bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression Anxiety Stress Scale-10: A Brief Measure for Routine Psychotherapy Outcome and Progress Assessment
Authors: Kim Halford W. , Frost Aaron D.J.
Published: August 2021

Routine outcome measurement and progress monitoring is well established to enhance quality assurance in clinical psychology service delivery but is not widely used in routine care. A major barrier to more widespread implementation is the lack of public domain, brief, psychometrically sound outcome measures that easily integrate into clinical information systems. The current study assessed a brief 10-item version of the widely used Depression Anxiety Stress (DASS)-42 scale, which we called the Depression Anxiety Stress-10 (DASS-10) scale. In two clinical samples of adults (n= 1036, 445 men, 591 women; andn= 1084, 493 men, 591 women), the DASS-10 had a replicable two-level factor structure, which at the lower level had two factors assessing stress-anxiety and depression, which each loaded onto a superordinate psychological distress scale. The items in the distress score discriminated between a clinical sample (n= 376) and a community sample (n= 379) and were sensitive to clinical change. The measure has the potential to make routine outcome measurement and progress monitoring more cost-effective to implement than existing measures, particularly when integrated with practice management software to make administration, scoring, and use easy.
Pediatric surgical site infection (SSI) following ambulatory surgery: Incidence, risk factors and patient outcomes
Authors: Rinke Michael L. , Bundy David G. , Heo Moonseong , Saiman Lisa , Rabin Barbara , Zachariah Philip , Rosenberg Rebecca E. , DeLaMora Patricia , Mirhaji Parsa , Drasher Michael , Klein Elizabeth , Obaro-Best Oghale , Ford William J.H. , Zarowin Diana , Peshansky Alexandre , Oyeku Suzette O.
Published: August 2021

Background:

Inpatient surgical site infections (SSIs) cause morbidity in children. The SSI rate among pediatric ambulatory surgery patients is less clear. To fill this gap, we conducted a multiple-institution, retrospective epidemiologic study to identify incidence, risk factors, and outcomes.

Methods:

We identified patients aged <22 years with ambulatory visits between October 2010 and September 2015 via electronic queries at 3 medical centers. We performed sample chart reviews to confirm ambulatory surgery and adjudicate SSIs. Weighted Poisson incidence rates were calculated. Separately, we used case–control methodology using multivariate backward logistical regression to assess risk-factor association with SSI.

Results:

In total, 65,056 patients were identified by queries, and we performed complete chart reviews for 13,795 patients; we identified 45 SSIs following ambulatory surgery. The weighted SSI incidence following pediatric ambulatory surgery was 2.00 SSI per 1,000 ambulatory surgeries (95% confidence interval [CI], 1.37–3.00). Integumentary surgeries had the highest weighted SSI incidence, 3.24 per 1,000 ambulatory surgeries (95% CI, 0.32–12). The following variables carried significantly increased odds of infection: clean contaminated or contaminated wound class compared to clean (odds ratio [OR], 9.8; 95% CI, 2.0–48), other insurance type compared to private (OR, 4.0; 95% CI, 1.6–9.8), and surgery on weekend day compared to weekday (OR, 30; 95% CI, 2.9–315). Of the 45 instances of SSI following pediatric ambulatory surgery, 40% of patients were admitted to the hospital and 36% required a new operative procedure or bedside incision and drainage.

Conclusions:

Our findings suggest that morbidity is associated with SSI following ambulatory surgery in children, and we also identified possible targets for intervention.
Is there a relationship between dietary sodium and potassium intake and clinical findings of a migraine headache?
Authors: Arab Arman , Khorvash Fariborz , Heidari Zahra , Askari Gholamreza
Published: August 2021

Few studies have assessed the association between sodium (Na) and potassium (K) and migraine headaches. In this study, we aimed to examine the relationship between 24-hour urine Na and K intakes and clinical findings of migraine in an Iranian sample. In this cross-sectional study, 262 participants, aged 20–50 years, were included with a body mass index (BMI) of 18·5–30 kg/m2 and a diagnosis of migraine. One 24-hour urine sample was collected from each subject to estimate the Na and K intakes. The clinical features of migraine, including frequency, duration, severity, Migraine Headache Index Score (MHIS), and Headache Impact Test (HIT) score, were assessed. Besides, a multiple linear regression analysis was performed, and beta estimates and the corresponding 95% confidence intervals (CIs) were reported. Overall, 224 women and 38 men, with a mean age of 36·10 years and BMI of 25·55 kg/m2comprised our study population. After controlling for potential confounders, the 24-hour urine Na was positively associated with a longer headache duration (β= 0·29; 95% CI: 0·06, 0·53) in the group with the highest urine Na levels as compared to the group with the lowest levels. After adjustments for potential confounders, an increase of 13·05 in the MHIS was observed when the 24-hour urine Na level increased from the first to the third tertile (β= 13·05; 95% CI: 1·70, 24·41). Our findings suggested that a higher 24-hour urine Na level was positively associated with a longer duration of migraine headaches and a higher MHIS.
The impact of personality on the risk and survival of breast cancer: a Mendelian randomization analysis
Authors: Ying Li , Chen Songzan , Li Ling , Pan Zhijun
Published: August 2021

Background

It has long been hypothesized that personality plays a causative role in incidence and outcome of breast cancer (BC), but epidemiological evidence of association between personality and BC is inconsistent.

Method

We used two-sample Mendelian randomization analysis to estimate the impact of personality on the risk and survival of BC. In total, 109 single nucleotide polymorphisms (SNPs) were utilized as instruments of neuroticism from a large-scale Genome-Wide Association Studies (GWAS), and five SNPs were utilized as instruments of extraversion from Genetic of Personality Consortium and 23andMe. Genetic association with the risk and survival of overall and individual subtype BC were obtained from the Breast Cancer Association Consortium.

Result

Neuroticism is significantly associated with the risk of overall BC [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.01–1.11; p = 0.015] and the risk of luminal A BC (OR 1.09; 95% CI 1.03–1.16; p = 0.004). Extraversion is not associated with the risk of BC. None of neuroticism or extraversion is associated with the survival of BC.

Conclusion

Neuroticism was associated with a modest increased risk of BC and particularly luminal A BC.
‘The metaphysical objection’ and concurrentist co-operation
Authors: Miller Timothy D.
Published: August 2021

The foundation of W. Matthews Grant's project in Free Will and God's Universal Causality is his Non-Occasionalist version of Divine Universal Causality (NODUC), which affirms the traditional concurrentist idea that God and secondary causes cooperate non-superfluously in such a way that they both produce the entire effect. Grant defends NODUC's concurrentist account by responding to ‘The Metaphysical Objection’, which alleges that concurrentism places an inconsistent set of demands upon secondary causes. I argue that Grant's responses to that objection are unconvincing, and thus, he fails to demonstrate that NODUC is a stable foundation for the rest of his project.
Doubly pointed trisection diagrams and surgery on 2-knots
Authors: GAY DAVID , MEIER JEFFREY
Published: August 2021

We study embedded spheres in 4–manifolds (2–knots) via doubly pointed trisection diagrams, showing that such descriptions are unique up to stabilisation and handleslides, and we describe how to obtain trisection diagrams for certain cut-and-paste operations along 2–knots directly from doubly pointed trisection diagrams. The operations described are classical surgery, Gluck surgery, blowdown, and (±4)–rational blowdown, and we illustrate our techniques and results with many examples.
Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico
Authors: Arce Rentería Miguel , Manly Jennifer J. , Vonk Jet M.J. , Mejia Arango Silvia , Michaels Obregon Alejandra , Samper-Ternent Rafael , Wong Rebeca , Barral Sandra , Tosto Giuseppe
Published: August 2021

Objective:

To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population.

Method:

Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease.

Results:

The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively).

Conclusions:

Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype.
Depressive symptoms among clients attending monk healers and primary care clinics in Thailand: a comparative follow-up study
Authors: Pengpid Supa , Peltzer Karl
Published: August 2021

Background:

The aim of this study was to conduct a comparative follow-up assessment of clients with depressive symptoms attending monk healers or primary care clinics in Thailand.

Methods:

Consecutively attending clients of three monk healing and three primary care centres who screened positive (a score of 9 or more) on the Primary Health Questionnaire (PHQ)-9 at the study site were followed up at 3 months after baseline assessment.

Results:

In 3 monk healer sites, 448 clients agreed to be screened with the PHQ-9 for depression, and 94 screened positive, and in 3 health centres 582 clients agreed to be screened, and 92 screened positive for depressive symptoms on the PHQ-9. In 2 monk healing sites, 79 clients (84%) were followed up at 3 months, and in 3 health centres, 79 clients (85.9%) were followed up at 3 months. At 3-month follow-up, mixed modelling found significant interaction effects (a time-by-condition interaction, i.e., between-group changes) on depression scores (P = <0.001). Depressive symptoms significantly decreased over time, but there was no significant difference in decline between the two groups.

Conclusion:

Clients attending monk healers decreased more in depressive scores compared to clients attending primary care centres, though there was no group effect with respect to number of depressed clients.
The challenges of ethical deliberation in palliative care settings: A descriptive study
Authors: Dumont Serge , Turcotte Véronique , Aubin Michèle , Casimiro Lynn , Lavoie Mireille , Picard Louise
Published: August 2021

Objective

Inadequate deliberation processes about ethical problems occurring in palliative care settings may negatively impact both patients and healthcare professionals. Better knowledge of the palliative care professionals’ practices regarding such processes could help identify specific education needs to improve the quality of palliative care in the context of complex ethical situations. Therefore, this descriptive study aimed to (1) examine ethical deliberation processes in interprofessional teams in five palliative care settings; (2) identify organizational factors that constrain such processes; and (3) based on this knowledge, identify priority education needs for future and current palliative care professionals.

Method

The study involved three data collection activities: (1) direct observation of simulated interprofessional ethical deliberations in various palliative care settings; (2) individual semi-structured interviews; and (3) deliberative dialogues.

Results

Thirty-six healthcare professionals took part in the simulated ethical deliberations and in the deliberative dialogue activities, and 13 were met in an individual interview. The study results revealed suboptimal interprofessional collaboration and ethical deliberation competencies, particularly regarding awareness of the ethical issue under consideration, clarification of conflicting values, reasonable decision making, and implementation planning. Participants also reported facing serious organizational constraints that challenged ethical deliberation processes.

Significance of results

This study confirmed the need for professional education in interprofessional collaboration and ethical deliberation so that palliative care professionals can adequately face current and future ethical challenges. It also enabled the identification of educational priorities in this regard. Future research should focus on identifying promising educational activities, assessing their effectiveness, and measuring their impact on patient and family experience and the quality of palliative care.
Fading Affect Bias in Intergroup Relations
Authors: Birtel Michèle D. , Di Bernardo Gian Antonio , Vezzali Loris
Published: August 2021

Abstract. Negative affect associated with autobiographical events fades faster over time than positive affect. This Fading Affect Bias (FAB) has been established in the individual and interpersonal domains. Two studies tested the FAB in intergroup relations with Muslims ( N= 76 White British non-Muslim) and opposite gender ( N = 242 women and men) as target outgroups. The results indicated that the FAB exists in an intergroup context, for both ingroup and outgroup memories. Mediation analyses showed that intergroup contact is related to a lower fading of positive affect associated with the outgroup memory, through greater memory strength and a more positive outgroup member evaluation. The findings are important for understanding affect associated with intergroup memories and the buffering effect of positive contact.
Modification of Crust and Mantle Lithosphere Beneath the Southern Part of the Eastern North American Passive Margin
Authors: Li Cong , Gao Haiying
Published: August 2021

The eastern North American passive margin was modified by Mesozoic rifting. Seismic data from recent deployment of onshore and offshore stations offer a unique opportunity for studying the signature of syn‐rifting and postrifting in lithospheric structures. Using full‐wave ambient noise tomography, we construct a new seismic velocity model for the lithosphere of the southeastern United States. Our model confirms an oceanic‐continental transitional crust over a ∼70 km wide zone across the coastline. Our model reveals (a) a patch of lower‐than‐average mantle lithospheric velocities underlying this transitional crust and (b) a low‐velocity column in the mantle lithosphere beneath the Virginia volcanoes. We propose that anomaly 1 represents cooled enriched mantle that underplated the thinning crust during the initial stages of rifting around 230 Ma. Anomaly 2 likely has a more recent origin in the Eocene and may result from an asthenospheric upwelling induced by a localized lithospheric delamination.
Refinement of Mean Dynamic Topography Over Island Areas Using Airborne Gravimetry and Satellite Altimetry Data in the Northwestern South China Sea
Authors: Wu Yihao , Abulaitijiang Adili , Andersen Ole Baltazar , He Xiufeng , Luo Zhicai , Wang Haihong
Published: August 2021

The determination of high‐quality mean dynamic topography (MDT) over island areas faces multiple challenges, due to the error in a global geopotential model (GGM) as well as the contaminated waveforms of satellite altimetry data and scarcity of surveyed gravimetric observations. We study the potential to enhance regional quasi‐geoid/MDT over island areas by using recently released satellite altimetric gravity data and airborne gravimetric observations. Numerical experiments over the Paracel Islands in the northwestern South China Sea show that the combination of airborne gravity data enhances the local gravity field, and reduces the errors in the associated quasi‐geoid, in comparison to the result directly derived from a GGM. The results demonstrate that the direct application of a GGM may cause significant oscillations in MDT determination over island areas, by a magnitude exceeding 6 cm. The incorporation of altimetric gravity data slightly reduces these errors; however, the bubble‐like errors are prominent, suggesting that altimetry data alone may be insufficient for high‐accuracy MDT recovery. In contrast, combining airborne gravity data dramatically reduces these oscillations, by a magnitude of several centimeters, indicating that airborne gravimetric surveys may be necessary for MDT determination with centimeter‐level accuracy over coastal/island areas. Further comparison with independent ocean data shows that the geostrophic velocities computed by merging a high‐degree GGM and local airborne gravity data can reconstruct real surface ocean circulation; and the GOCE‐based (Gravity Field and Steady‐State Ocean Circulation Explorer) GGMs may be preferable as the reference models in MDT determination.
A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review
Authors: Zhang Jia , Shen Yajun , Yang Zuozhen , Yang Fan , Li Yang , Yu Bo , Chen Wanlin , Gan Jing
Published: August 2021

NPRL2 (nitrogen permease regulator like 2) is a component of the GATOR1(GAP activity towards rags complex 1) proteins, which is an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). However, FFEVF caused byNPRL2variants has not been widely explored. Here, we describe a variant, 339+2T>C, inNPRL2identified by trio whole-exome sequencing (WES) in a family. This splicing variant that occurred at the 5′ end of exon 3 was confirmed by minigene assays, which affected alternative splicing and led to exon 3 skipping inNPRL2. Our cases presented multiple seizure types (febrile seizures, infantile spasms, focal seizures, or focal to generalized tonic-clonic seizures). Electroencephalogram (EEG) showed frequent discharges in the left frontal and central regions. A favorable prognosis was achieved in response to vitamin B6 and topiramate when the patient was seven months old. Our study expands the phenotype and genotype spectrum of FFEVF and provides solid diagnostic evidence for FFEVF.
Methyltransferase like 13 mediates the translation of Snail in head and neck squamous cell carcinoma
Authors: Wang Xiaochen , Li Kang , Wan Yuehan , Chen Fangfang , Cheng Maosheng , Xiong Gan , Wang Ganping , Chen Shuang , Chen Zhi , Chen Jianwen , Xu Xiuyun , Wang Cheng , Peng Liang , Chen Demeng
Published: August 2021

Methyltransferase like 13 (METTL13), a kind of methyltransferase, is implicated in protein binding and synthesis. The upregulation of METTL13 has been reported in a variety of tumors. However, little was known about its potential function in head and neck squamous cell carcinoma (HNSCC) so far. In this study, we found that METTL13 was significantly upregulated in HNSCC at both mRNA and protein level. Increased METTL13 was negatively associated with clinical prognosis. And METTL13 markedly affected HNSCC cellular phenotypes in vivo and vitro. Further mechanism study revealed that METTL13 could regulate EMT signaling pathway by mediating enhancing translation efficiency of Snail, the key transcription factor in EMT, hence regulating the progression of EMT. Furthermore, Snail was verified to mediate METTL13-induced HNSCC cell malignant phenotypes. Altogether, our study had revealed the oncogenic role of METTL13 in HNSCC, and provided a potential therapeutic strategy.
Decreased inhibition of exosomal miRNAs on SARS-CoV-2 replication underlies poor outcomes in elderly people and diabetic patients
Authors: Wang Yanbo , Zhu Xiaoju , Jiang Xia-Ming , Guo Jingwei , Fu Zheng , Zhou Zhen , Yang Ping , Guo Hongyuan , Guo Xu , Liang Gaoli , Zeng Ping , Xiao Gengfu , Ma Jizheng , Yin Xin , Zhang Lei-Ke , Yan Chao , Zhang Chen-Yu
Published: August 2021

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks’ continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.
Fusion genes in gynecologic tumors: the occurrence, molecular mechanism and prospect for therapy
Authors: Lu Bingfeng , Jiang Ruqi , Xie Bumin , Wu Wu , Zhao Yang
Published: August 2021

Gene fusions are thought to be driver mutations in multiple cancers and are an important factor for poor patient prognosis. Most of them appear in specific cancers, thus satisfactory strategies can be developed for the precise treatment of these types of cancer. Currently, there are few targeted drugs to treat gynecologic tumors, and patients with gynecologic cancer often have a poor prognosis because of tumor progression or recurrence. With the application of massively parallel sequencing, a large number of fusion genes have been discovered in gynecologic tumors, and some fusions have been confirmed to be involved in the biological process of tumor progression. To this end, the present article reviews the current research status of all confirmed fusion genes in gynecologic tumors, including their rearrangement mechanism and frequency in ovarian cancer, endometrial cancer, endometrial stromal sarcoma, and other types of uterine tumors. We also describe the mechanisms by which fusion genes are generated and their oncogenic mechanism. Finally, we discuss the prospect of fusion genes as therapeutic targets in gynecologic tumors.
Human umbilical cord mesenchymal stem cells-derived extracellular vesicles facilitate the repair of spinal cord injury via the miR-29b-3p/PTEN/Akt/mTOR axis
Authors: Xiao Xiao , Li Weiwei , Rong Dingchao , Xu Zhenchao , Zhang Zhen , Ye Hongru , Xie Liqiong , Wu Yunqi , Zhang Yilu , Wang Xiyang
Published: August 2021

Spinal cord injury (SCI) is a salient traumatic disease that often leads to permanent disability, and motor and sensory impairments. Human umbilical cord mesenchymal stem cells (HucMSCs) have a wide application prospect in the treatment of SCI. This study explored the repair effect of HucMSCs-derived extracellular vesicles (HucMSCs-EVs) on SCI. HucMSCs and HucMSCs-EVs were cultured and identified. The rat model of SCI was established, and SCI rats were treated with HucMSCs-EVs. The motor function of SCI rats and morphology of spinal cord tissues were evaluated. Levels of NeuN, GFAP, and NF200 in spinal cord tissues were detected and cell apoptosis was measured. SCI rats were treated with EVs extracted from miR-29b-3p inhibitor-transfected HucMSCs. The downstream gene and pathway of miR-29b-3p were examined. HucMSCs-EVs-treated rats showed obvious motor function recovery and reduced necrosis, nuclear pyknosis, and cavity. HucMSCs-EVs alleviated spinal cord neuronal injury. miR-29b-3p was poorly expressed in SCI tissues, but highly expressed in EVs and SCI rats treated with EVs. miR-29b-3p targeted PTEN. Inhibition of miR-29b-3p or overexpression of PTEN reversed the repair effect of EVs on SCI. EVs activated the AKT/mTOR pathway via the miR-29b-3p/PTEN. In conclusion, HucMSCs-EVs reduced pathological changes, improved motor function, and promoted nerve function repair in SCI rats via the miR-29b-3p/PTEN/Akt/mTOR axis.
Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis
Authors: Liu Yan , Chen Qiuyun , Zhu Yanan , Wang Tiying , Ye Lijuan , Han Lei , Yao Zhihong , Yang Zuozhang
Published: August 2021

Distant metastasis is the main cause of death for cancer patients. Recently, the newly discovered programmed cell death includes necroptosis, pyroptosis, and ferroptosis, which possesses an important role in the process of tumor metastasis. At the same time, it is widely reported that non-coding RNA precisely regulates programmed death and tumor metastasis. In the present review, we summarize the function and role of necroptosis, pyrolysis, and ferroptosis involving in cancer metastasis, as well as the regulatory factors, including non-coding RNAs, of necroptosis, pyroptosis, and ferroptosis in the process of tumor metastasis.
GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis
Authors: Kremer Daniel M. , Nelson Barbara S. , Lin Lin , Yarosz Emily L. , Halbrook Christopher J. , Kerk Samuel A. , Sajjakulnukit Peter , Myers Amy , Thurston Galloway , Hou Sean W. , Carpenter Eileen S. , Andren Anthony C. , Nwosu Zeribe C. , Cusmano Nicholas , Wisner Stephanie , Mbah Nneka E. , Shan Mengrou , Das Nupur K. , Magnuson Brian , Little Andrew C. , Savani Milan R. , Ramos Johanna , Gao Tina , Sastra Stephen A. , Palermo Carmine F. , Badgley Michael A. , Zhang Li , Asara John M. , McBrayer Samuel K. , di Magliano Marina Pasca , Crawford Howard C. , Shah Yatrik M. , Olive Kenneth P. , Lyssiotis Costas A.
Published: August 2021

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.
Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation
Authors: Tan Xiaohong , Tong Lu , Li Lin , Xu Jinjin , Xie Shaofang , Ji Lei , Fu Junjiang , Liu Qingwu , Shen Shihui , Liu Yun , Xiao Yanhui , Gao Feiran , Moses Robb E. , Bardeesy Nabeel , Wang Yanxiao , Zhang Jishuai , Tang Longying , Li Lei , Wong Kwok-kin , Song Dianwen , Yang Xiao , Liu Jian , Li Xiaotao
Published: August 2021

SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3′UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
Dendrimer end-terminal motif-dependent evasion of human complement and complement activation through IgM hitchhiking
Authors: Wu Lin-Ping , Ficker Mario , Christensen Jørn B. , Simberg Dmitri , Trohopoulos Panagiotis N. , Moghimi Seyed M.
Published: August 2021

Complement is an enzymatic humoral pattern-recognition defence system of the body. Non-specific deposition of blood biomolecules on nanomedicines triggers complement activation through the alternative pathway, but complement-triggering mechanisms of nanomaterials with dimensions comparable to or smaller than many globular blood proteins are unknown. Here we study this using a library of <6 nm poly(amido amine) dendrimers bearing different end-terminal functional groups. Dendrimers are not sensed by C1q and mannan-binding lectin, and hence do not trigger complement activation through these pattern-recognition molecules. While, pyrrolidone- and carboxylic acid-terminated dendrimers fully evade complement response, and independent of factor H modulation, binding of amine-terminated dendrimers to a subset of natural IgM glycoforms triggers complement activation through lectin pathway-IgM axis. These findings contribute to mechanistic understanding of complement surveillance of dendrimeric materials, and provide opportunities for dendrimer-driven engineering of complement-safe nanomedicines and medical devices.
Malaria parasites both repress host CXCL10 and use it as a cue for growth acceleration
Authors: Ofir-Birin Yifat , Ben Ami Pilo Hila , Cruz Camacho Abel , Rudik Ariel , Rivkin Anna , Revach Or-Yam , Nir Netta , Block Tamin Tal , Abou Karam Paula , Kiper Edo , Peleg Yoav , Nevo Reinat , Solomon Aryeh , Havkin-Solomon Tal , Rojas Alicia , Rotkopf Ron , Porat Ziv , Avni Dror , Schwartz Eli , Zillinger Thomas , Hartmann Gunther , Di Pizio Antonella , Quashie Neils Ben , Dikstein Rivka , Gerlic Motti , Torrecilhas Ana Claudia , Levy Carmit , Nolte-‘t Hoen Esther N. M. , Bowie Andrew G. , Regev-Rudzki Neta
Published: August 2021

Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf ‘decision-sensing-system’ controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3’UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.
A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis
Authors: Pradella Davide , Deflorian Gianluca , Pezzotta Alex , Di Matteo Anna , Belloni Elisa , Campolungo Daniele , Paradisi Andrea , Bugatti Mattia , Vermi William , Campioni Matteo , Chiapparino Antonella , Scietti Luigi , Forneris Federico , Giampietro Costanza , Volf Nina , Rehman Michael , Zacchigna Serena , Paronetto Maria Paola , Pistocchi Anna , Eichmann Anne , Mehlen Patrick , Ghigna Claudia
Published: August 2021

The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.
Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19
Authors: Nouailles Geraldine , Wyler Emanuel , Pennitz Peter , Postmus Dylan , Vladimirova Daria , Kazmierski Julia , Pott Fabian , Dietert Kristina , Muelleder Michael , Farztdinov Vadim , Obermayer Benedikt , Wienhold Sandra-Maria , Andreotti Sandro , Hoefler Thomas , Sawitzki Birgit , Drosten Christian , Sander Leif E. , Suttorp Norbert , Ralser Markus , Beule Dieter , Gruber Achim D. , Goffinet Christine , Landthaler Markus , Trimpert Jakob , Witzenrath Martin
Published: August 2021

In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.
Clinal genomic analysis reveals strong reproductive isolation across a steep habitat transition in stickleback fish
Authors: Haenel Quiterie , Oke Krista B. , Laurentino Telma G. , Hendry Andrew P. , Berner Daniel
Published: August 2021

How ecological divergence causes strong reproductive isolation between populations in close geographic contact remains poorly understood at the genomic level. We here study this question in a stickleback fish population pair adapted to contiguous, ecologically different lake and stream habitats. Clinal whole-genome sequence data reveal numerous genome regions (nearly) fixed for alternative alleles over a distance of just a few hundred meters. This strong polygenic adaptive divergence must constitute a genome-wide barrier to gene flow because a steep cline in allele frequencies is observed across the entire genome, and because the cline center closely matches the habitat transition. Simulations confirm that such strong divergence can be maintained by polygenic selection despite high dispersal and small per-locus selection coefficients. Finally, comparing samples from near the habitat transition before and after an unusual ecological perturbation demonstrates the fragility of the balance between gene flow and selection. Overall, our study highlights the efficacy of divergent selection in maintaining reproductive isolation without physical isolation, and the analytical power of studying speciation at a fine eco-geographic and genomic scale.
The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Authors: Yuste-Checa Patricia , Trinkaus Victoria A. , Riera-Tur Irene , Imamoglu Rahmi , Schaller Theresa F. , Wang Huping , Dudanova Irina , Hipp Mark S. , Bracher Andreas , Hartl F. Ulrich
Published: August 2021

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.
High efficiency blue organic light-emitting diodes with below-bandgap electroluminescence
Authors: Vasilopoulou Maria , Mohd Yusoff Abd. Rashid bin , Daboczi Matyas , Conforto Julio , Gavim Anderson Emanuel Ximim , da Silva Wilson Jose , Macedo Andreia Gerniski , Soultati Anastasia , Pistolis George , Schneider Fabio Kurt , Dong Yifan , Jacoutot Polina , Rotas Georgios , Jang Jin , Vougioukalakis Georgios C. , Chochos Christos L. , Kim Ji-Seon , Gasparini Nicola
Published: August 2021

Blue organic light-emitting diodes require high triplet interlayer materials, which induce large energetic barriers at the interfaces resulting in high device voltages and reduced efficiencies. Here, we alleviate this issue by designing a low triplet energy hole transporting interlayer with high mobility, combined with an interface exciplex that confines excitons at the emissive layer/electron transporting material interface. As a result, blue thermally activated delay fluorescent organic light-emitting diodes with a below-bandgap turn-on voltage of 2.5 V and an external quantum efficiency (EQE) of 41.2% were successfully fabricated. These devices also showed suppressed efficiency roll-off maintaining an EQE of 34.8% at 1000 cd m−2. Our approach paves the way for further progress through exploring alternative device engineering approaches instead of only focusing on the demanding synthesis of organic compounds with complex structures.
Global variation in the fraction of leaf nitrogen allocated to photosynthesis
Authors: Luo Xiangzhong , Keenan Trevor F. , Chen Jing M. , Croft Holly , Colin Prentice I. , Smith Nicholas G. , Walker Anthony P. , Wang Han , Wang Rong , Xu Chonggang , Zhang Yao
Published: August 2021

Plants invest a considerable amount of leaf nitrogen in the photosynthetic enzyme ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO), forming a strong coupling of nitrogen and photosynthetic capacity. Variability in the nitrogen-photosynthesis relationship indicates different nitrogen use strategies of plants (i.e., the fraction nitrogen allocated to RuBisCO; fLNR), however, the reason for this remains unclear as widely different nitrogen use strategies are adopted in photosynthesis models. Here, we use a comprehensive database of in situ observations, a remote sensing product of leaf chlorophyll and ancillary climate and soil data, to examine the global distribution in fLNR using a random forest model. We find global fLNR is 18.2 ± 6.2%, with its variation largely driven by negative dependence on leaf mass per area and positive dependence on leaf phosphorus. Some climate and soil factors (i.e., light, atmospheric dryness, soil pH, and sand) have considerable positive influences on fLNR regionally. This study provides insight into the nitrogen-photosynthesis relationship of plants globally and an improved understanding of the global distribution of photosynthetic potential.
Periodically modulated skyrmion strings in Cu2OSeO3
Authors: Burn D. M. , Brearton R. , Ran K. J. , Zhang S. L. , van der Laan G. , Hesjedal T.
Published: August 2021

Magnetic skyrmions are vortex-like spin textures, which are usually treated as two-dimensional objects. In their lattice state, they form well-ordered, hexagonal structures, which have been studied in great detail. To obtain a three-dimensional (3D) skyrmion crystal, these planes can be envisaged to be stacked up forming skyrmion strings in the third dimension. Here, we report the observation of a 3D skyrmion phase in Cu2OSeO3 by carrying out reciprocal space mapping in resonant elastic x-ray scattering. We observe regions in the magnetic field-cooling phase diagram in which the skyrmion phase apparently coexists with the conical phase. However, such a coexistence is forbidden due to symmetry arguments. Instead, the skyrmion strings themselves are periodically modulated along their axes, as confirmed by micromagnetic simulations. The periodic modulation is in fact a necessary consequence of the evolution of the skyrmion phase out of the conical state and should therefore be a universal property of skyrmion strings in chiral helimagnets.
Benefit of COVID-19 vaccination accounting for potential risk compensation
Authors: Ioannidis John P. A.
Published: August 2021

People receiving COVID-19 vaccines may subsequently markedly increase their previously suppressed exposure risk. A simple model can evaluate the benefit of vaccination to the vaccinated (index) person and others exposed to that person; and calculate the amount of risk compensation required to eliminate all the benefits or to halve the benefit. As shown, 2.5-fold increase in exposure will eliminate the benefit of a vaccine of moderate efficacy (E = 0.6) unless the probability of infection in the population of interest is very high. With very high vaccine efficacy (E = 0.95), substantial benefit is maintained except in situations where there is a very low probability of infection in the population. If the vaccine efficacy decreases to 0.8, the benefit gets eroded easily with modest risk compensation. Risk compensation may markedly affect the benefit of COVID-19 vaccination, especially if vaccine efficacy in real-life or specific high-risk populations (e.g., nursing home residents) is not very high.
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis
Authors: Kabinger Florian , Stiller Carina , Schmitzová Jana , Dienemann Christian , Kokic Goran , Hillen Hauke S. , Höbartner Claudia , Cramer Patrick
Published: August 2021

Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β-d-N4-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp–RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.
Numerical study on the influence of wall temperature gradient on aerodynamic characteristics of low aspect ratio flying wing configuration
Authors: Lin Peng , Liu Xueqiang , Xiong Neng , Wang Xiaobing , Shang Ma , Liu Guangyuan , Tao Yang
Published: August 2021

With the aim for a low-aspect-ratio flying wing configuration, this study explores the influence of wall temperature gradient on the laminar and turbulent boundary layers of aircraft surface and determines the effect on the transition Reynolds number and wall friction drag. A four-equation turbulence model with transition mode is used to numerically simulate the flow around the model. The variation of wall friction coefficient, transition Reynolds number, and turbulent boundary layer flow with wall temperature are emphatically investigated. Results show that when the wall temperature increases from 288 to 500 K, the boundary layer transition Reynolds number for the wing section increased by approximately 28% and the surface friction drags decreases by approximately 10.7%. The hot wall enhances the viscous effects of the laminar temperature boundary layer, reduces the Reynolds shear stress and turbulent kinetic energy, and increases the flow stability. However, the velocity gradient and shear stress in the bottom of the turbulent boundary layer decreases, which leads to reduced friction shear stress on the wall surface. Therefore, for the low-aspect-ratio flying wing model, the hot wall can delay the boundary layer transition and reduce the friction drag coefficient in the turbulent region.