bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac rehabilitation in the paediatric Fontan population: development of a home-based high-intensity interval training programme
Authors: Khoury Michael , Phillips Devin B. , Wood Peter W. , Mott William R. , Stickland Michael K. , Boulanger Pierre , Rempel Gwen R. , Conway Jennifer , Mackie Andrew S. , Khoo Nee S.
Published: July 2020

Introduction:

We evaluated the safety and feasibility of high-intensity interval training via a novel telemedicine ergometer (MedBIKE™) in children with Fontan physiology.

Methods:

The MedBIKE™ is a custom telemedicine ergometer, incorporating a video game platform and live feed of patient video/audio, electrocardiography, pulse oximetry, and power output, for remote medical supervision and modulation of work. There were three study phases: (I) exercise workload comparison between the MedBIKE™ and a standard cardiopulmonary exercise ergometer in 10 healthy adults. (II) In-hospital safety, feasibility, and user experience (via questionnaire) assessment of a MedBIKE™ high-intensity interval training protocol in children with Fontan physiology. (III) Eight-week home-based high-intensity interval trial programme in two participants with Fontan physiology.

Results:

There was good agreement in oxygen consumption during graded exercise at matched work rates between the cardiopulmonary exercise ergometer and MedBIKE™ (1.1 ± 0.5 L/minute versus 1.1 ± 0.5 L/minute, p = 0.44). Ten youth with Fontan physiology (11.5 ± 1.8 years old) completed a MedBIKE™ high-intensity interval training session with no adverse events. The participants found the MedBIKE™ to be enjoyable and easy to navigate. In two participants, the 8-week home-based protocol was tolerated well with completion of 23/24 (96%) and 24/24 (100%) of sessions, respectively, and no adverse events across the 47 sessions in total.

Conclusion:

The MedBIKE™ resulted in similar physiological responses as compared to a cardiopulmonary exercise test ergometer and the high-intensity interval training protocol was safe, feasible, and enjoyable in youth with Fontan physiology. A randomised-controlled trial of a home-based high-intensity interval training exercise intervention using the MedBIKE™ will next be undertaken.
Schizotypal personality disorder in clinical obsessive–compulsive disorder samples: a brief overview
Authors: Attademo Luigi , Bernardini Francesco
Published: July 2020

Obsessive–compulsive disorder (OCD) is a chronic and disabling mental disorder characterized by the presence of obsessions and/or compulsions that cause major distress and impair important areas of functioning. About 9 out of 10 patients with OCD have comorbid psychiatric diagnoses. A high proportion of clinically diagnosed OCD patients fulfill diagnostic criteria of a schizophrenia spectrum disorder, to the point that significant evidence in the literature supports the existence and the clinical relevance of a schizo-obsessive spectrum of disorders, including schizotypal personality disorder (SPD) with OCD (schizotypal OCD). In this paper, we provide a brief but comprehensive analysis of the literature on the clinical coexistence between OCD and SPD. The clinical validity of the so-called schizotypal OCD is analyzed through a comprehensive investigation of the relationship between SPD features and obsessive–compulsive phenomena in clinical OCD samples. This review describes the potential connections between OCD and SPD on the epidemiological, sociodemographic, psychopathological, and clinical levels. SPD is commonly observed in OCD patients: about 10% of OCD patients have a full categorical diagnosis of SPD. Early clinical identification of SPD features—and, more generally, of psychotic features and personality disorders—in OCD patients is strongly recommended. In fact, a proper and early diagnosis with early treatment may have benefits for prognosis. However, although schizotypal OCD seems to have clinical and predictive validity, further neurobiological and genetic studies on etiological specificity are warranted.
Participant characteristics and self-reported weight status in a cross-sectional pilot survey of self-identified followers of popular diets: Adhering to Dietary Approaches for Personal Taste (ADAPT) Feasibility Survey
Authors: Karlsen Micaela C , Lichtenstein Alice H , Economos Christina D , Folta Sara C , Chang Remco , Rogers Gail , Jacques Paul F , Livingston Kara A , McKeown Nicola M
Published: July 2020

Objective:

To describe characteristics of self-identified popular diet followers and compare mean BMI across these diets, stratified by time following diet.

Design:

Cross-sectional, web-based survey administered in 2015.

Setting:

Non-localised, international survey.

Participants:

Self-selected followers of popular diets (n 9019) were recruited to the survey via social media and email announcements by diet community leaders, categorised into eight major diet groups.

Results:

General linear models were used to compare mean BMI among (1) short-term (<1 year) and long-term (≥1 year) followers within diet groups and (2) those identifying as ‘try to eat healthy’ (TTEH) to all other diet groups, stratified by time following the specific diet. Participants were 82 % female, 93 % White and 96 % non-Hispanic. Geometric mean BMI was lower (P < 0·05 for all) among longer-term followers (≥1 year) of whole food, plant-based (WFPB), vegan, whole food and low-carb diets compared with shorter-term followers. Among those following their diet for 1–5 years (n 4067), geometric mean BMI (kg/m2) were lower (P < 0·05 for all) for all groups compared with TTEH (26·4 kg/m2): WFPB (23·2 kg/m2), vegan (23·5 kg/m2), Paleo (24·6 kg/m2), vegetarian (25·0 kg/m2), whole food (24·6 kg/m2), Weston A. Price (23·5 kg/m2) and low-carb (24·7 kg/m2).

Conclusion:

Our findings suggest that BMI is lower among individuals who made active decisions to adhere to a specific diet, particularly more plant-based diets and/or diets limiting highly processed foods, compared with those who simply TTEH. BMI is also lower among individuals who follow intentional eating plans for longer time periods.
Economic hardship and child intake of foods high in saturated fats and added sugars: the mediating role of parenting stress among high-risk families
Authors: Schuler Brittany R , Daundasekara Sajeevika S , Hernandez Daphne C , Dumenci Levent , Clark Michael , Fisher Jennifer O , Miller Alison L
Published: July 2020

Objective:

Economic hardship (EH) may link to poorer child diet, however whether this association is due to resource limitations or effects on family functioning is unknown. This study examines whether parenting stress mediates the association between EH and child consumption of foods high in saturated fats and added sugars (SFAS).

Design:

Data were collected from the Fragile Families and Child Wellbeing study. EH was assessed using eight items collected when children were between 1–9 years old. Mothers reported parenting stress and frequency of child consumption of high SFAS foods when children were 9 years old. Latent growth curve modelling (LGCM) and structural equation modelling tested direct associations between the starting level/rate of change in EH and high SFAS food consumption, and parenting stress as a mediator of the association.

Setting:

Twenty US cities.

Participants:

Mothers/children (n3846) followed birth through age 9 years, oversampled ‘high-risk’, unmarried mothers.

Results:

LGCM indicated a curvilinear trend in EH from ages 1–9, with steeper increases from ages 3–9 years. EH did not directly predict the frequency of high SFAS foods. Average EH at 3 and 5 years and change in EH from ages 1–9 predicted higher parenting stress, which in turn predicted more frequent consumption of high SFAS foods.

Conclusions:

Findings suggest it may be important to consider parenting stress in early prevention efforts given potential lasting effects of early life EH on child consumption of high SFAS foods. Future research should explore how supports and resources may buffer effects of EH-related stress on parents and children.
The Diffusion of Urban Medieval Representation: The Dominican Order as an Engine of Regime Change
Authors: Doucette Jonathan
Published: July 2020

How do representative institutions diffuse from one polity to another? I investigate the effect of the Dominican order on the transition from autocratic to representative city government in medieval Europe. I argue that the order’s practices of representation diffused to local lay politics because of the persistent interaction between Dominican monks and urban elites. Using a difference-in-difference design, I offer evidence that the presence of Dominican houses fostered the development of representative city government. My findings highlight the important role that religious institutions can play in the diffusion of political institutions and principles.
I Rate My Memory Quite Similar at Age 40 and at Age 70
Authors: Johansson Boo , Björk Marcus Praetorius , Thorvaldsson Valgeir
Published: July 2020

Abstract. In 1987, we administered a subjective memory questionnaire to 143 40-year-old men, and 30 years later 67 of them again responded to the same questionnaire at age 70. At the follow-up, we also instructed participants to answer the questionnaire in the same manner as they thought they did at age 40 and to perform a picture recognition and a public event test. We employed confirmatory factor analysis to model a latent subjective memory construct. A single-factor solution provided acceptable model fit to data (χ2(12) = 9.33, p = .68; χ2(12) = 10.48, p = .57) and a decent reliability at both ages for the subjective memory measurements (omega = .82 and .93, respectively). Our longitudinal invariance testing revealed only a partial weak invariance. We also fitted a latent change-score model to the data. As expected, participants on average rated their memory as poorer at age 70 than at 40. Those who reported better overall health and less anxiety reported less memory decline up to age 70. Notably, this was also the case for those who rated memory as worse at age 40. Higher stress and depression at age 70, however, were associated with worse subjective memory already at age 40. The correspondences between memory ratings and tests were low. The correlation between the subjective memory factors at age 40 and 70 was 0.58, while the correlation between the memory factor at age 70 and the retrospective subjective memory factor was 0.87. Our findings suggest that subjective memory is quite consistent, and that we are inclined to preserve the continuity of our own memory functioning over the adult lifespan.
Improving a Biogeochemical Model to Simulate Surface Energy, Greenhouse Gas Fluxes, and Radiative Forcing for Different Land Use Types in Northeastern United States
Authors: Deng Jia , Xiao Jingfeng , Ouimette Andrew , Zhang Yu , Sanders‐DeMott Rebecca , Frolking Steve , Li Changsheng
Published: July 2020

Land use changes exert important impacts on climate, primarily through altering greenhouse gas (GHG) and surface energy fluxes. Biogeochemical models have incorporated a relatively complete suite of biogeochemical processes to simulate GHG fluxes. However, these models often lack detailed processes of surface energy exchange, limiting their ability to assess the impacts of land use change on climate. In this study, we incorporated processes of surface energy exchange into a widely used biogeochemistry model, DeNitrification‐DeComposition (DNDC), so that it can quantify both GHG and energy fluxes between the biosphere and the atmosphere. When tested against field observations for the three dominant land use types (forest, hayfield, and cornfield) in the northeastern United States, the improved DNDC successfully captured the observed fluxes of outgoing shortwave radiation, latent heat, sensible heat, net ecosystem exchange of CO2, and their differences among the three land use types. To evaluate the differences in radiative forcing among these land use types, we conducted 100‐year simulations and converted the modeled GHG fluxes to radiative forcing using an atmospheric impulse response model. Our results show that the 100‐year cumulative differences in net radiative forcing are 3.35 nW m−2 between the hayfield and forest (slight warming) and 43.2 nW m−2 between the cornfield and forest (warming) per hectare land use difference. The cooling effects of increased albedo after the conversion of forest to hayfield or cornfield (observed and modeled in recent years) are gradually offset by the warming effects of the increasing release of GHG as the forest becomes older.
Rapid Net Carbon Loss From a Whole‐Ecosystem Warmed Peatland
Authors: Hanson Paul J. , Griffiths Natalie A. , Iversen Colleen M. , Norby Richard J. , Sebestyen Stephen D. , Phillips Jana R. , Chanton Jeffrey P. , Kolka Randall K. , Malhotra Avni , Oleheiser Keith C. , Warren Jeffrey M. , Shi Xiaoying , Yang Xiaojuan , Mao Jiafu , Ricciuto Daniel M.
Published: July 2020

To evaluate boreal peatland C losses from warming, novel technologies were used to expose intact bog plots in northern Minnesota to a range of future temperatures (+0°C to +9°C) with and without elevated CO2 (eCO2). After 3 years, warming linearly increased net C loss at a rate of 31.3 g C·m−2·year−1·°C−1. Increasing losses were associated with increased decomposition and corroborated by measures of declining peat elevation. Effects of eCO2 were minor. Results indicate a range of C losses from boreal peatlands 4.5 to 18 times faster than historical rates of accumulation, with substantial emissions of CO2 and CH4 to the atmosphere. A model of peatland C cycle captured the temperature response dominated by peat decomposition under ambient CO2, but improvements will be needed to predict the lack of observable responses to elevated CO2 concentrations thus far.
Receiver Function Velocity Analysis Technique and Its Application to Remove Multiples
Authors: Shi Jing , Wang Tao , Chen Ling
Published: July 2020

Results of P wave receiver function (RF) analysis (e.g., H‐κ stacking, common conversion point (CCP) stacking, and migration) depend on the velocity models employed. Converted phases of crustal and upper mantle discontinuities are often interfered by multiple reflections from shallower structures, adding further complexity to the interpretation of P wave RF images. In this study, we propose a receiver function velocity analysis technique (RFVAT) that can constrain the velocity structure above discontinuities and remove multiple reflections arising from target discontinuities. By scanning the amplitude spectra of the Ps and PpPs phases, we can obtain precise arrival times of these phases for interfaces above 250 km (errors < 0.13 s) and derive the average velocities and thicknesses of the layers between interfaces in the crust and upper mantle. Synthetic experiments are used to demonstrate that crustal and upper mantle discontinuities can be coherently identified and that multiple reflections can be effectively removed in the CCP stacking images of P wave RFs using the RFVAT even with low signal‐to‐noise ratio data. By applying the proposed RFVAT to real P wave RF data from the northeastern part of the North China Craton, we achieve an improvement in CCP stacking image of lithospheric discontinuities, especially for the lithosphere‐asthenosphere boundary (LAB). Our P wave RF images reveal distinct lateral variations of the LAB depth. The lithospheric thickness extends to ~120 km beneath the central orogenic belt and decreases sharply to ~80 km at the west edge of the eastern block, consistent with previous S wave RF studies.
The Atlantic Water Boundary Current in the Chukchi Borderland and Southern Canada Basin
Authors: Li Jianqiang , Pickart Robert S. , Lin Peigen , Bahr Frank , Arrigo Kevin R. , Juranek Laurie , Yang Xiao‐Yi
Published: July 2020

Synoptic shipboard measurements, together with historical hydrographic data and satellite data, are used to elucidate the detailed structure of the Atlantic Water (AW) boundary current system in the southern Canada Basin and its connection to the upstream source of AW in the Chukchi Borderland. Nine high‐resolution occupations of a transect extending from the Beaufort shelf to the deep basin near 152°W, taken between 2003 and 2018, reveal that there are two branches of the AW boundary current that flow beneath and counter to the Beaufort Gyre. Each branch corresponds to a warm temperature core and transports comparable amounts of Fram Strait Branch Water between roughly 200–700 m depth, although they are characterized by a different temperature/salinity (T/S) structure. The mean volume flux of the combined branches is 0.87 ± 0.13 Sv. Using the historical hydrographic data, the two branches are tracked upstream by their temperature cores and T/S signatures. This sheds new light on how the AW negotiates the Chukchi Borderland and why two branches emerge from this region. Lastly, the propagation of warm temperature anomalies through the region is quantified and shown to be consistent with the deduced circulation scheme.
Relative Contribution of Precipitation and Air Temperature on Dry Season Drying in India, 1951–2018
Authors: Mishra Vimal
Published: July 2020

Soil moisture plays an essential role in food production and land‐atmosphere feedback. However, the relative contribution of precipitation and air temperature on dry season (October–December) soil moisture has not been systematically examined in India. Using observations and simulations from the Variable Infiltration Capacity model, a significant (4%, p value = 0.04) decline in soil moisture (dry season drying hereafter) was found in a large part of India during the 1951–2018. The decline in the summer monsoon precipitation in India during 1951–2018 is mainly due to a decrease in rainfall during the late monsoon season (August–September). A substantial decline (−18.6%, p value = 0.009) in the late monsoon and (−26%, p value = 0.19) dry season precipitation was observed. A significant warming (0.75°C, p value = 0.002) has occurred during the dry season between 1951 and 2018. The relative contribution of decline in precipitation in the late monsoon (30%) and dry season (34%) is considerably higher than the dry season warming (15%). The previously unexplored role of climate warming on the dry season drying was analyzed using Maximum Covariance Analysis between precipitation and sea surface temperature, which suggests both large‐scale and localized influences. Climate warming over the Indian and Atlantic Oceans is associated with declining precipitation during the late monsoon and dry seasons over central India. Also, climate warming over land exacerbates the dry season drying by depleting soil moisture. The dry season drying over a large part of India contributed by climate warming has substantial implications for irrigation water management and groundwater abstraction.
Greening Hiatus in Eurasian Boreal Forests Since 1997 Caused by a Wetting and Cooling Summer Climate
Authors: Gao Xueyuan , Liang Shunlin , Sauer Jeffery
Published: July 2020

The Eurasian boreal forest ecosystem is a strong sink in the global carbon cycle. Satellite observations show significant change in the ecosystem in recent decades, specifically an increase in vegetation productivity since 1982 and a hiatus after 1997. Previous studies attributed this enhanced vegetation growth (also known as greening) to air temperature increases and a longer growing season, and the recent greening hiatus as a result of a warmer and drier climate. However, using satellite data, we found observational evidence that increases in summer peak growth dominated the overall greening trend and that a wetting and cooling climate during the peak growing season was the primary cause of the hiatus.
Shallow Anatomy of the San Ramón Fault (Chile) Constrained by Geophysical Methods: Implications for its Role in the Andean Deformation
Authors: Yáñez G. , Perez‐Estay N. , Araya‐Vargas J. , Sanhueza J. , Figueroa R. , Maringue J. , Rojas T.
Published: July 2020

The San Ramón Fault (SRF) runs for 30 km along the western flank of the Andes in front of the city of Santiago, Chile (33.5°S). Geological studies have highlighted the SRF role in the Neogene uplift of the Andes at this latitude, but the fault geometry at depth is not well constrained. Here we infer the structure of the sedimentary cover and bedrock up to a depth of 500 m along the SRF by integrating gravimetric, electrical resistivity, seismic, and magnetic methods. In a section crossing the central segment of the SRF, lateral variations inPwave velocity models indicate that the sedimentary cover is more deformed close to SRF scarps, while coincident low‐density and low‐resistivity zones suggest that the presence of two depocenters in the sedimentary cover below the SRF scarps. Gravimetric profiles distributed along the entire trace of the SRF show the same configuration of two depocenters, but the geometry of these depocenters is complex and varies along strike. Our findings suggest that the bedrock and sediments deformation along the SRF exhibit a complex geometry, which can be explained by the interplay of reverse and strike‐slip movements during the late Cenozoic. Based on our results, the distribution of crustal seismicity and shortening rates interpreted across the Andes, we estimated that SRF deformation represents 5–20% of the whole Andean shortening for the last 4 Ma. Using empirical length scales for crustal seismicity, this deformation pattern is consistent with a maximum earthquake magnitude in the range of 6.0–6.5 Mw.
A microfluidic approach for synchronous and nondestructive study of the permeability of multiple oocytes
Authors: Chen Zhongrong , Memon Kashan , Cao Yunxia , Zhao Gang
Published: July 2020

Investigation of oocyte membrane permeability plays a crucial role in fertility preservation, reproductive medicine, and reproductive pharmacology. However, the commonly used methods have disadvantages such as high time consumption, low efficiency, and cumbersome data processing. In addition, the developmental potential of oocytes after measurement has not been fully validated in previous studies. Moreover, oocytes can only maintain their best status in vitro within a very limited time. To address these limitations, we developed a novel multichannel microfluidic chip with newly designed micropillars that provide feasible and repeatable oocyte capture. The osmotic responses of three oocytes at different or the same cryoprotectant (CPA) concentrations were measured simultaneously, which greatly improved the measurement efficiency. Importantly, the CPA concentration dependence of mouse oocyte membrane permeability was found. Moreover, a neural network algorithm was employed to improve the efficiency and accuracy of data processing. Furthermore, analysis of fertilization and embryo transfer after perfusion indicated that the microfluidic approach does not damage the developmental potential of oocytes. In brief, we report a new method based on a multichannel microfluidic chip that enables synchronous and nondestructive measurement of the permeability of multiple oocytes.
Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study
Authors: Thygesen Johan H. , Presman Amelia , Harju-Seppänen Jasmine , Irizar Haritz , Jones Rebecca , Kuchenbaecker Karoline , Lin Kuang , Alizadeh Behrooz Z. , Austin-Zimmerman Isabelle , Bartels-Velthuis Agna , Bhat Anjali , Bruggeman Richard , Cahn Wiepke , Calafato Stella , Crespo-Facorro Benedicto , de Haan Liewe , de Zwarte Sonja M. C. , Di Forti Marta , Díez-Revuelta Álvaro , Hall Jeremy , Hall Mei-Hua , Iyegbe Conrad , Jablensky Assen , Kahn Rene , Kalaydjieva Luba , Kravariti Eugenia , Lawrie Stephen , Luykx Jurjen J. , Mata Igancio , McDonald Colm , McIntosh Andrew M. , McQuillin Andrew , Muir Rebecca , Ophoff Roel , Picchioni Marco , Prata Diana P. , Ranlund Siri , Rujescu Dan , Rutten Bart P. F. , Schulze Katja , Shaikh Madiha , Schirmbeck Frederike , Simons Claudia J. P. , Toulopoulou Timothea , van Amelsvoort Therese , van Haren Neeltje , van Os Jim , van Winkel Ruud , Vassos Evangelos , Walshe Muriel , Weisbrod Matthias , Zartaloudi Eirini , Bell Vaughan , Powell John , Lewis Cathryn M. , Murray Robin M. , Bramon Elvira
Published: July 2020

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
Suppression of G6PD induces the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin to block epithelial-mesenchymal transition and lymphatic metastasis
Authors: Wang Yifei , Li Qingxiang , Niu Lixuan , Xu Le , Guo Yuxing , Wang Lin , Guo Chuanbin
Published: July 2020

Background

As the rate-limit enzyme of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD) plays important roles in tumour progression, but the exact mechanism through which G6PD controls cancer metastasis remains unclear.

Methods

G6PD expression in resected oral squamous cell carcinoma (OSCC) samples was analysed by immunohistochemistry. The effects and mechanism of G6PD suppression on OSCC cell lines were measured by transwell assay, wound healing assay, western and lectin blot, mass spectrometer analysis, ChIP-PCR, and luciferase reporter assay. BALB/c-nude mice were used to establish orthotopic xenograft model.

Results

G6PD expression in the tumours of 105 OSCC patients was associated with lymphatic metastasis and prognosis. In vitro cellular study suggested that G6PD suppression impaired cell migration, invasion, and epithelial-mesenchymal transition. Furtherly, G6PD knockdown activated the JNK pathway, which then blocked the AKT/GSK-3β/Snail axis to induce E-Cadherin expression and transcriptionally regulated MGAT3 expression to promote bisecting GlcNAc-branched N-glycosylation of E-Cadherin. An orthotopic xenograft model further confirmed that dehydroepiandrosterone reduced lymphatic metastatic rate of OSCC, which was partially reversed by JNK inhibition.

Conclusions

Suppression of G6PD promoted the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin via activating the JNK pathway, which thus acted on OSCC metastasis.
SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages
Authors: Campbell Grant R. , To Rachel K. , Zhang Gang , Spector Stephen A.
Published: July 2020

Human immunodeficiency type 1 (HIV)-infected macrophages (HIV-Mφ) are a reservoir for latent HIV infection and a barrier to HIV eradication. In contrast to CD4+ T cells, HIV-Mφ are resistant to the cytopathic effects of acute HIV infection and have increased expression of cell survival factors, including X-linked inhibitor of apoptosis (XIAP), baculoviral IAP repeat containing (BIRC) 2/cIAP1, beclin-1, BCL2, BCL-xl, triggering receptor expressed on myeloid cells 1, mitofusin (MFN) 1, and MFN2. DIABLO/SMAC mimetics are therapeutic agents that affect cancer cell survival and induce cell death. We found that DIABLO/SMAC mimetics (LCL-161, AT-406 (also known as SM-406 or Debio 1143), and birinapant) selectively kill HIV-Mφ without increasing bystander cell death. DIABLO/SMAC mimetic treatment of HIV-Mφ-induced XIAP and BIRC2 degradation, leading to the induction of autophagy and the formation of a death-inducing signaling complex on phagophore membranes that includes both pro-apoptotic or necroptotic (FADD, receptor-interacting protein kinase (RIPK) 1, RIPK3, caspase 8, and MLKL) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacologic inhibition of early stages of autophagy, but not late stages of autophagy, ablated this interaction and inhibited apoptosis. Furthermore, DIABLO/SMAC mimetic-mediated apoptosis of HIV-Mφ is dependent upon tumor necrosis factor signaling. Our findings thus demonstrate that DIABLO/SMAC mimetics selectively induce autophagy-dependent apoptosis in HIV-Mφ.
Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer
Authors: Qi Jianjun , Zhou Ningning , Li Liyi , Mo Shouyong , Zhou Yidan , Deng Yao , Chen Ting , Shan Changliang , Chen Qin , Lu Bin
Published: July 2020

Ciclopirox (CPX) modulates multiple cellular pathways involved in the growth of a variety of tumor cell types. However, the effects of CPX on colorectal cancer (CRC) and the underlying mechanisms for its antitumor activity remain unclear. Herein, we report that CPX exhibited strong antitumorigenic properties in CRC by inducing cell cycle arrest, repressing cell migration, and invasion by affecting N-cadherin, Snail, E-cadherin, MMP-2, and MMP-9 expression, and disruption of cellular bioenergetics contributed to CPX-associated inhibition of cell growth, migration, and invasion. Interestingly, CPX-induced reactive oxygen species (ROS) production and impaired mitochondrial respiration, whereas the capacity of glycolysis was increased. CPX (20 mg/kg, intraperitoneally) substantially inhibited CRC xenograft growth in vivo. Mechanistic studies revealed that the antitumor activity of CPX relies on apoptosis induced by ROS-mediated endoplasmic reticulum (ER) stress in both 5-FU-sensitive and -resistant CRC cells. Our data reveal a novel mechanism for CPX through the disruption of cellular bioenergetics and activating protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent ER stress to drive cell death and overcome drug resistance in CRC, indicating that CPX could potentially be a novel chemotherapeutic for the treatment of CRC.
Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer
Authors: Lin Yung-Wei , Wen Yu-Ching , Chu Chih-Ying , Tung Min-Che , Yang Yi-Chieh , Hua Kuo-Tai , Pan Ke-Fan , Hsiao Michael , Lee Wei-Jiunn , Chien Ming-Hsien
Published: July 2020

N-α-Acetyltransferase 10 protein (Naa10p) was reported to be an oncoprotein in androgen-dependent prostate cancer (PCa; ADPC) through binding and increasing transcriptional activity of the androgen receptor (AR). PCa usually progresses from an androgen-dependent to an androgen-independent stage, leading to an increase in the metastatic potential and an incurable malignancy. At present, the role of Naa10p in androgen-independent prostate cancer (AIPC) remains unclear. In this study, in silico and immunohistochemistry analyses showed that Naa10 transcripts or the Naa10p protein were more highly expressed in primary and metastatic PCa cancer tissues compared to adjacent normal tissues and non-metastatic cancer tissues, respectively. Knockdown and overexpression of Naa10p in AIPC cells (DU145 and PC-3M), respectively, led to decreased and increased cell clonogenic and invasive abilities in vitro as well as tumor growth and metastasis in AIPC xenografts. From the protease array screening, we identified a disintegrin and metalloprotease 9 (ADAM9) as a potential target of Naa10p, which was responsible for the Naa10p-induced invasion of AIPC cells. Naa10p can form a complex with ADAM9 to maintain ADAM9 protein stability and promote AIPC’s invasive ability which were independent of its acetyltransferase activity. In contrast to the Naa10p-ADAM9 axis, ADAM9 exerted positive feedback regulation on Naa10p to modulate progression of AIPC in vitro and in vivo. Taken together, for the first time, our results reveal a novel cross-talk between Naa10p and ADAM9 in regulating the progression of AIPC. Disruption of Naa10p–ADAM9 interactions may be a potential intervention for AIPC therapy.
High-dimensional single-cell analysis delineates radiofrequency ablation induced immune microenvironmental remodeling in pancreatic cancer
Authors: Fei Qinglin , Pan Yu , Lin Wenji , Zhou Yuanyuan , Yu Xingxing , Hou Zelin , Yu Xunbin , Lin Xianchao , Lin Ronggui , Lu Fengchun , Guan Hongdan , Huang Heguang
Published: July 2020

Radiofrequency ablation (RFA) is an effective local therapy approach for treating solitary tumor of many types of malignancy. The impact of RFA on the tumor immune microenvironment on distant tumors after RFA treatment is still unclear. In this study, by using syngeneic tumor models and single-cell RNA and T-cell receptor sequencing, we have investigated the alterations of tumor-infiltrating immune cells in distant non-RFA tumors. Single-cell RNA sequencing identified six distinct lymphoid clusters, five distinct monocyte/macrophage clusters, three dendritic cells clusters, and one cluster of neutrophils. We found that RFA treatment reduced the proportions of immunosuppressive cells including regulatory T cells, tumor-associated macrophages and tumor-associated neutrophils, whereas increased the percentages of functional T cells in distant non-RFA tumors. Moreover, RFA treatment also altered gene expressions in single-cell level in each cell cluster. By using pseudo-time analysis, we have described the biological processes of tumor-infiltrating CD8+ T cells and monocytes/macrophages based on the transcriptional profiles. In addition, the immune checkpoints including PD-1 and LAG3 were upregulated in the T cells in distant non-RFA tumors after RFA treatment. In conclusion, our data indicate that RFA treatment induced remodeling of tumor immune microenvironment in distant non-RFA tumors in pancreatic cancer mouse model and suggest that combining RFA with immune checkpoint inhibitors may be an effective treatment approach.
MiR-3622a-3p acts as a tumor suppressor in colorectal cancer by reducing stemness features and EMT through targeting spalt-like transcription factor 4
Authors: Chang Shuchen , Sun Guangli , Zhang Dan , Li Qing , Qian Haihua
Published: July 2020

MicroRNAs are a class of small non-coding RNAs which act as oncogenes or tumor suppressors through targeting specific mRNAs. Colorectal cancer (CRC) is one of the most common malignancies worldwide. MiR-3622a-3p is found to be decreased in colorectal cancer (CRC) by analyzing data from TCGA database and there are few reports about the role of miR-3622a-3p in cancers. Our research aimed to explore the effects of miR-3622a-3p on CRC. MiR-3622a-3p was found to be down-regulated in CRC tissues and cells by qRT-PCR. The effect of miR-3622a-3p on proliferation, apoptosis, cell cycle, migration and invasion of CRC cells were investigated by a serious of biological function assays and the results revealed that miR-3622a-3p could inhibit the malignant biological properties of CRC. We performed dual luciferase assay, RNA immunoprecipitation (RIP) assay and pull-down assay to confirm the interaction between miR-3622a-3p and spalt-like transcription factor 4 (SALL4). Western blot was carried out to determine the effects of miR-3622a-3p and SALL4 on stemness features and EMT. We found that miR-3622a-3p suppressed stemness features and EMT of CRC cells by SALL4 mRNA degradation. MiR-3622a-3p could inhibit CRC cell proliferation and metastasis in vivo with tumor xenograft model and in vivo metastasis model. The CRC organoid model was constructed with fresh CRC tissues and the growth of organoids was suppressed by miR-3622a-3p. Taken together, the results of our study indicate miR-3622a-3p exerts antioncogenic role in CRC by downregulation of SALL4. The research on miR-3622a-3p might provide a new insight into treatment of CRC.
LIF is essential for ISC function and protects against radiation-induced gastrointestinal syndrome
Authors: Wang Huaying , Wang Jianming , Zhao Yuhan , Zhang Xiao , Liu Juan , Zhang Cen , Haffty Bruce , Verzi Michael , Zhang Lanjing , Gao Nan , Feng Zhaohui , Hu Wenwei
Published: July 2020

Leukemia inhibitory factor (LIF) is a cytokine essential for maintaining pluripotency of mouse embryonic stem cells. However, its role in adult intestinal stem cells (ISCs) is unclear. The adult intestinal epithelium has a high self-renewal rate driven by ISCs in crypts. Here, we find that LIF is present in the ISC niche in crypts and critical for the function of ISCs in maintaining the intestinal epithelial homeostasis and regeneration. Mechanistically, LIF maintains β-catenin activity through the AKT/GSK3β signaling to regulate ISC functions. LIF deficiency in mice impairs the renewal of the intestinal epithelium under the physiological condition. Further, LIF deficiency in mice impairs the regeneration of intestinal epithelium in response to radiation and shortens the lifespan of mice after high doses of radiation due to gastrointestinal (GI) syndrome, which can be rescued by administering recombinant LIF (rLIF). Importantly, LIF exhibits a radioprotective role in wild-type (WT) mice by protecting mice from lethal radiation-induced GI syndrome; administering rLIF promotes intestinal epithelial regeneration and prolongs survival in WT mice after radiation. These results reveal a previously unidentified and a crucial role of LIF in ensuring ISC function, promoting regeneration of the intestinal epithelium in response to radiation and protecting against radiation-induced GI syndrome.
Association of lncRNA SH3PXD2A-AS1 with preeclampsia and its function in invasion and migration of placental trophoblast cells
Authors: Chen Qian , Jiang Sijia , Liu Haihua , Gao Yue , Yang Xiaoxue , Ren Zhonglu , Gao Yunfei , Xiao Lu , Hu Haoyue , Yu Yanhong , Yang Xinping , Zhong Mei
Published: July 2020

Accumulating evidence suggests that the pathogenesis of preeclampsia involves poor placentation caused by insufficient trophoblast invasion and impaired uterine spiral artery remodeling, yet the underlying molecular mechanism remains unclear. We carried out transcriptome profiling on placentae from preeclamptic patients and normal subjects, and identified about four hundred long non-coding RNAs differentially expressed in placentae of patients with early-onset severe preeclampsia. Here, we report our identification of lncRNA SH3PXD2A-AS1 as a potential causal factor for this disease and its downstream pathways involved in placentation. We found that expression level of SH3PXD2A-AS1 in the placentae is positively correlated with clinical severity of the patients. We demonstrated that SH3PXD2A-AS1 inhibited invasion and migration through recruiting CCCTC-binding factor (CTCF) to the promoters of SH3PXD2A and CCR7 to inhibit their transcription. Therefore, we conclude that the upregulation of lncRNA SH3PXD2A-AS1 may contribute to the pathogenesis of preeclampsia through prohibiting trophoblast invasion during placentation.
Bioactive DNA from extracellular vesicles and particles
Authors: Malkin Ethan Z. , Bratman Scott V.
Published: July 2020

Extracellular vesicles (EVs) and particles (EPs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication. While most investigations have focused exclusively on the protein, lipid and RNA constituents of these extracellular entities, EV/EP DNA remains poorly understood, despite DNA being found in association with virtually all EV/EP populations. The functional potential of EV/EP DNA has been proposed in a number of pathological states, including malignancies and autoimmune diseases. Moreover, the effectiveness of cell-free DNA as the biomarker of choice in emerging liquid biopsy applications highlights the role that EV/EP DNA may play as a novel disease biomarker. In this review, we provide a comprehensive overview of EV/EP DNA studies conducted to date, with a particular focus on the roles of EV/EP DNA as a functional mediator and molecular biomarker in various pathologic states. We also review what is currently known about the origins, structure, localisation and distribution of EV/EP DNA, highlighting current controversies as well as opportunities for future investigation.
Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition
Authors: Makino Elena , Fröhlich Lisa Marie , Sinnberg Tobias , Kosnopfel Corinna , Sauer Birgit , Garbe Claus , Schittek Birgit
Published: July 2020

Rad51 is an essential factor of the homologous recombination DNA repair pathway and therefore plays an important role in maintaining genomic stability. We show that RAD51 and other homologous recombination repair genes are overexpressed in metastatic melanoma cell lines and in melanoma patient samples, which correlates with reduced survival of melanoma patients. In addition, Rad51 expression in melanoma cells was regulated on a transcriptional level by the MAPK signaling pathway with Elk1 as the main downstream transcriptional effector. Most strikingly, melanoma cells which developed resistance towards MAPK inhibitors could be efficiently targeted by Rad51 inhibitors similar to their sensitive counterparts, leading to DNA damage, G2/M arrest and apoptosis. Furthermore, the treatment of MAPK inhibitor resistant cells with Rad51 inhibitors enhances the susceptibility of these cells for MAPK inhibitor treatment in vitro and in vivo. These data indicate that Rad51 plays a critical role in the survival of metastatic melanoma cells and is a promising target for the therapy of melanoma irrespective of its MAPK inhibitor resistance status.
TEX15 is an essential executor of MIWI2-directed transposon DNA methylation and silencing
Authors: Schöpp Theresa , Zoch Ansgar , Berrens Rebecca V. , Auchynnikava Tania , Kabayama Yuka , Vasiliauskaitė Lina , Rappsilber Juri , Allshire Robin C. , O’Carroll Dónal
Published: July 2020

The PIWI protein MIWI2 and its associated PIWI-interacting RNAs (piRNAs) instruct DNA methylation of young active transposable elements (TEs) in the male germline. piRNAs are proposed to recruit MIWI2 to the transcriptionally active TE loci by base pairing to nascent transcripts, however the downstream mechanisms and effector proteins utilized by MIWI2 in directing de novo TE methylation remain incompletely understood. Here, we show that MIWI2 associates with TEX15 in foetal gonocytes. TEX15 is predominantly a nuclear protein that is not required for piRNA biogenesis but is essential for piRNA-directed TE de novo methylation and silencing. In summary, TEX15 is an essential executor of mammalian piRNA-directed DNA methylation.
Tracing animal genomic evolution with the chromosomal-level assembly of the freshwater sponge Ephydatia muelleri
Authors: Kenny Nathan J. , Francis Warren R. , Rivera-Vicéns Ramón E. , Juravel Ksenia , de Mendoza Alex , Díez-Vives Cristina , Lister Ryan , Bezares-Calderón Luis A. , Grombacher Lauren , Roller Maša , Barlow Lael D. , Camilli Sara , Ryan Joseph F. , Wörheide Gert , Hill April L. , Riesgo Ana , Leys Sally P.
Published: July 2020

The genomes of non-bilaterian metazoans are key to understanding the molecular basis of early animal evolution. However, a full comprehension of how animal-specific traits, such as nervous systems, arose is hindered by the scarcity and fragmented nature of genomes from key taxa, such as Porifera. Ephydatia muelleri is a freshwater sponge found across the northern hemisphere. Here, we present its 326 Mb genome, assembled to high contiguity (N50: 9.88 Mb) with 23 chromosomes on 24 scaffolds. Our analyses reveal a metazoan-typical genome architecture, with highly shared synteny across Metazoa, and suggest that adaptation to the extreme temperatures and conditions found in freshwater often involves gene duplication. The pancontinental distribution and ready laboratory culture of E. muelleri make this a highly practical model system which, with RNAseq, DNA methylation and bacterial amplicon data spanning its development and range, allows exploration of genomic changes both within sponges and in early animal evolution.
Molecular determinants for dsDNA translocation by the transcription-repair coupling and evolvability factor Mfd
Authors: Brugger Christiane , Zhang Cheng , Suhanovsky Margaret M. , Kim David D. , Sinclair Amy N. , Lyumkis Dmitry , Deaconescu Alexandra M.
Published: July 2020

Mfd couples transcription to nucleotide excision repair, and acts on RNA polymerases when elongation is impeded. Depending on impediment severity, this action results in either transcription termination or elongation rescue, which rely on ATP-dependent Mfd translocation on DNA. Due to its role in antibiotic resistance, Mfd is also emerging as a prime target for developing anti-evolution drugs. Here we report the structure of DNA-bound Mfd, which reveals large DNA-induced structural changes that are linked to the active site via ATPase motif VI. These changes relieve autoinhibitory contacts between the N- and C-termini and unmask UvrA recognition determinants. We also demonstrate that translocation relies on a threonine in motif Ic, widely conserved in translocases, and a family-specific histidine near motif IVa, reminiscent of the “arginine clamp” of RNA helicases. Thus, Mfd employs a mode of DNA recognition that at its core is common to ss/ds translocases that act on DNA or RNA.
Molecular engineering of safe and efficacious oral basal insulin
Authors: Hubálek Frantisek , Refsgaard Hanne H. F. , Gram-Nielsen Sanne , Madsen Peter , Nishimura Erica , Münzel Martin , Brand Christian Lehn , Stidsen Carsten Enggaard , Claussen Christian Hove , Wulff Erik Max , Pridal Lone , Ribel Ulla , Kildegaard Jonas , Porsgaard Trine , Johansson Eva , Steensgaard Dorte Bjerre , Hovgaard Lars , Glendorf Tine , Hansen Bo Falck , Jensen Maja Kirkegaard , Nielsen Peter Kresten , Ludvigsen Svend , Rugh Susanne , Garibay Patrick W. , Moore Mary Courtney , Cherrington Alan D. , Kjeldsen Thomas
Published: July 2020

Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.
Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model
Authors: Guttenplan Kevin A. , Weigel Maya K. , Adler Drew I. , Couthouis Julien , Liddelow Shane A. , Gitler Aaron D. , Barres Ben A.
Published: July 2020

Reactive astrocytes have been implicated in the pathogenesis of neurodegenerative diseases, including a non-cell autonomous effect on motor neuron survival in ALS. We previously defined a mechanism by which microglia release three factors, IL-1α, TNFα, and C1q, to induce neurotoxic astrocytes. Here we report that knocking out these three factors markedly extends survival in the SOD1G93A ALS mouse model, providing evidence for gliosis as a potential ALS therapeutic target.