bluuebunny/crossref_metadata_2025 huggingface dataset:
The M-CSF receptor in osteoclasts and beyond
Authors: Mun Se Hwan , Park Peter Sang Uk , Park-Min Kyung-Hyun
Published: August 2020

Colony-stimulating factor 1 receptor (CSF1R, also known as c-FMS) is a receptor tyrosine kinase. Macrophage colony-stimulating factor (M-CSF) and IL-34 are ligands of CSF1R. CSF1R-mediated signaling is crucial for the survival, function, proliferation, and differentiation of myeloid lineage cells, including osteoclasts, monocytes/macrophages, microglia, Langerhans cells in the skin, and Paneth cells in the intestine. CSF1R also plays an important role in oocytes and trophoblastic cells in the female reproductive tract and in the maintenance and maturation of neural progenitor cells. Given that CSF1R is expressed in a wide range of myeloid cells, altered CSF1R signaling is implicated in inflammatory, neoplastic, and neurodegenerative diseases. Inhibiting CSF1R signaling through an inhibitory anti-CSF1R antibody or small molecule inhibitors that target the kinase activity of CSF1R has thus been a promising therapeutic strategy for those diseases. In this review, we cover the recent progress in our understanding of the various roles of CSF1R in osteoclasts and other myeloid cells, highlighting the therapeutic applications of CSF1R inhibitors in disease conditions.
Machine-learning classification using neuroimaging data in schizophrenia, autism, ultra-high risk and first-episode psychosis
Authors: Yassin Walid , Nakatani Hironori , Zhu Yinghan , Kojima Masaki , Owada Keiho , Kuwabara Hitoshi , Gonoi Wataru , Aoki Yuta , Takao Hidemasa , Natsubori Tatsunobu , Iwashiro Norichika , Kasai Kiyoto , Kano Yukiko , Abe Osamu , Yamasue Hidenori , Koike Shinsuke
Published: August 2020

Neuropsychiatric disorders are diagnosed based on behavioral criteria, which makes the diagnosis challenging. Objective biomarkers such as neuroimaging are needed, and when coupled with machine learning, can assist the diagnostic decision and increase its reliability. Sixty-four schizophrenia, 36 autism spectrum disorder (ASD), and 106 typically developing individuals were analyzed. FreeSurfer was used to obtain the data from the participant’s brain scans. Six classifiers were utilized to classify the subjects. Subsequently, 26 ultra-high risk for psychosis (UHR) and 17 first-episode psychosis (FEP) subjects were run through the trained classifiers. Lastly, the classifiers’ output of the patient groups was correlated with their clinical severity. All six classifiers performed relatively well to distinguish the subject groups, especially support vector machine (SVM) and Logistic regression (LR). Cortical thickness and subcortical volume feature groups were most useful for the classification. LR and SVM were highly consistent with clinical indices of ASD. When UHR and FEP groups were run with the trained classifiers, majority of the cases were classified as schizophrenia, none as ASD. Overall, SVM and LR were the best performing classifiers. Cortical thickness and subcortical volume were most useful for the classification, compared to surface area. LR, SVM, and DT’s output were clinically informative. The trained classifiers were able to help predict the diagnostic category of both UHR and FEP Individuals.
The association of PTSD symptom severity with amygdala nuclei volumes in traumatized youths
Authors: Ousdal Olga Therese , Milde Anne Marita , Hafstad Gertrud Sofie , Hodneland Erlend , Dyb Grete , Craven Alexander R. , Melinder Annika , Endestad Tor , Hugdahl Kenneth
Published: August 2020

The amygdala is a core component in neurobiological models of stress and stress-related pathologies, including post-traumatic stress disorder (PTSD). While numerous studies have reported increased amygdala activity following traumatic stress exposure and in PTSD, the findings regarding amygdala volume have been mixed. One reason for these mixed findings may be that the amygdala has been considered as a homogenous entity, while it in fact consists of several nuclei with unique cellular and connectivity profiles. Here, we investigated amygdala nuclei volumes of the basolateral and the centrocorticomedial complex in relation to PTSD symptom severity in 47 young survivors from the 2011 Norwegian terror attack 24–36 months post-trauma. PTSD symptoms were assessed 4–5, 14–15 and 24–36 months following the trauma. We found that increased PTSD symptom severity 24–36 months post-trauma was associated with volumetric reductions of all basolateral as well as the central and the medial nuclei. However, only the lateral nucleus was associated with longitudinal symptom development, and mediated the association between 4–5 months and 24–36 months post-trauma symptoms. The results suggest that the amygdala nuclei may be differentially associated with cross-sectional and longitudinal measures of PTSD symptom severity. As such, investigations of amygdala total volume may not provide an adequate index of the association between amygdala and stress-related mental illness.
Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats
Authors: Berg Elizabeth L. , Pedersen Lauren R. , Pride Michael C. , Petkova Stela P. , Patten Kelley T. , Valenzuela Anthony E. , Wallis Christopher , Bein Keith J. , Wexler Anthony , Lein Pamela J. , Silverman Jill L.
Published: August 2020

Epidemiological studies consistently implicate traffic-related air pollution (TRAP) and/or proximity to heavily trafficked roads as risk factors for developmental delays and neurodevelopmental disorders (NDDs); however, there are limited preclinical data demonstrating a causal relationship. To test the effects of TRAP, pregnant rat dams were transported to a vivarium adjacent to a major freeway tunnel system in northern California where they were exposed to TRAP drawn directly from the face of the tunnel or filtered air (FA). Offspring remained housed under the exposure condition into which they were born and were tested in a variety of behavioral assays between postnatal day 4 and 50. To assess the effects of near roadway exposure, offspring of dams housed in a standard research vivarium were tested at the laboratory. An additional group of dams was transported halfway to the facility and then back to the laboratory to control for the effect of potential transport stress. Near roadway exposure delayed growth and development of psychomotor reflexes and elicited abnormal activity in open field locomotion. Near roadway exposure also reduced isolation-induced 40-kHz pup ultrasonic vocalizations, with the TRAP group having the lowest number of call emissions. TRAP affected some components of social communication, evidenced by reduced neonatal pup ultrasonic calling and altered juvenile reciprocal social interactions. These findings confirm that living in close proximity to highly trafficked roadways during early life alters neurodevelopment.
A bioenergetic shift is required for spermatogonial differentiation
Authors: Chen Wei , Zhang Zhaoran , Chang Chingwen , Yang Zhichang , Wang Pengxiang , Fu Haihui , Wei Xiao , Chen Eric , Tan Suxu , Huang Wen , Sun Liangliang , Ni Ting , Yang Yi , Wang Yuan
Published: August 2020

A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference for bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid (RA)-induced differentiation. To accommodate this elevated energy demand, RA signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. Disrupting mitochondrial respiration significantly blocked spermatogonial differentiation. Inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway also repressed the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon RA-induced differentiation, with both RNA-seq and quantitative proteomic analyses. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration that is required for spermatogonial proliferation and differentiation.
T-cells produce acidic niches in lymph nodes to suppress their own effector functions
Authors: Wu Hao , Estrella Veronica , Beatty Matthew , Abrahams Dominique , El-Kenawi Asmaa , Russell Shonagh , Ibrahim-Hashim Arig , Longo Dario Livio , Reshetnyak Yana K. , Moshnikova Anna , Andreev Oleg A. , Luddy Kimberly , Damaghi Mehdi , Kodumudi Krithika , Pillai Smitha R. , Enriquez-Navas Pedro , Pilon-Thomas Shari , Swietach Pawel , Gillies Robert J.
Published: August 2020

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.
OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation
Authors: Sharanek Ahmad , Burban Audrey , Laaper Matthew , Heckel Emilie , Joyal Jean-Sebastien , Soleimani Vahab D. , Jahani-Asl Arezu
Published: August 2020

Glioblastoma contains a rare population of self-renewing brain tumor stem cells (BTSCs) which are endowed with properties to proliferate, spur the growth of new tumors, and at the same time, evade ionizing radiation (IR) and chemotherapy. However, the drivers of BTSC resistance to therapy remain unknown. The cytokine receptor for oncostatin M (OSMR) regulates BTSC proliferation and glioblastoma tumorigenesis. Here, we report our discovery of a mitochondrial OSMR that confers resistance to IR via regulation of oxidative phosphorylation, independent of its role in cell proliferation. Mechanistically, OSMR is targeted to the mitochondrial matrix via the presequence translocase-associated motor complex components, mtHSP70 and TIM44. OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I and promotes mitochondrial respiration. Deletion of OSMR impairs spare respiratory capacity, increases reactive oxygen species, and sensitizes BTSCs to IR-induced cell death. Importantly, suppression of OSMR improves glioblastoma response to IR and prolongs lifespan.
Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13
Authors: Pitrez Patricia R. , Estronca Luís , Monteiro Luís Miguel , Colell Guillem , Vazão Helena , Santinha Deolinda , Harhouri Karim , Thornton Daniel , Navarro Claire , Egesipe Anne-Laure , Carvalho Tânia , Dos Santos Rodrigo L. , Lévy Nicolas , Smith James C. , de Magalhães João Pedro , Ori Alessandro , Bernardo Andreia , De Sandre-Giovannoli Annachiara , Nissan Xavier , Rosell Anna , Ferreira Lino
Published: August 2020

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaG609G/G609GMmp13−/− mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.
Lithium niobate photonic-crystal electro-optic modulator
Authors: Li Mingxiao , Ling Jingwei , He Yang , Javid Usman A. , Xue Shixin , Lin Qiang
Published: August 2020

Modern advanced photonic integrated circuits require dense integration of high-speed electro-optic functional elements on a compact chip that consumes only moderate power. Energy efficiency, operation speed, and device dimension are thus crucial metrics underlying almost all current developments of photonic signal processing units. Recently, thin-film lithium niobate (LN) emerges as a promising platform for photonic integrated circuits. Here, we make an important step towards miniaturizing functional components on this platform, reporting high-speed LN electro-optic modulators, based upon photonic crystal nanobeam resonators. The devices exhibit a significant tuning efficiency up to 1.98 GHz V−1, a broad modulation bandwidth of 17.5 GHz, while with a tiny electro-optic modal volume of only 0.58μm3. The modulators enable efficient electro-optic driving of high-Q photonic cavity modes in both adiabatic and non-adiabatic regimes, and allow us to achieve electro-optic switching at 11 Gb s−1with a bit-switching energy as low as 22 fJ. The demonstration of energy efficient and high-speed electro-optic modulation at the wavelength scale paves a crucial foundation for realizing large-scale LN photonic integrated circuits that are of immense importance for broad applications in data communication, microwave photonics, and quantum photonics.
CTCF-mediated chromatin looping in EGR2 regulation and SUZ12 recruitment critical for peripheral myelination and repair
Authors: Wang Jincheng , Wang Jiajia , Yang Lijun , Zhao Chuntao , Wu Laiman Natalie , Xu Lingli , Zhang Feng , Weng Qinjie , Wegner Michael , Lu Q. Richard
Published: August 2020

Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.
Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints
Authors: Kong Yi Wen , Dreaden Erik C. , Morandell Sandra , Zhou Wen , Dhara Sanjeev S. , Sriram Ganapathy , Lam Fred C. , Patterson Jesse C. , Quadir Mohiuddin , Dinh Anh , Shopsowitz Kevin E. , Varmeh Shohreh , Yilmaz Ömer H. , Lippard Stephen J. , Reinhardt H. Christian , Hemann Michael T. , Hammond Paula T. , Yaffe Michael B.
Published: August 2020

In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment.
Adaptation to the cervical environment is associated with increased antibiotic susceptibility in Neisseria gonorrhoeae
Authors: Ma Kevin C. , Mortimer Tatum D. , Hicks Allison L. , Wheeler Nicole E. , Sánchez-Busó Leonor , Golparian Daniel , Taiaroa George , Rubin Daniel H. F. , Wang Yi , Williamson Deborah A. , Unemo Magnus , Harris Simon R. , Grad Yonatan H.
Published: August 2020

Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.
Measuring the Hubble constant with a sample of kilonovae
Authors: Coughlin Michael W. , Antier Sarah , Dietrich Tim , Foley Ryan J. , Heinzel Jack , Bulla Mattia , Christensen Nelson , Coulter David A. , Issa Lina , Khetan Nandita
Published: August 2020

Kilonovae produced by the coalescence of compact binaries with at least one neutron star are promising standard sirens for an independent measurement of the Hubble constant (H0). Through their detection via follow-up of gravitational-wave (GW), short gamma-ray bursts (sGRBs) or optical surveys, a large sample of kilonovae (even without GW data) can be used for H0 contraints. Here, we show measurement of H0 using light curves associated with four sGRBs, assuming these are attributable to kilonovae, combined with GW170817. Including a systematic uncertainty on the models that is as large as the statistical ones, we find $${H}_{0}=73.{8}_{-5.8}^{+6.3}\ {\rm{km}}\ {{\rm{s}}}^{-1}\ {{\rm{Mpc}}}^{-1}$$

H

0

=
73
.

8

−
5.8

+
6.3

km

s

−
1

Mpc

−
1

and $${H}_{0}=71.{2}_{-3.1}^{+3.2}\ {\rm{km}}\ {{\rm{s}}}^{-1}\ {{\rm{Mpc}}}^{-1}$$

H

0

=
71
.

2

−
3.1

+
3.2

km

s

−
1

Mpc

−
1

for two different kilonova models that are consistent with the local and inverse-distance ladder measurements. For a given model, this measurement is about a factor of 2-3 more precise than the standard-siren measurement for GW170817 using only GWs.
Photon-counting spectral basis component material decomposition for musculoskeletal radiographs
Authors: Beck Stefanie , Sellerer Thorsten , Mechlem Korbinian , Bodden Jannis , Meurer Felix , Sauter Andreas , Herzen Julia , Pfeiffer Franz , Pfeiffer Daniela
Published: August 2020

As a very fast and non-invasive examination, conventional X-ray radiography is well established as the first line diagnostic imaging method of the human bone system. While major bone injuries such as fractures and dislocations are usually easily detectable on conventional X-ray images, more subtle injuries such as microfractures are often missed, leading to mistreatment and potential long-term consequences. The technology of Photon-Counting Dual-Energy Radiography (PCDER) yields the possibility to decompose conventional X-ray images into basis material images such as bone- and soft-tissue-equivalence images. The obtained basis material images offer significant advantages in terms of image contrast and image details over the raw attenuation image which shows an overlap of bone and soft tissue. Whereas the advantages of bone- and soft-tissue-equivalence images have been broadly discussed referring to bone subtraction images in the detection of pulmonary diseases, this method has not been considered for the analysis of musculoskeletal images until present. In this study we show that basis component equivalence images have high potential to improve the diagnostic accuracy of the detection of minor bone lesions during clinical trauma imaging. A reader study performed by three experienced radiologists compares the image quality of basis material images to a standard radiograph image of a non-fractured cadaveric hand.
Post-stimulatory activity in primate auditory cortex evoked by sensory stimulation during passive listening
Authors: Cooke James E. , Lee Julie J. , Bartlett Edward L. , Wang Xiaoqin , Bendor Daniel
Published: August 2020

Under certain circumstances, cortical neurons are capable of elevating their firing for long durations in the absence of a stimulus. Such activity has typically been observed and interpreted in the context of performance of a behavioural task. Here we investigated whether post-stimulatory activity is observed in auditory cortex and the medial geniculate body of the thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and auditory thalamus of awake, passively-listening marmosets. We observed post-stimulatory activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus. Post-stimulatory activity was observed following both adapting, sustained and suppressed response profiles during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from the auditory thalamus. As well as being of shorter duration, thalamic post-stimulatory activity emerged following a longer latency than in cortex, indicating that post-stimulatory activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of an explicit behavioural task, post-stimulatory activity in sensory cortex may play a functional role in processes such as echoic memory and temporal integration that occur during passive listening.
Oral Phyto-thymol ameliorates the stress induced IBS symptoms
Authors: Subramaniyam Selvaraj , Yang Shuyou , Diallo Bakary N’tji , Fanshu Xu , Lei Luo , Li Chong , Tastan Bishop Özlem , Bhattacharyya Sanjib
Published: August 2020

Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HT3AR expression level while thymol treatment normalized the 5-HT3AR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HT3AR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HT3AR. Our study suggest that thymol improves IBS symptoms through 5-HT3AR, could be useful for the treatment of IBS.
Adoptive transfer of bone marrow-derived dendritic cells (BMDCs) alleviates OVA-induced allergic airway inflammation in asthmatic mice
Authors: Xu Kan , Wu Nan , Min Zhihui , Li Zheng , Zhu Tao , Liu Chunfang , Zeng Yuzhen , Song Juan , Mao Ruolin , Ji Hong , Jiang Zhilong , Chen Zhihong
Published: August 2020

Airway dendritic cells (DCs) are recognized as important factors in the mechanisms of allergic inflammatory diseases. Suppressor of cytokine signaling 3 (SOCS3) is involved in regulating the functions of T cells and macrophages, but the roles of SOCS3-expressing DCs in the pathogeneses of allergic inflammatory diseases are still controversial. We compared the effects of adoptively transferred SOCS3−/− and SOCS3+/+ bone marrow-derived DCs (BMDCs) on airway inflammation in ovalbumin (OVA)-sensitized asthmatic mice. Adoptive transfer of mature DCs (lipopolysaccharide [LPS]-induced DCs, DClps) with or without SOCS3 gene expression significantly ameliorated allergic airway inflammation. SOCS3−/− DCs slightly attenuated BMDC-induced immunogenic tolerance. DClps migrated to OVA-sensitized lungs with higher efficiency than immature DCs (DCim). DClps with or without SOCS3 greatly improved lung pathology scores and alleviated airway inflammatory cell infiltration after adoptive transfer into mice; they also increased interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production and inhibited signal transducer and activator of transcription (STAT) 4 and STAT6 signaling in the lungs after OVA sensitization. In conclusion, the BMDC adoptive transfer-induced immunogenic tolerance in OVA-sensitized mice might not be due to SOCS3 gene depletion. BMDC adoptive transfer may be developed into a new approach that alleviates asthma by modulating the balance between immune tolerance and inflammation.
Social isolation, loneliness and physical performance in older-adults: fixed effects analyses of a cohort study
Authors: Philip Keir E. J. , Polkey Michael I. , Hopkinson Nicholas S. , Steptoe Andrew , Fancourt Daisy
Published: August 2020

Isolation and loneliness are related to various aspects of health. Physical performance is a central component of health. However, its relationship with isolation and loneliness is not well understood. We therefore assessed the relationship between loneliness, different aspects of social isolation, and physical performance over time. 8,780 participants from the English Longitudinal Study of Ageing, assessed three times over 8 years of follow-up, were included. Measures included physical performance (Short Physical Performance Battery), loneliness (modified UCLA Loneliness Scale), and isolation considered in three ways (domestic isolation, social disengagement, low social contact). Fixed effects regression models were used to estimate the relationship between changes in these parameters. Missing data were imputed to account for variable response and ensure a representative sample. Loneliness, domestic isolation and social disengagement were longitudinally associated with poorer physical performance when accounting for both time-invariant and time-variant confounders (loneliness: coef = − 0.06, 95% CI − 0.09 to − 0.02; domestic isolation: coef = − 0.32, 95% CI − 0.46 to − 0.19; social disengagement: coef = − 0.10, 95% CI − 0.12 to − 0.07). Low social contact was not associated with physical performance. These findings suggest social participation and subjectively meaningful interpersonal interactions are related to physical performance, and highlight additional considerations regarding social distancing related to COVID-19 control measures.
TMPRSS13 promotes cell survival, invasion, and resistance to drug-induced apoptosis in colorectal cancer
Authors: Varela Fausto A. , Foust Victoria L. , Hyland Thomas E. , Sala-Hamrick Kimberley E. , Mackinder Jacob R. , Martin Carly E. , Murray Andrew S. , Todi Sokol V. , List Karin
Published: August 2020

Cancer progression is often accompanied by increased levels of extracellular proteases capable of remodeling the extracellular matrix and promoting pro-cancerous signaling pathways by activating growth factors and receptors. The type II transmembrane serine protease (TTSP) family encompasses several proteases that play critical roles in cancer progression; however, the expression or function of the TTSP TMPRSS13 in carcinogenesis has not been examined. In the present study, we found TMPRSS13 to be differentially expressed at both the transcript and protein levels in human colorectal cancer (CRC). Immunohistochemical analyses revealed consistent high expression of TMPRSS13 protein on the cancer cell surface in CRC patient samples; in contrast, the majority of normal colon samples displayed no detectable expression. On a functional level, TMPRSS13 silencing in CRC cell lines increased apoptosis and impaired invasive potential. Importantly, transgenic overexpression of TMPRSS13 in CRC cell lines increased tolerance to apoptosis-inducing agents, including paclitaxel and HA14-1. Conversely, TMPRSS13 silencing rendered CRC cells more sensitive to these agents. Together, our findings suggest that TMPRSS13 plays an important role in CRC cell survival and in promoting resistance to drug-induced apoptosis; we also identify TMPRSS13 as a potential new target for monotherapy or combination therapy with established chemotherapeutics to improve treatment outcomes in CRC patients.
Cellists’ sound quality is shaped by their primary postural behavior
Authors: Rozé Jocelyn , Aramaki Mitsuko , Kronland-Martinet Richard , Ystad Sølvi
Published: August 2020

During the last 20 years, the role of musicians’ body movements has emerged as a central question in instrument practice: Why do musicians make so many postural movements, for instance, with their torsos and heads, while playing musical instruments? The musical significance of such ancillary gestures is still an enigma and therefore remains a major pedagogical challenge, since one does not know if these movements should be considered essential embodied skills that improve musical expressivity. Although previous studies established clear connections between musicians’ body movements and musical structures (particularly for clarinet, piano or violin performances), no evidence of direct relationships between body movements and the quality of the produced timbre has ever been found. In this study, focusing on the area of bowed-string instruments, we address the problem by showing that cellists use a set of primary postural directions to develop fluid kinematic bow features (velocity, acceleration) that prevent the production of poor quality (i.e., harsh, shrill, whistling) sounds. By comparing the body-related angles between normal and posturally constrained playing situations, our results reveal that the chest rotation and vertical inclination made by cellists act as coordinative support for the kinematics of the bowing gesture. These findings support the experimental works of Alexander, especially those that showed the role of head movements with respect to the upper torso (the so-called primary control) in ensuring the smooth transmission of fine motor control in musicians all the way to the produced sound. More generally, our research highlights the importance of focusing on this fundamental postural sense to improve the quality of human activities across different domains (music, dance, sports, rehabilitation, working positions, etc.).
Plasmid-based complementation of large deletions in Phaeodactylum tricornutum biosynthetic genes generated by Cas9 editing
Authors: Slattery Samuel S. , Wang Helen , Giguere Daniel J. , Kocsis Csanad , Urquhart Bradley L. , Karas Bogumil J. , Edgell David R.
Published: August 2020

The model diatom Phaeodactylum tricornutum is an attractive candidate for synthetic biology applications. Development of auxotrophic strains of P. tricornutum would provide alternative selective markers to commonly used antibiotic resistance genes. Here, using CRISPR/Cas9, we show successful editing of genes in the uracil, histidine, and tryptophan biosynthetic pathways. Nanopore long-read sequencing indicates that editing events are characterized by the occurrence of large deletions of up to ~ 2.7 kb centered on the editing site. The uracil and histidine-requiring phenotypes can be complemented by plasmid-based copies of the intact genes after curing of the Cas9-editing plasmid. Growth of uracil auxotrophs on media supplemented with 5-fluoroorotic acid and uracil results in loss of the complementing plasmid, providing a facile method for plasmid curing with potential applications in strain engineering and CRISPR editing. Metabolomic characterization of uracil auxotrophs revealed changes in cellular orotate concentrations consistent with partial or complete loss of orotate phosphoribosyltransferase activity. Our results expand the range of P. tricornutum auxotrophic strains and demonstrate that auxotrophic complementation markers provide a viable alternative to traditionally used antibiotic selection markers. Plasmid-based auxotrophic markers should expand the range of genome engineering applications and provide a means for biocontainment of engineered P. tricornutum strains.
Coronary artery bypass grafting and perioperative stroke: imaging of atherosclerotic plaques in the ascending aorta with ungated high-pitch CT-angiography
Authors: Asenbaum Ulrika , Nolz Richard , Puchner Stefan B. , Schoster Tobias , Baumann Lukas , Furtner Julia , Zimpfer Daniel , Laufer Guenther , Loewe Christian , Sandner Sigrid E.
Published: August 2020

Perioperative stroke is a devastating complication after coronary artery bypass graft (CABG) surgery, with atherosclerosis of the ascending aorta as important risk factor. During surgical manipulation, detachment of plaques can lead to consecutive embolization into brain-supplying arteries. High-pitch computed tomography angiography (HP-CTA) represents a non-invasive imaging modality, which provides the opportunity for comprehensive imaging of the ascending aorta, including plaque detection and advanced characterization. In our present retrospective study on 719 individuals, who had undergone HP-CTA within 6 months prior to CABG, atherosclerotic disease of the ascending aorta was evaluated with respect to perioperative stroke rates. For image analysis, the ascending aorta was divided into a proximal and distal part, consisting of four segments, and evaluated for presence and distribution of calcified and mixed plaques. All patients with perioperative stroke presented with atherosclerotic disease of the ascending aorta. The stroke rate was significantly associated with the presence and extent of atherosclerotic disease. Patients burdened with mixed plaques presented with significantly higher perioperative stroke rates. This study demonstrates that HP-CTA allows accurate evaluation of plaque extent and composition in the ascending aorta, and therefore may improve risk stratification of stroke prior to CABG.
Liberalizing the killing of endangered wolves was associated with more disappearances of collared individuals in Wisconsin, USA
Authors: Santiago-Ávila Francisco J. , Chappell Richard J. , Treves Adrian
Published: August 2020

Although poaching (illegal killing) is an important cause of death for large carnivores globally, the effect of lethal management policies on poaching is unknown for many populations. Two opposing hypotheses have been proposed: liberalizing killing may decrease poaching incidence (‘tolerance hunting’) or increase it (‘facilitated poaching’). For gray wolves in Wisconsin, USA, we evaluated how five causes of death and disappearances of monitored, adult wolves were influenced by policy changes. We found slight decreases in reported wolf poaching hazard and incidence during six liberalized killing periods, but that was outweighed by larger increases in hazard and incidence of disappearance. Although the observed increase in the hazard of disappearance cannot be definitively shown to have been caused by an increase in cryptic poaching, we discuss two additional independent lines of evidence making this the most likely explanation for changing incidence among n = 513 wolves’ deaths or disappearances during 12 replicated changes in policy. Support for the facilitated poaching hypothesis suggests the increase (11–34%) in disappearances reflects that poachers killed more wolves and concealed more evidence when the government relaxed protections for endangered wolves. We propose a refinement of the hypothesis of ‘facilitated poaching’ that narrows the cognitive and behavioral mechanisms underlying wolf-killing.
Effect of image quality fluctuations on the repeatability of thickness measurements in swept-source optical coherence tomography
Authors: Yang Heon , Lee Hye Sun , Bae Hyoung Won , Seong Gong Je , Kim Chan Yun , Lee Sang Yeop
Published: August 2020

This study investigated the effect of image quality fluctuations on the repeatability of thickness measurements of the peripapillary retinal nerve fibre (PP-RNFL) and ganglion cell-inner plexiform (GC-IPL) layers using swept-source optical coherence tomography (SS-OCT). Three consecutive OCT scans each were performed on 56 healthy subject. Finally, 168 SS-OCT results were analysed. Based on the tertile values of the mean absolute difference of image quality score, all subjects were divided into the following three groups—low-(LIQD), moderate-(MIQD), and high-(HIQD) image quality score difference groups. A linear mixed model and intraclass correlation coefficients (ICCs) were used for analyses. Despite high ICC values (> 0.9), several sectors showed significant differences in the ICC values in intergroup comparisons. For LIQD-HIQD and MIQD-HIQD, most PP-RNFL sectors showed significant differences. For GC-IPL sectors, the LIQD-HIQD comparison showed significant differences in the temporosuperior (p = 0.012), inferior (p < .001), and temporoinferior (p = 0.042) sectors. Significant differences existed in the average GC-IPL (p = 0.009), nasoinferior (p = 0.035), and inferior GC-IPL sectors (p < .001) for MIQD-HIQD comparison. With higher image quality fluctuations, the repeatability of SS-OCT decreased in several sectors, which are considered clinically relevant in evaluating glaucoma status. Therefore, maintaining high-quality image status is essential to enhance the reliability of SS-OCT.
Sleep disturbances as risk factors for suicidal thoughts and behaviours: a meta-analysis of longitudinal studies
Authors: Harris Lauren M. , Huang Xieyining , Linthicum Kathryn P. , Bryen Chloe P. , Ribeiro Jessica D.
Published: August 2020

In recent years, there has been a growing interest in understanding the relationship between sleep and suicide. Although sleep disturbances are commonly cited as critical risk factors for suicidal thoughts and behaviours, it is unclear to what degree sleep disturbances confer risk for suicide. The aim of this meta-analysis was to clarify the extent to which sleep disturbances serve as risk factors (i.e., longitudinal correlates) for suicidal thoughts and behaviours. Our analyses included 156 total effects drawn from 42 studies published between 1982 and 2019. We used a random effects model to analyse the overall effects of sleep disturbances on suicidal ideation, attempts, and death. We additionally explored potential moderators of these associations. Our results indicated that sleep disturbances are statistically significant, yet weak, risk factors for suicidal thoughts and behaviours. The strongest associations were found for insomnia, which significantly predicted suicide ideation (OR 2.10 [95% CI 1.83–2.41]), and nightmares, which significantly predicted suicide attempt (OR 1.81 [95% CI 1.12–2.92]). Given the low base rate of suicidal behaviours, our findings raise questions about the practicality of relying on sleep disturbances as warning signs for imminent suicide risk. Future research is necessary to uncover the causal mechanisms underlying the relationship between sleep disturbances and suicide.
Prepregnancy smoking and the risk of gestational diabetes requiring insulin therapy
Authors: Kim Mee Kyoung , Han Kyungdo , You Sang Youn , Kwon Hyuk-Sang , Yoon Kun-Ho , Lee Seung-Hwan
Published: August 2020

The relationship between maternal smoking and gestational diabetes mellitus (GDM) is inconclusive. We investigated whether prepregnancy smoking is a risk factor for insulin-requiring GDM in Korean women. Using the National Health Insurance Service database, 325,297 women who delivered between 2011 and 2015 and who received a health examination within 52 weeks before pregnancy were included. Insulin-requiring GDM was defined as no claims for diabetes mellitus and a fasting blood glucose level of < 126 mg/dL before pregnancy, and initiation of insulin treatment during pregnancy. Smoking status was identified in a self-reported questionnaire completed during the health examination. There were 2,114 women (0.65%) with GDM who required insulin therapy. Compared with nonsmokers, the fully adjusted odd ratios (ORs) of former smokers and current smokers for insulin-requiring GDM were 1.55 (95% confidence interval [CI] 1.27–1.90) and 1.73 (1.42–2.09), respectively. The ORs (95% CIs) of insulin-requiring GDM among women who reported ≤ 2, 2–≤ 4, 4–≤ 6, 6–≤ 8, 8–≤ 10, and > 10 pack-years of smoking were 1.50 (1.22–1.84), 1.71 (1.31–2.22), 1.60 (1.13–2.26), 1.97 (1.14–3.40), 2.34 (1.22–4.51), and 2.29 (1.25–4.22), respectively, compared with nonsmokers (P for trend < 0.001). This association was similar in women with or without obesity and abdominal obesity. In conclusions, women who smoke have a significantly higher risk of GDM requiring insulin therapy, which may be proportional to the cumulative exposure to smoking. Cessation of smoking should be emphasized in women of childbearing age for the prevention of GDM.
A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+
Authors: Silveira Sandra Cunha , Buhagiar-Labarchède Géraldine , Onclercq-Delic Rosine , Gemble Simon , Bou Samra Elias , Mameri Hamza , Duchambon Patricia , Machon Christelle , Guitton Jérôme , Amor-Guéret Mounira
Published: August 2020

Cytidine deaminase (CDA) deficiency causes pyrimidine pool disequilibrium. We previously reported that the excess cellular dC and dCTP resulting from CDA deficiency jeopardizes genome stability, decreasing basal poly(ADP-ribose) polymerase 1 (PARP-1) activity and increasing ultrafine anaphase bridge (UFB) formation. Here, we investigated the mechanism underlying the decrease in PARP-1 activity in CDA-deficient cells. PARP-1 activity is dependent on intracellular NAD+ concentration. We therefore hypothesized that defects of the NAD+ salvage pathway might result in decreases in PARP-1 activity. We found that the inhibition or depletion of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage biosynthesis pathway, mimicked CDA deficiency, resulting in a decrease in basal PARP-1 activity, regardless of NAD+ levels. Furthermore, the expression of exogenous wild-type NAMPT fully restored basal PARP-1 activity and prevented the increase in UFB frequency in CDA-deficient cells. No such effect was observed with the catalytic mutant. Our findings demonstrate that (1) the inhibition of NAMPT activity in CDA-proficient cells lowers basal PARP-1 activity, and (2) the expression of exogenous wild-type NAMPT, but not of the catalytic mutant, fully restores basal PARP-1 activity in CDA-deficient cells; these results strongly suggest that basal PARP-1 activity in CDA-deficient cells decreases due to a reduction of NAMPT activity.
Electrochemical immunosensor with Cu(I)/Cu(II)-chitosan-graphene nanocomposite-based signal amplification for the detection of newcastle disease virus
Authors: Huang Jiaoling , Xie Zhixun , Huang Yihong , Xie Liji , Luo Sisi , Fan Qing , Zeng Tingting , Zhang Yanfang , Wang Sheng , Zhang Minxiu , Xie Zhiqin , Deng Xianwen
Published: August 2020

An electrochemical immunoassay for the ultrasensitive detection of Newcastle disease virus (NDV) was developed using graphene and chitosan-conjugated Cu(I)/Cu(II) (Cu(I)/Cu(II)-Chi-Gra) for signal amplification. Graphene (Gra) was used for both the conjugation of an anti-Newcastle disease virus monoclonal antibody (MAb/NDV) and the immobilization of anti-Newcastle disease virus polyclonal antibodies (PAb/NDV). Cu(I)/Cu(II) was selected as an electroactive probe, immobilized on a chitosan-graphene (Chi-Gra) hybrid material, and detected by differential pulse voltammetry (DPV) after a sandwich-type immune response. Because Gra had a large surface area, many antibodies were loaded onto the electrochemical immunosensor to effectively increase the electrical signal. Additionally, the introduction of Gra significantly increased the loading amount of electroactive probes (Cu(I)/Cu(II)), and the electrical signal was further amplified. Cu(I)/Cu(II) and Cu(I)/Cu(II)-Chi-Gra were compared in detail to characterize the signal amplification ability of this platform. The results showed that this immunosensor exhibited excellent analytical performance in the detection of NDV in the concentration range of 100.13 to 105.13 EID50/0.1 mL, and it had a detection limit of 100.68 EID50/0.1 mL, which was calculated based on a signal-to-noise (S/N) ratio of 3. The resulting immunosensor also exhibited high sensitivity, good reproducibility and acceptable stability.
Tanshinone II A attenuates vascular remodeling through klf4 mediated smooth muscle cell phenotypic switching
Authors: Lou Guanhua , Hu Wangming , Wu Ziqiang , Xu Huan , Yao Huan , Wang Yang , Huang Qinwan , Wang Baojia , Wen Li , Gong Daoying , Chen Xiongbing , Shi Yaping , Yang Lan , Xu Yiming , Wang Yong
Published: August 2020

The aim of this study is to investigate the therapeutic role of Tanshinone II A, a key integrant from salvia miltiorrhiza, against pathological vascular remodeling. Completed ligation of mouse left common carotid arteries animal model and rat smooth muscle cells used to investigate the role of Tanshinone II A in regulating pathological vascular remodeling through hematoxylin and eosin staining, immunohistochemistry staining, immunofluorescence staining, adenovirus infection, real time PCR and western blotting. Our data demonstrated that Tanshinone II A treatment suppresses vascular injury-induced neointima formation. In vitro studies on rat smooth muscle cell indicated that Tanshinone II A treatment attenuates PDGF-BB induced cell growth, and promotes smooth muscle cell differentiated marker genes expression that induced by rapamycin treatment. Tanshinone II A treatment significant inhibits rat smooth muscle cell proliferation and migration. Tanshinone II A promotes KLF4 expression during smooth muscle phenotypic switching. Overexpression of KLF4 exacerbates Tanshinone II A mediated smooth muscle cell growth inhibition. Tanshinone II A plays a pivotal role in regulating pathological vascular remodeling through KLF4 mediated smooth muscle cell phenotypic switching. This study demonstrated that Tanshinone II A is a potential therapeutic agent for vascular diseases.