate our method on a small group of dendrobatid frogs and show that it can make inferences given species with restricted ranges and little occurrence data. We also use simulations to show that our method can reliably reconstruct the niche of a known ancestor in both geographic and environmental space. Our method brings together fields as disparate as ecological niche modeling, phylogenetics, and ancestral range estimation in a user-friendly package. [Ancestral range estimation; ancestral state reconstruction; biogeography; Dendrobatidae; ecological niche modeling; paleoclimate; phylogeography; species distribution modeling.]
Comparative efficacy of commercially available deoxynivalenol detoxifying feed additives on growth performance, total tract digestibility of components, and physiological responses in nursery pigs fed diets formulated with naturally contaminated corn1
Authors: Mwaniki Alice W , Buis Quincy R , Trott David , Huber Lee-Anne , Yang Chengbo , Kiarie Elijah G
Published: March 2021

Comparative efficacy of deoxynivalenol (DON) detoxifying feed additives (FA) was evaluated in growth performance (exp. 1) and apparent total tract digestibility (ATTD; exp. 2) nursery pig studies. Six corn–soybean meal-based diets were used: 1) positive control (PC, formulated with <1.5 ppm DON corn), negative control (NC, formulated with 5.5 ppm DON corn), NC + FA1 (clay plus yeast cell wall extract), NC + FA2 (aluminosilicate), NC + FA3 (aluminosilicate plus fungal extract), and NC + FA4 (sodium metabisulfite, SMB). In exp. 1, 144 pigs (body weight [BW], 10.2 ± 0.1kg) were housed (4 pigs/pen), allocated to diets (n = 6) based on BW, and fed for 4-wk. The BW and feed intake were monitored weekly. On d 7, one pig/pen was bled for plasma and euthanized for organ weight and tissue samples. Assayed DON concentration in PC, NC, NC + FA4 was 0.29, 2.86, and 1.21 ppm, respectively. In wk-1, the average daily gain (ADG) of pigs fed NC + FA4 was not different (P > 0.05) to that of pigs fed PC diet but greater (P = 0.01) than for pigs fed NC without or with other FA. Pigs fed NC and NC + FA2 had lower (P = 0.026) average daily feed intake (ADFI) than pigs fed PC and NC + FA3. Pigs fed NC + FA4 had greater (P = 0.003) G:F than pigs fed the other diets. Diets had no effect (P > 0.05) on ADG, ADFI, and G: F after first week, plasma concentration of urea and creatinine or liver and spleen weight. Pigs fed NC diets had greater (P = 0.01) jejunal mRNA expression of superoxide dismutase 1 relative to pigs fed PC or NC plus FA. Jejunal histomorphology and mRNA expression of nutrient transporters, inflammatory cytokines, and tight junction proteins and ceca digesta concentration of short-chain fatty acids were not affected (P > 0.05) by the diet. In exp. 2, 24 barrows (BW 10.2 ± 0.3 kg) were individually placed in metabolism crates and allocated to four diets: PC, NC, NC + FA3, and NC + FA4 (n = 6) containing TiO2 as digestibility marker. Pigs were adjusted to diets for 5 d, followed by a 2-d grab fecal sample collection. Pigs fed PC and NC + FA4 diets had higher ATTD of dry matter, gross energy, and crude protein than NC fed pigs. The FA3 was intermediate in digestibility response. In conclusion, FA containing sequestering component plus fungal extract or SMB in DON-contaminated feed resulted in commensurate nursery pig performance to PC. The tested FA mitigated intestinal oxidative stress through decreased expression of genes for superoxide dismutase.
Associations of DNA Methylation Mortality Risk Markers with Congenital Microcephaly from Zika Virus: A Study of Brazilian Children Less than 4 Years of Age
Authors: Nwanaji-Enwerem Jamaji C , Laan Lars Van Der , Avakame Elorm F , Scott Kristan A , Burris Heather H , Cardenas Andres
Published: March 2021

Background

Zika virus (ZIKV)-associated congenital microcephaly is an important contributor to pediatric death, and more robust pediatric mortality risk metrics are needed to help guide life plans and clinical decision making for these patients. Although common etiologies of pediatric and adult mortality differ, early life health can impact adult outcomes—potentially through DNA methylation. Hence, in this pilot study, we take an early step in identifying pediatric mortality risk metrics by examining associations of ZIKV infection and associated congenital microcephaly with existing adult DNA methylation-based mortality biomarkers: GrimAge and Zhang’s mortality score (ZMS).

Methods

Mortality measures were calculated from previously published HumanMethylationEPIC BeadChip data from 44 Brazilian children aged 5–40 months (18 with ZIKV-associated microcephaly; 7 normocephalic, exposed to ZIKV in utero; and 19 unexposed controls). We used linear models adjusted for chronological age, sex, methylation batch and white blood cell proportions to evaluate ZIKV and mortality marker relationships.

Results

We observed significant decreases in GrimAge-component plasminogen activator inhibitor-1 [PAI-1; β = −2453.06 pg/ml, 95% confidence interval (CI) −3652.96, −1253.16, p = 0.0002], and ZMS-site cg14975410 methylation (β = −0.06, 95% CI −0.09, −0.03, p = 0.0003) among children with microcephaly compared to controls. PAI-1 (β = −2448.70 pg/ml, 95% CI −4384.45, −512.95, p = 0.01) and cg14975410 (β = 0.01, 95% CI −0.04, 0.06, p = 0.64) results in comparisons of normocephalic, ZIKV-exposed children to controls were not statistically significant.

Conclusion

Our results suggest that elements of previously-identified adult epigenetic markers of mortality risk are associated with ZIKV-associated microcephaly, a known contributor to pediatric mortality risk. These findings may provide insights for efforts aimed at developing pediatric mortality markers.
Postpartum Recovery From Meningioma-Related Oculomotor Palsy
Authors: Dawoud Salma A. , Silverman Joanna I. M. , Chung Sophia M.
Published: March 2021

BACKGROUND:

We summarize a case of transient oculomotor nerve palsy in a pregnant woman with a cavernous sinus meningioma. When pregnant women present with acute ophthalmic signs and symptoms, meningioma should be considered during diagnostic workup given the common proximity of growing meningiomas to visual pathways and ocular motor nerves within the parasellar region.

CASE:

A 32-year-old woman, gravida 2 para 1, at 37 weeks of gestation, presented with 2 weeks of diplopia, left-sided ptosis, and left periocular headache. There were no signs of preeclampsia. Examination revealed a left mydriatic pupil, complete left-sided ptosis, and motility deficits consistent with a left pupil–involving oculomotor nerve palsy. Magnetic resonance imaging of the brain revealed a cavernous sinus meningioma. Five days after cesarean birth, the ptosis significantly improved; 2 weeks later, the diplopia resolved.

CONCLUSION:

Pregnancy is associated with increased likelihood of intracranial meningioma growth, particularly in the parasellar region. We highlight a rare case of a transient cranial nerve III palsy in a pregnant patient due to cavernous sinus meningioma and review prior published reports.
The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020)
Authors: Wu Wenming , Chen Jie , Bai Chunmei , Chi Yihebali , Du Yiqi , Feng Shiting , Huo Li , Jiang Yuxin , Li Jingnan , Lou Wenhui , Luo Jie , Shao Chenghao , Shen Lin , Wang Feng , Wang Liwei , Wang Ou , Wang Yu , Wu Huanwen , Xing Xiaoping , Xu Jianming , Xue Huadan , Xue Ling , Yang Yang , Yu Xianjun , Yuan Chunhui , Zhao Hong , Zhu Xiongzeng , Zhao Yupei
Published: March 2021

Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Chinese Pancreatic Surgery Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.
Angiotensin receptors and neuropathic pain
Authors: Balogh Mihály , Aguilar Clarissa , Nguyen Nicholas T. , Shepherd Andrew J.
Published: March 2021

Growing evidence implicates the renin–angiotensin system (RAS) in multiple facets of neuropathic pain (NP). This narrative review focuses primarily on the major bioactive RAS peptide, Angiotensin II (Ang II), and its receptors, namely type 1 (AT1R) and type 2 (AT2R). Both receptors are involved in the development of NP and represent potential therapeutic targets. We first discuss the potential role of Ang II receptors in modulation of NP in the central nervous system. Ang II receptor expression is widespread in circuits associated with the perception and modulation of pain, but more studies are required to fully characterize receptor distribution, downstream signaling, and therapeutic potential of targeting the central nervous system RAS in NP. We then describe the peripheral neuronal and nonneuronal distribution of the RAS, and its contribution to NP. Other RAS modulators (such as Ang (1-7)) are briefly reviewed as well. AT1R antagonists are analgesic across different pain models, including NP. Several studies show neuronal protection and outgrowth downstream of AT2R activation, which may lead to the use of AT2R agonists in NP. However, blockade of AT2R results in analgesia. Furthermore, expression of the RAS in the immune system and a growing appreciation of neuroimmune crosstalk in NP add another layer of complexity and therapeutic potential of targeting this pathway. A growing number of human studies also hint at the analgesic potential of targeting Ang II signaling. Altogether, Ang II receptor signaling represents a promising, far-reaching, and novel strategy to treat NP.
Changes in blood–spinal cord barrier permeability and neuroimmune interactions in the underlying mechanisms of chronic pain
Authors: Montague-Cardoso Karli , Malcangio Marzia
Published: March 2021

Advancing our understanding of the underlying mechanisms of chronic pain is instrumental to the identification of new potential therapeutic targets. Neuroimmune communication throughout the pain pathway is of crucial mechanistic importance and has been a major focus of preclinical chronic pain research over the last 2 decades. In the spinal cord, not only do dorsal horn neurons partake in mechanistically important bidirectional communication with resident immune cells such as microglia, but in some cases, they can also partake in bidirectional crosstalk with immune cells, such as monocytes/macrophages, which have infiltrated into the spinal cord from the circulation. The infiltration of immune cells into the spinal cord can be partly regulated by changes in permeability of the blood–spinal cord barrier (BSCB). Here, we discuss evidence for and against a mechanistic role for BSCB disruption and associated changes in neuroimmune crosstalk in preclinical chronic pain. We also consider recent evidence for its potential involvement in the vincristine model of chemotherapy-induced painful neuropathy. We conclude that current knowledge warrants further investigation to establish whether preventing BSCB disruption, or targeting the changes associated with this disruption, could be used for the development of novel approaches to treating chronic pain.
Contribution of colony-stimulating factor 1 to neuropathic pain
Authors: Yu Xiaobing , Basbaum Allan , Guan Zhonghui
Published: March 2021

Molecular and cellular interactions among spinal dorsal horn neurons and microglia, the resident macrophages of the central nervous system, contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. Emerging evidence also demonstrates that reciprocal interactions between macrophages and nociceptive sensory neurons in the dorsal root ganglion contribute to the initiation and persistence of nerve injury-induced mechanical hypersensitivity (allodynia). We previously reported that sensory neuron-derived colony-stimulating factor 1 (CSF1), by engaging the CSF1 receptor (CSF1R) that is expressed by both microglia and macrophages, triggers the nerve injury-induced expansion of both resident microglia in the spinal cord and macrophages in the dorsal root ganglion and induces their respective contributions to the neuropathic pain phenotype. Here, we review recent research and discuss unanswered questions regarding CSF1/CSF1R-mediated microglial and macrophage signaling in the generation of neuropathic pain.
Neuroimmune interactions and osteoarthritis pain: focus on macrophages
Authors: Geraghty Terese , Winter Deborah R. , Miller Richard J. , Miller Rachel E. , Malfait Anne-Marie
Published: March 2021

Bidirectional interactions between the immune system and the nervous system are increasingly appreciated as playing a pathogenic role in chronic pain. Unraveling the mechanisms by which inflammatory pain is mediated through communication between nerves and immune cells may lead to exciting new strategies for therapeutic intervention. In this narrative review, we focus on the role of macrophages in the pathogenesis of osteoarthritis (OA) pain. From regulating homeostasis to conducting phagocytosis, and from inducing inflammation to resolving it, macrophages are plastic cells that are highly adaptable to their environment. They rely on communicating with the environment through cytokines, growth factors, neuropeptides, and other signals to respond to inflammation or injury. The contribution of macrophages to OA joint damage has garnered much attention in recent years. Here, we discuss how macrophages may participate in the initiation and maintenance of pain in OA. We aim to summarize what is currently known about macrophages in OA pain and identify important gaps in the field to fuel future investigations.
Spike vs nucleocapsid SARS-CoV-2 antigen detection: application in nasopharyngeal swab specimens
Authors: Barlev-Gross Moria , Weiss Shay , Ben-Shmuel Amir , Sittner Assa , Eden Keren , Mazuz Noam , Glinert Itai , Bar-David Elad , Puni Reut , Amit Sharon , Kriger Or , Schuster Ofir , Alcalay Ron , Makdasi Efi , Epstein Eyal , Noy-Porat Tal , Rosenfeld Ronit , Achdout Hagit , Mazor Ohad , Israely Tomer , Levy Haim , Mechaly Adva
Published: March 2021

Public health experts emphasize the need for quick, point-of-care SARS-CoV-2 detection as an effective strategy for controlling virus spread. To this end, many “antigen” detection devices were developed and commercialized. These devices are mostly based on detecting SARS-CoV-2’s nucleocapsid protein. Recently, alerts issued by both the FDA and the CDC raised concerns regarding the devices’ tendency to exhibit false positive results. In this work we developed a novel alternative spike-based antigen assay, comprised of four high-affinity, specific monoclonal antibodies, directed against different epitopes on the spike’s S1 subunit. The assay’s performance was evaluated for COVID-19 detection from nasopharyngeal swabs, compared to an in-house nucleocapsid-based assay, composed of antibodies directed against the nucleocapsid. Detection of COVID-19 was carried out in a cohort of 284 qRT-PCR positive and negative nasopharyngeal swab samples. The time resolved fluorescence (TRF) ELISA spike-assay displayed very high specificity (99%) accompanied with a somewhat lower sensitivity (66% for Ct<25), compared to the nucleocapsid ELISA assay which was more sensitive (85% for Ct<25) while less specific (87% specificity). Despite being out-performed by qRT-PCR, we suggest that there is room for such tests in the clinical setting, as cheap and rapid pre-screening tools. Our results further suggest that when applying antigen detection, one must consider its intended application (sensitivity vs specificity), taking into consideration that the nucleocapsid might not be the optimal target. In this regard, we propose that a combination of both antigens might contribute to the validity of the results.

Abstract Figure

Graphic abstract

Schematic representation of sample collection and analysis. The figure was created using BioRender.com
Efficacy of high-pressure balloon for the treatment of arteriovenous fistula stenosis: a meta-analysis
Authors: Li Yu , Cui Wenhao , Wang Jukun , Zhang Chao , Luo Tao
Published: March 2021

Objective

The objective of the present study was to compare the effectiveness of high-pressure balloon (HPB) versus conventional balloon angioplasty (BA) in treating arteriovenous fistula (AVF) stenosis.

Materials and Methods

A meta-analysis was conducted using data acquired from PubMed, EMBASE, the Cochrane Library, SinoMed, CNKI, WanFang and VIP databases from the time the databases were established to November 2020. All analyses included in the studies comprised the subgroups of HPB and BA. The patency of AVF was compared between the two groups at 3 months, 6 months and 12 months after operation.

Results

Nine studies comprising 475 patients were included in the meta-analysis. The pooled results revealed that stenosis rate of AVFs treated with HPB was significantly lower than that of AVFs treated with conventional balloon at 3 months (OR= 0.37, 95% CI 0.21 to 0.67, p<0.001) and 6 months after operation (OR= 0.33, 95% CI 0.15 to 0.75, p=0.008). In addition, the technical success rate of HPB groups was high (OR= 0.14, 95% CI 0.05 to 0.35, p<0.001). However, no significant difference was observed between the experimental and control groups at 12 months after operation (OR= 0.61, 95% CI 0.29 to 1.25, p=0.18). No significant publication bias was observed in the analyses.

Conclusion

HPB is a potential primary option for the treatment of AVF stenosis, with a lower 3- and 6-month stenosis rate than BA. However, the long-term effect of HPB was not satisfactory; therefore, further research should be conducted to elucidate the relationship between the two groups.
Structural connectome quantifies tumor invasion and predicts survival in glioblastoma patients
Authors: Wei Yiran , Li Chao , Cui Zaixu , Mayrand Roxanne C. , Zou Jingjing , Wong Adrianna L.K.C. , Sinha Rohitashwa , Matys Tomasz , Schönlieb Carola-Bibiane , Price Stephen John
Published: March 2021

Glioblastoma widely affects brain structure and function, and remodels neural connectivity. Characterizing the neural connectivity in glioblastoma may provide a tool to understand tumor invasion. Here, using a structural connectome approach based on diffusion MRI, we quantify the global and regional connectome disruptions in individual glioblastoma patients and investigate the prognostic value of connectome disruptions and topological properties. We show that the disruptions in the normal-appearing brain beyond the lesion could mediate the topological alteration of the connectome (P<0.001), associated with worse patient performance (P<0.001), cognitive function (P<0.001), and survival (overall survival: HR: 1.46,P= 0.049; progression-free survival: HR: 1.49,P= 0.019). Further, the preserved connectome in the normal-appearing brain demonstrates evidence of remodeling, where increased connectivity is associated with better overall survival (log-rankP= 0.005). Our approach reveals the glioblastoma invasion invisible on conventional MRI, promising to benefit patient stratification and precise treatment.
Ecophysiology of the cosmopolitan OM252 bacterioplankton (Gammaproteobacteria)
Authors: Savoie Emily R. , Lanclos V. Celeste , Henson Michael W. , Cheng Chuankai , Getz Eric W. , Barnes Shelby J. , LaRowe Douglas E. , Rappé Michael S. , Thrash J. Cameron
Published: March 2021

Among the thousands of species that comprise marine bacterioplankton communities, most remain functionally obscure. One key cosmopolitan group in this understudied majority is the OM252 clade of Gammaproteobacteria. Although frequently found in sequence data and even previously cultured, the diversity, metabolic potential, physiology, and distribution of this clade has not been thoroughly investigated. Here we examined these features of OM252 bacterioplankton using a newly isolated strain and genomes from publicly available databases. We demonstrated that this group constitutes a globally distributed novel genus (CandidatusHalomarinus), sister toLitoricola, comprising two subclades and multiple distinct species. OM252 organisms have small genomes (median 2.21 Mbp) and are predicted obligate aerobes capable of alternating between chemoorganoheterotrophic and chemolithotrophic growth using reduced sulfur compounds as electron donors, with subclade I genomes encoding the Calvin-Benson-Bassham cycle for carbon fixation. One representative strain of subclade I, LSUCC0096, had extensive halotolerance but a mesophilic temperature range for growth, with a maximum of 0.36 doublings/hr at 35°C. Cells were curved rod/spirillum-shaped, ~1.5 × 0.2 μm. Growth on thiosulfate as the sole electron donor under autotrophic conditions was roughly one third that of heterotrophic growth, even though calculations indicated similar Gibbs energies for both catabolisms. These phenotypic data show that someCa.Halomarinus organisms can switch between serving as carbon sources or sinks and indicate the likely anabolic cost of lithoautotrophic growth. Our results thus provide new hypotheses about the roles of these organisms in global biogeochemical cycling of carbon and sulfur.

Importance

Marine microbial communities are teeming with understudied taxa due to the sheer numbers of species in any given sample of seawater. One group, the OM252 clade of Gammaproteobacteria, has been identified in gene surveys from myriad locations, and one isolated organism has even been genome sequenced (HIMB30). However, further study of these organisms has not occurred. Using another isolated representative (strain LSUCC0096) and publicly available genome sequences from metagenomic and single-cell genomic datasets, we examined the diversity within the OM252 clade, the distribution of these taxa in the world’s oceans, reconstructed the predicted metabolism of the group, and quantified growth dynamics in LSUCC0096. Our results generate new knowledge about the previously enigmatic OM252 clade and point towards the importance of facultative chemolithoautotrophy for supporting some clades of ostensibly “heterotrophic” taxa.
Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response
Authors: Nguyen Long Chi , Yang Dongbo , Nicolaescu Vlad , Best Thomas J. , Ohtsuki Takashi , Chen Shao-Nong , Friesen J. Brent , Drayman Nir , Mohamed Adil , Dann Christopher , Silva Diane , Gula Haley , Jones Krysten A. , Millis J. Michael , Dickinson Bryan C. , Tay Savaş , Oakes Scott A. , Pauli Guido F. , Meltzer David O. , Randall Glenn , Rosner Marsha Rich
Published: March 2021

The rapid spread of COVID-19 underscores the need for new treatments. Here we report that cannabidiol (CBD), a compound produced by the cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after cellular infection, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD induces interferon expression and up-regulates its antiviral signaling pathway. A cohort of human patients previously taking CBD had significantly lower SARS-CoV-2 infection incidence of up to an order of magnitude relative to matched pairs or the general population. This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection.
Myogenetic oligodeoxynucleotide (myoDN) recovers the differentiation of skeletal muscle myoblasts deteriorated by diabetes mellitus
Authors: Nakamura Shunichi , Yonekura Shinichi , Shimosato Takeshi , Takaya Tomohide
Published: March 2021

Sarcopenic obesity is a complication of decreased muscle mass and strength associated with obesity, and sarcopenia associated with diabetes mellitus (DM) is a serious risk factor that may result in mortality. Deteriorated differentiation of muscle precursor cells, called myoblasts, in DM patients is considered to be one of the causes of muscle atrophy. We recently developed myogenetic oligodeoxynucleotides (myoDNs), which are 18-base single-strand DNAs that promote myoblast differentiation by targeting nucleolin. Herein, we report the applicability of a myoDN, iSN04, to myoblasts isolated from patients with type 1 and type 2 DM. Myogenesis of DM myoblasts was exacerbated concordantly with a delayed shift of myogenic transcription and induction of interleukins. Analogous phenotypes were reproduced in healthy myoblasts cultured with excessive glucose or palmitic acid, mimicking hyperglycemia or hyperlipidemia. iSN04 treatment recovered the deteriorated differentiation of plural DM myoblasts by downregulating myostatin and interleukin-8. iSN04 also ameliorated the impaired myogenic differentiation induced by glucose or palmitic acid. These results demonstrate that myoDNs can directly facilitate myoblast differentiation in DM patients, making them novel candidates for nucleic acid drugs to treat sarcopenic obesity.
Efficient Genomic Control for Mixed Model Associations in Large-scale Population
Authors: Hao Zhiyu , Gao Jin , Song Yuxin , Yang Runqing , Liu Di
Published: March 2021

Among linear mixed model-based association methods, GRAMMAR has the lowest computing complexity for association tests, but it produces a high false-negative rate due to the deflation of test statistics for complex population structure. Here, we present an optimized GRAMMAR method by efficient genomic control, Optim-GRAMMAR, that estimates the phenotype residuals by regulating downward genomic heritability in the genomic best linear unbiased prediction. Even though using the fewer sampling markers to evaluate genomic relationship matrices and genomic controls, Optim-GRAMMAR retains a similar statistical power to the exact mixed model association analysis, which infers an extremely efficient approach to handle large-scale data. Moreover, joint association analysis significantly improved statistical power over existing methods.
DeepSea: An efficient deep learning model for single-cell segmentation and tracking of time-lapse microscopy images
Authors: Zargari Abolfazl , Lodewijk Gerrald A. , Mashhadi Najmeh , Cook Nathan , Neudorf Celine W. , Araghbidikashani Kimiasadat , Rubio Stefany , Hrabeta-Robinson Eva , Brooks Angela N. , Hinck Lindsay , Shariati S. Ali
Published: March 2021

Dynamics and non-genetic heterogeneity are two fundamental characteristics of basic processes of life such as cell division or differentiation. Time-lapse microscopy is the only method that can directly capture the dynamics and heterogeneity of fundamental cellular processes at the singlecell level with high temporal resolution. Successful application of single-cell time-lapse microscopy requires automated segmentation and tracking of hundreds of individual cells over several time points. Recently, deep learning models have ushered in a new era in the quantitative analysis of microscopy images. However, integrated segmentation and tracking of single cells remain challenges for the analysis of time-lapse microscopy images. This work presents a versatile and trainable deep-learning software, termed DeepSea, that allows for both segmentation and tracking of single cells in sequences of phase-contrast live microscopy images. Our segmentation model can easily be trained to segment phase-contrast images of different cell types with higher precision than existing models. Our tracking model allows for quantification of dynamics of several cell biological features of individual cells, such as cell division cycle, mitosis, cell morphology, and cell size, with high precision using phase-contrast images. We showcase the application of DeepSea by analyzing cell size regulation in embryonic stem cells. Our findings show that embryonic stem cells exhibit cell size control in the G1 phase of the cell cycle despite their unusual fast division cycle. Our training dataset, user-friendly software, and code are available herehttps://deepseas.org.
SNHG16 promotes cell proliferation and inhibits cell apoptosis via regulation of the miR-1303p/STARD9 axis in renal cell carcinoma
Authors: Cheng Tao , Shuang Weibing , Ye Dawen , Zhang Wenzhi , Yang Zhao , Fang Wenge , Xu Haibin , Gu Mingli , Xu Weiqiang , Guan Chao
Published: March 2021

Background

Renal cell carcinoma (RCC) is a fatal malignant tumor with high morbidity. Numerous medical studies have suggested that long noncoding RNAs (lncRNAs) exert their biological function on various cancerous progresses. Herein, functions of lncRNA SNHG16 in RCC cells and the mechanism medicated by SNHG16 were investigated.

Methods

The expression levels of SNHG16 and its downstream genes in RCC cells and tissues were examined utilizing reverse transcription quantitative polymerase chain reaction analyses. Cell counting kit-8 and 5-Ethynyl-2’-deoxyuridine assays were carried out to evaluate the proliferation of RCC cells, and flow cytometry analyses were employed to determine the apoptosis of RCC cells. Western blot analysis was applied to examine protein levels associated with cell proliferation and apoptosis. The combination between SNHG16 and miRNA as well as miRNA and its target gene were explored by luciferase reporter, RNA pull down, and RNA immunoprecipitation assays.

Results

The significant upregulation of SNHG16 was observed in RCC tissues and cells. SNHG16 downregulation inhibited the proliferation and promoted the apoptosis of RCC cells. In addition, SNHG16 served as a competing endogenous RNA for miR-1301-3p, and STARD9 was a target gene of miR-1301-3p in RCC cells. SNHG16 upregulated STARD9 expression by binding with miR-1301-3p in RCC cells. Rescue assays validated that SNHG16 promoted RCC cell promotion and induced RCC cell apoptosis by upregulating STARD9 expression.

Conclusions

SNHG16 promotes RCC cell proliferation and suppresses RCC cell apoptosis via interaction with miR-1301-3p to upregulate STARD9 expression in RCC cells.