bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Effects of COVID-19 Among Health Care Workers, and How They Are Coping: A Web-Based, Cross-Sectional Study During the First Wave of COVID-19 in Pakistan
Authors: Salman Muhammad , Mustafa Zia Ul , Raza Muhammad Husnnain , Khan Tahir Mehmood , Asif Noman , Tahir Humera , Shehzadi Naureen , Mallhi Tauqeer Hussain , Khan Yusra Habib , Sultana Kishwar , Saleem Fahad , Hussain Khalid
Published: January 2022

Objective:

The aim of this study is to ascertain the psychological impacts of coronavirus disease (COVID-19) among the Pakistani health care workers (HCWs) and their coping strategies.

Methods:

This web-based, cross-sectional study was conducted among HCWs (N = 398) from Punjab Province of Pakistan. The generalized anxiety scale (GAD-7), patient health questionnaire (PHQ-9), and Brief-COPE were used to assess anxiety, depression, and coping strategies, respectively.

Results:

The average age of respondents was 28.67 years (SD = 4.15), with the majority being medical doctors (52%). Prevalences of anxiety and depression were 21.4% and 21.9%, respectively. There was no significant difference in anxiety and depression scores among doctors, nurses, and pharmacists. Females had significantly higher anxiety (P = 0.003) and depression (P = 0.001) scores than males. Moreover, frontline HCWs had significantly higher depression scores (P = 0.010) than others. The depression, not anxiety, score was significantly higher among those who did not receive the infection prevention training (P = 0.004). The most frequently adopted coping strategies were religious coping (M = 5.98, SD = 1.73), acceptance (M = 5.59, SD = 1.55), and coping planning (M = 4.91, SD = 1.85).

Conclusion:

A considerable proportion of HCWs are having generalized anxiety and depression during the ongoing COVID-19 pandemic. Our findings call for interventions to mitigate mental health risks in HCWs.
Topological models for stable motivic invariants of regular number rings
Authors: Bachmann Tom , Østvær Paul Arne
Published: January 2022

For an infinity of number rings we express stable motivic invariants in terms of topological data determined by the complex numbers, the real numbers and finite fields. We use this to extend Morel’s identification of the endomorphism ring of the motivic sphere with the Grothendieck–Witt ring of quadratic forms to deeper base schemes.
Compensation method for performance degradation of optically addressed spatial light modulator induced by CW laser
Authors: Du Tongyao , Huang Dajie , Cheng He , Fan Wei , Xing Zhibo , Li Xuechun , Zhu Jianqiang
Published: January 2022

In this paper, we propose an effective method to compensate for the performance degradation of optically addressed spatial light modulators (OASLMs). The thermal deposition problem usually leads to the on-off ratio reduction of amplitude OASLM, so it is difficult to achieve better results in high-power laser systems. Through the analysis of the laser-induced temperature rise model and the liquid crystal layer voltage model, it is found that reducing the driving voltage of the liquid crystal light valve and increasing the driving current of the optical writing module can compensate for the decrease of on–off ratio caused by temperature rise. This is the result of effectively utilizing the photoconductive effect of Bi12SiO20 (BSO) crystal. The experimental results verify the feasibility of the proposed method and increase the laser withstand power of amplitude-only OASLM by about a factor of 2.5.
Rhythms of learning — a model of practice supporting youth mental health in the era of COVID-19
Authors: Faulkner Simon C.
Published: January 2022

The COVID-19 pandemic has led to a significant increase in demand for mental health services for young people. This demand comes on top of a preexisting surge in mental health presentations for our youth, and it places extraordinary demand on support services and the professionals who deliver them. Concurrently, it is recognised that engaging and working with young people and their mental health has its own unique challenges, and that many young people find direct ‘talk-based’ therapies confronting. This article examines the use of a model of group work practice combining the benefits of rhythmic music with reflective discussions as a response to the dual challenges of workplace burnout and client engagement. It reflects on the important role music has to play in young lives and how this can be extended into therapy in a fun and uplifting manner. It draws attention to the long history of rhythmic music within traditional healing practices and the emerging scientific evidence supporting this approach.
Disestablishing Hospitals
Authors: Sepper Elizabeth , Nelson James D.
Published: January 2022

We argue that concentration of power in religious hospitals threatens disestablishment values. When hospitals deny care for religious reasons, they dominate patients’ bodies and convictions. Health law should — and to some extent already does — constrain such religious domination.
Curbside Consults in Clinical Medicine: Empirical and Liability Challenges
Authors: Zacharias Rachel L. , Feldman Eric A. , Joffe Steven , Lynch Holly Fernandez
Published: January 2022

In most U.S. jurisdictions, clinicians providing informal “curbside” consults are protected from medical malpractice liability due to the absence of a doctor-patient relationship. A recent Minnesota Supreme Court case, Warren v. Dinter, offers the opportunity to reassess whether the majority rule is truly serving the best interests of patients.
Rethinking the Principle of Justice for Marginalized Populations During COVID-19
Authors: Ashworth Henry , Soled Derek , Morse Michelle
Published: January 2022

In the face of limited resources during the COVID-19 pandemic response, public health experts and ethicists have sought to apply guiding principles in determining how those resources, including vaccines, should be allocated.
Management research contributions to the COVID-19: a bibliometric literature review and analysis of the contributions from the Journal of Management & Organization
Authors: Ayoko Oluremi B. , Caputo Andrea , Mendy John
Published: January 2022

The COVID-19 health crisis triggered changes in the workplace. This paper explores the insights from scholarly work published in the Journal of Management and Organization (JMO) and systematizes this body of knowledge to build a scientific overview that looks at how the COVID-19 health crisis and its repercussions may be managed by organizations. We conducted a bibliometric investigation of JMO's most influential papers published from 1995 to June 2020 that offers insights into the management of the COVID-19 crisis. Our bibliometric investigation reveals six clusters: (1) conservation of resources theory, entrepreneurs, gender and work–family conflict; (2) corporate governance, corporate social responsibility and stakeholder salience; (3) family firms, innovation and research methods; (4) creativity, leadership and organizational change; (5) job satisfaction and psychological empowerment; and (6) team performance. We discuss the theoretical and practical implications of our findings.
Petrogenesis, W metallogenic and tectonic implications of granitic intrusions in the southern Great Xing’an Range W belt, NE China: insights from the Narenwula Complex
Authors: Xie Wei , Zeng Qing-Dong , Yang Jin-Hui , Li Rui , Zhang Zhuang , Wang Rui-Liang , Wu Jin-Jian
Published: January 2022

Extensive magmatism in NE China, eastern Central Asian Orogenic Belt, has produced multi-stage granitic plutons and accompanying W mineralization. The Narenwula complex in the southwestern Great Xing’an Range provides important insights into the petrogenesis, geodynamic processes and relationship with W mineralization. The complex comprises granodiorites, monzogranites and granite porphyry. Mafic microgranular enclaves are common in the granodiorites, and have similar zircon U–Pb ages as their host rocks (258.5–253.9 Ma), whereas the W-bearing granitoids yield emplacement ages of 149.8–148.1 Ma. Permian granodiorites are I-type granites that are enriched in large-ion lithophile elements and light rare earth elements, and depleted in high field strength elements and heavy rare earth elements. Both the mafic microgranular enclaves and granodiorites have nearly identical zircon Hf isotopic compositions. The results suggest that the mafic microgranular enclaves and granodiorites formed by the mixing of mafic and felsic magmas. W-bearing granitoids are highly fractionated A-type granites, enriched in Rb, Th, U and Pb, and depleted in Ba, Sr, P, Ti and Eu. They have higher W concentrations and Rb/Sr ratios, and lower Nb/Ta, Zr/Hf and K/Rb ratios than the W-barren granodiorites. These data and negative ϵHf(t) values (–6.0 to –2.1) suggest that they were derived from the partial melting of ancient lower crust and subsequently underwent extreme fractional crystallization. Based on the regional geology, we propose that the granodiorites were generated in a volcanic arc setting related to the subduction of the Palaeo-Asian Ocean, whereas the W-bearing granitoids and associated deposits formed in a post-orogenic extensional setting controlled by the Mongol–Okhotsk Ocean and Palaeo-Pacific Ocean tectonic regimes.
Knowledge, attitude and practices regarding cochlear implants among medical doctors other than otolaryngologists: a prospective cross-sectional study
Authors: Reddy Y Mounika , Anjali L , Augustine A , Mary J , Ajay P
Published: January 2022

Objective

Cochlear implant is the standard treatment of choice for children and adults with severe to profound sensorineural hearing loss. The main objective of this study was to assess the knowledge, attitude and practices regarding cochlear implant among doctors other than otolaryngologists in a tertiary care academic institution.

Method

A 24-item knowledge, attitude and practices questionnaire was developed based on an extensive literature review and expert opinion and was administered to 100 non-otolaryngologists in a tertiary care academic institution to be completed in about 15 minutes. The data obtained was analysed to assess knowledge, attitude and practices regarding cochlear implant in this group.

Results

The results showed that awareness regarding the option of cochlear implants for elderly and unilateral deafness was deficient. Surgeons and doctors in higher specialties did better when it came to practice related to cochlear implant. The age and experience of doctors also improved knowledge and practice with regards to cochlear implant.

Conclusion

Improving awareness about cochlear implants and their benefits among non-otolaryngology colleagues can ensure that more people who could potentially benefit from cochlear implants will receive appropriate counselling and referral.
A report on quality-of-life outcomes following transmastoid plugging of superior semicircular canal dehiscence in a newly established service in a UK hospital
Authors: Hussain M H , Irving R , Baruah P
Published: January 2022

Objective

This study aimed to evaluate the quality-of-life outcomes following transmastoid plugging of semicircular canal dehiscence in a newly established service in a UK hospital.

Method

Quality-of-life outcomes were measured using the Glasgow benefit Inventory score in three patients who underwent transmastoid plugging for superior semicircular canal dehiscence between September 2019 and March 2020. Patients also completed pre- and post-operative symptomatic questionnaires and vestibular-evoked myogenic potential testing.

Results

All three patients reported an improvement in overall quality-of-life outcomes with a mean overall Glasgow Benefit Inventory score of +37 (range, +22.2–66.6). There were no immediate post-operative complications and hearing was preserved in all patients.

Conclusion

This study reported an initial successful experience with transmastoid plugging of superior semicircular canal dehiscence. In all patients, improvement in quality-of-life measures and symptoms was reported.
Twenty-seven years of primary salivary gland carcinoma in Wales: an analysis of histological subtype and associated risk factors
Authors: Leopard D , El-Hitti E , Puttasiddaiah P , Mcleod R , Owens D
Published: January 2022

Objective

Risk factors for salivary gland carcinoma are poorly understood. Although links between background radiation, smoking and obesity have been previously suggested, no studies have so far established any significant results. This study aimed to establish correlations between common environmental and lifestyle risk factors and different subtypes of salivary gland carcinoma.

Method

A study of population data in Wales spanning 27 years was conducted; 2 national databases were used to identify 356 cases of primary salivary gland carcinoma over this period. Histological subtype of cancer and geographical location of each case was recorded. Public health data was used to establish radon levels, smoking, obesity and activity levels of populations in each geographical location. A population matched multivariate analysis of variance analysis was performed using histological subtype and risk factor data for each geographical location.

Results

A significantly higher incidence of mucoepidermoid cancer in populations with higher background radon levels (p =0.006), epithelial-myoepithelial cancer in populations with higher smoking levels (p =0.029) and adenoid cystic cancer in populations with higher obesity levels (p =0.028) was found.

Conclusion

To the authors’ knowledge, this is the first study to establish significant links between background radiation, smoking and obesity with different subtypes of salivary gland carcinoma.
Forging Mixtec Identity in the Mexican Metropolis: Race, Indigenismo and Mixtec Migrant Associations in Mexico City, 1940−70
Authors: Yee David
Published: January 2022

This article presents a social history of the Coalición de los Pueblos Mixtecos Oaxaqueños (Coalition of Mixtec Oaxacan Communities, CPMO), a grouping of mutual-aid associations formed by Indigenous migrants in Mexico City during the middle of the twentieth century. It draws on the coalition's archives to demonstrate how years of migration to Mexico City eroded traditional inter-village conflicts and created the conditions for a broader ethnic identity among Mixtec migrants in the capital. In addition, the coalition's collaboration with the federal government's Instituto Nacional Indigenista (National Indigenous Institute, INI) challenges common depictions of Indigeneity and modernisation as being inherently antagonistic with one another. The coalition's collaboration with the INI led its members to more consciously and visibly identify with their Indigenous roots; they had to become more Indigenous in order to become more modern.
Attentional bias toward health-threat in health anxiety: a systematic review and three-level meta-analysis
Authors: Shi Congrong , Taylor Steven , Witthöft Michael , Du Xiayu , Zhang Tao , Lu Shan , Ren Zhihong
Published: January 2022

Attentional bias toward health-threat may theoretically contribute to the development and maintenance of health anxiety, but the empirical findings have been controversial. This study aimed to synthesize and explore the heterogeneity in a health-threat related attentional bias of health-anxious individuals, and to determine the theoretical model that better represents the pattern of attentional bias in health anxiety. Four databases (Web of Science, PubMed, PsycINFO, and Scopus) were searched for relevant studies, with 17 articles (N = 1546) included for a qualitative review and 16 articles (18 studies) for a three-level meta-analysis (N = 1490). The meta-analytic results indicated that the health anxiety group, compared to the control group, showed significantly greater attentional bias toward health-threat (g = 0.256). Further analyses revealed that attentional bias type, paradigm, and stimuli type were significant moderators. Additionally, compared to the controls, health-anxious individuals displayed significantly greater attention maintenance (g = 0.327) but nonsignificant attention vigilance to health-threat (g = −0.116). Our results provide evidence for the attention maintenance model in health-anxious individuals. The implications for further research and treatment of elevated health anxiety in the context of coronavirus disease-2019 (COVID-19) were also discussed.
Climatology of the Soil Surface Diurnal Temperature Range in a Warming World: Annual Cycles, Regional Patterns, and Trends in China
Authors: Liu Binhui , Zhou Wanying , Henderson Mark , Sun Yingjie , Shen Xiangjin
Published: January 2022

The soil surface diurnal temperature range (SSDTR), reflecting the synchronicity of changes in the daily extremes of soil surface temperatures, provides an important and sensitive indicator of climate change. The climatology of SSDTR and its trends have a strong connection with the land surface energy budget, but this has received little notice up to now. Our research examines the spatial‐temporal characteristics of the annual cycle of SSDTR and its connection with other climate variables in China. The results demonstrate that the annual SSDTR curve changes gradually across space, with both regional and zonal characteristics. The shape of the annual SSDTR curve varies among regions. While it shows consistently strong positive associations with solar irradiance across China, a strong negative association with relative humidity is evident only in the dry western regions and the connection with relative humidity progressively decouples as we move toward the moist eastern regions. Atmospheric circulation affects SSDTR indirectly through derived changes in the seasonal cycles of moisture and solar irradiance. This produces a zonal character of the SSDTR annual curve in the east, while in the west the positive land‐atmosphere feedback under low moisture conditions is associated with a regional character. The magnitude of the annual cycle of SSDTR is large compared with temporal change, contributing to the generally stable nature of the cycle under global warming conditions.
Plutonium Isotopes: An Effective Tool for Fluvial Sediment Sourcing in Urbanized Catchments
Authors: Percich Abigal , Husic Admin , Ketterer Michael E.
Published: January 2022

Sediment management is currently limited by uncertainties in the applicability of existing radionuclide tracers and the effects of urbanization. Here, we use plutonium isotopes (239+240Pu) from weapons‐testing fallout to trace sediment transport across five watersheds in an urbanizing landscape in Kansas, USA. Historic flooding in the region provided an opportunity to assess extreme connectivity of sediment sources. 239+240Pu activity of transported sediment decreased as catchments urbanized, indicating a greater contribution from subsurface bank sediment; Bayesian modeling predicted 50% (8%–80%) bank sourcing in the most rural watershed, which rose to 93% (73%–100%) in the most urban catchment. 239+240Pu activity provides explanatory information on the superposition of sediment sources, which is beyond that given by traditional organic and geochemical tracers that primarily infer vegetative and geologic sourcing, respectively. Our study demonstrates the utility of 239+240Pu as a sediment tracer for managing erosion under anthropogenic change.
Using End‐Member Models to Estimate Seasonal Carbonate Chemistry and Acidification Sensitivity in Temperate Estuaries
Authors: Simpson Eleanor , Ianson Debby , Kohfeld Karen E.
Published: January 2022

We measured the carbonate system (between 2015 and 2018) in an isolated and a well‐connected temperate estuary, both known for shellfish growth. We evaluated end‐member model estimates of inorganic carbon, alkalinity, pH, mineral saturation states (Ωa), and pH sensitivity (βDIC). We find winter conditions are estimated within observational uncertainty. Spring‐summer primary productivity elevates observed pH and Ωa above theoretical lines, beyond uncertainty. Both estuaries are sensitive in winter and likely to experience rapid pH changes with increased inorganic carbon inputs. Summer pH sensitivity is reduced by productivity and is least sensitive in the midsalinity region. We estimate carbon increased by up to 49 μmol kg−1, since the pre‐industrial period resulting in significant decreases in pH (0.2) and Ωa (0.5). The largest pH decrease occurred outside the minimum buffer zone, at higher salinities where carbon increase was greatest. The largest pH decrease occurred in winter, but the largest Ωa decrease occured in summer.
Assessing Volcanic Controls on Miocene Climate Change
Authors: Longman Jack , Mills Benjamin J. W. , Donnadieu Yannick , Goddéris Yves
Published: January 2022

The Miocene period saw substantially warmer Earth surface temperatures than today, particularly during a period of global warming called the Mid Miocene Climatic Optimum (MMCO; ∼17–15 Ma). However, the long‐term drivers of Miocene climate remain poorly understood. By using a new continuous climate‐biogeochemical model (SCION), we can investigate the interaction between volcanism, climate and biogeochemical cycles through the Miocene. We identify high tectonic CO2 degassing rates and further emissions associated with the emplacement of the Columbia River Basalt Group as the primary driver of the background warmth and the MMCO respectively. We also find that enhanced weathering of the basaltic terrane and input of explosive volcanic ash to the oceans are not sufficient to drive the immediate cooling following the MMCO and suggest that another mechanism, perhaps the change in ocean chemistry due to massive evaporite deposition, was responsible.
On the All‐India Rainfall Index and Sub‐India Rainfall Heterogeneity
Authors: Hill Spencer A. , Sobel Adam H. , Biasutti Michela , Cane Mark A.
Published: January 2022

We revisit longstanding controversies regarding summer‐mean relationships among the all‐India rainfall index (AIRI), sub‐India rainfall, El Niño‐Southern Oscillation (ENSO), and the Indian Ocean dipole (IOD) using 120‐year sea surface temperature and high‐resolution rainfall datasets. AIRI closely tracks with the spatial extent of wet anomalies and with the average across grid points in rainy day count. The leading rainfall variability mode is a monopole associated primarily with rainy day count and ENSO. The second mode is a tripole with same‐signed loadings in the high‐rainfall Western Ghats and Central Monsoon Zone regions and opposite‐signed loadings in Southeastern India between. The IOD projects onto this tripole and, as such, is weakly correlated with AIRI. However, when the linear influence of ENSO is removed, the IOD rainfall regressions become quasi‐homogeneously more positive, making the ENSO‐residual IOD and AIRI time series significantly correlated.
A Comparative Study of Magnetic Flux Ropes in the Nightside Induced Magnetosphere of Mars and Venus
Authors: Hara Takuya , Huang Zesen , Mitchell David L. , DiBraccio Gina A. , Brain David A. , Harada Yuki , Luhmann Janet G.
Published: January 2022

We analyzed Mars Atmosphere and Volatile Evolution (MAVEN) and Venus Express (VEX) data of magnetic flux ropes observed in both Mars and Venus nightside induced magnetosphere, in order to understand their statistical characteristics and possible formation processes. We statistically identified 382 (286) events at Mars (Venus) via the minimum variance analysis and investigated the flux rope properties including their geometrical configurations of axial core field direction and spatial distributions. Interestingly, there is no significant difference with respect to the variety of the flux rope axial orientation between Mars and Venus, indicating that about at least one fourth of events do not necessitate magnetotail reconnection for their formations. However, the spatial distribution shows that flux ropes at Venus tend to be observed near the central plasma sheet, whereas those at Mars are more spread out. Moreover, the events tend to be observed more frequently in the −E hemisphere, where the solar wind electric field (ESW) is pointing toward the planet, rather than in +E hemisphere, where the ESW direction is away from the planet. The geographical distribution shows that flux ropes at Mars tend to be observed more frequently in the southern hemisphere where the strong crustal magnetic fields are primarily distributed. Therefore, such a tendency indicates that the Martian crustal magnetic fields could play significant roles on generating flux ropes in the nightside magnetosphere of Mars.
Quantitative Attribution of Vertical Motion Responsible for Summer Heavy Rainfall Over North China
Authors: Zhao Yang , Deng Lin , Li Ziwei , Wang Yinjun
Published: January 2022

This study explores synoptic‐scale circulation conditions that favor vertical motion on heavy rainfall days (HRDs) over North China (NC) and analyzes the quantitative contribution to vertical motion by different forcings using the quasi‐geostrophic (QG) omega equation. On HRDs, moisture is brought from the South China Sea and East China seas by surface cyclonic vortex activity. When South Asian High is located anomalously northward, NC is on the south side of the upper‐level jet (ULJ) stream entrance region. Diagnosis of the QG omega equation shows that vertical motion on HRDs is caused by dynamic forcing, diabatic forcing, and topographic forcing. The greatest contribution to vertical motion is from diabatic forcing, while topographic contributes to vertical motion at low levels. The dynamic forcing, which is manifested by the Q‐vector, indicates that both the ULJ and baroclinic trough generate the vertical motion. Furthermore, the effect of the baroclinic trough is larger than that of the ULJ. On medium rainfall days, the contributions from dynamic forcing, diabatic forcing, and topographic forcing are clearly weaker than on HRDs, with reductions of 62.3%, 71.3%, and 73.8%, respectively.
Drought Cycle Analysis to Evaluate the Influence of a Dense Network of Small Reservoirs on Drought Evolution
Authors: Ribeiro Neto G. G. , Melsen L. A. , Martins E. S. P. R. , Walker D. W. , van Oel P. R.
Published: January 2022

Drought‐affected regions often contain high densities of small reservoirs, usually informally built, as drought‐coping mechanism. These structures influence socio‐hydrological dynamics and have the potential to alter hydrological processes relevant to drought emergence and development. This study aimed to analyze the influence of a high concentration of small reservoirs on the intensification and evolution of drought events. We present an innovative method, which we call “Drought Cycle Analysis”, that tracks the concomitance of precipitation and water storage deficit and associates this with four drought stages: Wet Period, Meteorological drought, Hydro‐meteorological drought and Hydrological drought period. The methodology was tested for the Riacho do Sangue River watershed located in the semi‐arid region of northeast Brazil. We used a combination of satellite imagery (Landsat 5, 7 and 8) and an empirical equation to estimate the volume stored in the dense network of small reservoirs. Using the Drought Cycle Analysis, we show that the unmonitored small reservoirs induced and modified drought events, extending the duration of hydrological drought on average by 30%. Furthermore, this extension can double for specific drought events. The Drought Cycle Analysis method proved useful for monitoring and comparing the evolution of different drought events, in addition to being applicable as an auxiliary tool in the improvement of water resources management of large reservoirs. This study demonstrates the importance of considering small reservoirs in water resource management strategy development for drought‐prone regions.
Development and validation of a circulating microRNA panel for the early detection of breast cancer
Authors: Zou Ruiyang , Loke Sau Yeen , Tang Yew Chung , Too Heng-Phon , Zhou Lihan , Lee Ann S. G. , Hartman Mikael
Published: January 2022

Background

Mammography is widely used for breast cancer screening but suffers from a high false-positive rate. Here, we perform the largest comprehensive, multi-center study to date involving diverse ethnic groups, for the identification of circulating miRNAs for breast cancer screening.

Methods

This study had a discovery phase (n = 289) and two validation phases (n = 374 and n = 379). Quantitative PCR profiling of 324 miRNAs was performed on serum samples from breast cancer (all stages) and healthy subjects to identify miRNA biomarkers. Two-fold cross-validation was used for building and optimising breast cancer-associated miRNA panels. An optimal panel was validated in cohorts with Caucasian and Asian samples. Diagnostic ability was evaluated using area under the curve (AUC) analysis.

Results

The study identified and validated 30 miRNAs dysregulated in breast cancer. An optimised eight-miRNA panel showed consistent performance in all cohorts and was successfully validated with AUC, accuracy, sensitivity, and specificity of 0.915, 82.3%, 72.2% and 91.5%, respectively. The prediction model detected breast cancer in both Caucasian and Asian populations with AUCs ranging from 0.880 to 0.973, including pre-malignant lesions (stage 0; AUC of 0.831) and early-stage (stages I–II) cancers (AUC of 0.916).

Conclusions

Our panel can potentially be used for breast cancer screening, in conjunction with mammography.
Cell-to-cell variability in inducible Caspase9-mediated cell death
Authors: Yuan Yuan , Ren Huixia , Li Yanjun , Qin Shanshan , Yang Xiaojing , Tang Chao
Published: January 2022

iCasp9 suicide gene has been widely used as a promising killing strategy in various cell therapies. However, different cells show significant heterogeneity in response to apoptosis inducer, posing challenges in clinical applications of killing strategy. The cause of the heterogeneity remains elusive so far. Here, by simultaneously monitoring the dynamics of iCasp9 dimerization, Caspase3 activation, and cell fate in single cells, we found that the heterogeneity was mainly due to cell-to-cell variability in initial iCasp9 expression and XIAP/Caspase3 ratio. Moreover, multiple-round drugging cannot increase the killing efficiency. Instead, it will place selective pressure on protein levels, especially on the level of initial iCasp9, leading to drug resistance. We further show this resistance can be largely eliminated by combinatorial drugging with XIAP inhibitor at the end, but not at the beginning, of the multiple-round treatments. Our results unveil the source of cell fate heterogeneity and drug resistance in iCasp9-mediated cell death, which may enlighten better therapeutic strategies for optimized killing.
EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation
Authors: Yin Hubin , Zhang Chen , Wei Zongjie , He Weiyang , Xu Ning , Xu Yingjie , Li Tinghao , Ren Ke , Kuang Youlin , Zhu Xin , Yuan Fangchao , Yu Haitao , Gou Xin
Published: January 2022

Bladder cancer is a highly heterogeneous and aggressive malignancy with a poor prognosis. EGF/EGFR activation causes the detachment of SHC-binding protein 1 (SHCBP1) from SHC adapter protein 1 (SHC1), which subsequently translocates into the nucleus and promotes cancer development via multiple signaling pathways. However, the role of the EGF-SHCBP1 axis in bladder cancer progression remains unexplored. Herein, we report that SHCBP1 is upregulated in bladder cancer tissues and cells, with cytoplasmic or nuclear localization. Released SHCBP1 responds to EGF stimulation by translocating into the nucleus following Ser273 phosphorylation. Depletion of SHCBP1 reduces EGF-induced cell migration and invasiveness of bladder cancer cells. Mechanistically, SHCBP1 binds to RACGAP1 via its N-terminal domain of amino acids 1 ~ 428, and this interaction is enhanced following EGF treatment. Furthermore, SHCBP1 facilitates cell migration by inhibiting RACGAP-mediated GTP-RAC1 inactivation, whose activity is indispensable for cell movement. Collectively, we demonstrate that the EGF-SHCBP1-RACGAP1-RAC1 axis acts as a novel regulatory mechanism of bladder cancer progression, which offers a new clinical therapeutic strategy to combat bladder cancer.
Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem
Authors: Das Soumyaparna , Popp Valerie , Power Michael , Groeneveld Kathrin , Yan Jie , Melle Christian , Rogerson Luke , Achury Marlly , Schwede Frank , Strasser Torsten , Euler Thomas , Paquet-Durand François , Nache Vasilica
Published: January 2022

Hereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.
The downregulation of type I IFN signaling in G-MDSCs under tumor conditions promotes their development towards an immunosuppressive phenotype
Authors: Sun Yingying , Han Xiaoqing , Shang Chao , Wang Yawei , Xu Boya , Jiang Shu , Mo Yan , Wang Dake , Ke Yueshuang , Zeng Xianlu
Published: January 2022

Tumors modify myeloid cell differentiation and induce an immunosuppressive microenvironment. Granulocytic myeloid-derived suppressor cells (G-MDSCs), the main subgroup of myeloid-derived suppressor cells (MDSCs), are immature myeloid cells (IMCs) with immunosuppressive activity and exist in tumor-bearing hosts. The reason why these cells diverge from a normal differentiation pathway and are shaped into immunosuppressive cells remains unclear. Here, we reported that the increase of granulocyte colony-stimulating factor (G-CSF) in mouse serum with tumor progression encouraged G-MDSCs to obtain immunosuppressive traits in peripheral blood through the PI3K-Akt/mTOR pathway. Importantly, we found that downregulation of type I interferon (IFN-I) signaling in G-MDSCs was a prerequisite for their immunosuppressive effects. Suppressor of cytokine signaling (SOCS1), the action of which is dependent on IFN-I signaling, inhibited the activation of the PI3K-Akt/mTOR pathway by directly interacting with Akt, indicating that the differentiation of immunosuppressive G-MDSCs involves a transition from immune activation to immune tolerance. Our study suggests that increasing IFN-I signaling in G-MDSCs may be a strategy for reprograming immunosuppressive myelopoiesis and slowing tumor progression.
PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer
Authors: Salvi Amrita , Young Alexandria N. , Huntsman Andrew C. , Pergande Melissa R. , Korkmaz Melissa A. , Rathnayake Rathnayake A. , Mize Brittney K. , Kinghorn A. Douglas , Zhang Xiaoli , Ratia Kiira , Schirle Markus , Thomas Jason R. , Brittain Scott M. , Shelton Claude , Aldrich Leslie N. , Cologna Stephanie M. , Fuchs James R. , Burdette Joanna E.
Published: January 2022

PHY34 is a synthetic small molecule, inspired by a compound naturally occurring in tropical plants of the Phyllanthus genus. PHY34 was developed to have potent in vitro and in vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, PHY34 induced apoptosis in ovarian cancer cells by late-stage autophagy inhibition. Furthermore, PHY34 significantly reduced tumor burden in a xenograft model of ovarian cancer. In order to identify its molecular target/s, we undertook an unbiased approach utilizing mass spectrometry-based chemoproteomics. Protein targets from the nucleocytoplasmic transport pathway were identified from the pulldown assay with the cellular apoptosis susceptibility (CAS) protein, also known as CSE1L, representing a likely candidate protein. A tumor microarray confirmed data from mRNA expression data in public databases that CAS expression was elevated in HGSOC and correlated with worse clinical outcomes. Overexpression of CAS reduced PHY34 induced apoptosis in ovarian cancer cells based on PARP cleavage and Annexin V staining. Compounds with a diphyllin structure similar to PHY34 have been shown to inhibit the ATP6V0A2 subunit of V(vacuolar)-ATPase. Therefore, ATP6V0A2 wild-type and ATP6V0A2 V823 mutant cell lines were tested with PHY34, and it was able to induce cell death in the wild-type at 246 pM while the mutant cells were resistant up to 55.46 nM. Overall, our data demonstrate that PHY34 is a promising small molecule for cancer therapy that targets the ATP6V0A2 subunit to induce autophagy inhibition while interacting with CAS and altering nuclear localization of proteins.
Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer’s disease
Authors: Lee Seung-Eun , Kwon Daekee , Shin Nari , Kong Dasom , Kim Nam Gyo , Kim Hee-Yeong , Kim Min-Ji , Choi Soon Won , Kang Kyung-Sun
Published: January 2022

Mitochondrial dysfunction is associated with familial Alzheimer’s disease (fAD), and the accumulation of damaged mitochondria has been reported as an initial symptom that further contributes to disease progression. In the amyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by β-secretase to generate a C-terminal fragment, which is then cleaved by γ-secretase to produce amyloid-beta (Aβ). The accumulation of Aβ and its detrimental effect on mitochondrial function are well known, yet the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) contributing to this pathology have rarely been reported. We demonstrated the effects of APP-CTFs-related pathology using induced neural stem cells (iNSCs) from AD patient-derived fibroblasts. APP-CTFs accumulation was demonstrated to mainly occur within mitochondrial domains and to be both a cause and a consequence of mitochondrial dysfunction. APP-CTFs accumulation also resulted in mitophagy failure, as validated by increased LC3-II and p62 and inconsistent PTEN-induced kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) recruitment to mitochondria and failed fusion of mitochondria and lysosomes. The accumulation of APP-CTFs and the causality of impaired mitophagy function were also verified in AD patient-iNSCs. Furthermore, we confirmed this pathological loop in presenilin knockout iNSCs (PSEN KO-iNSCs) because APP-CTFs accumulation is due to γ-secretase blockage and similarly occurs in presenilin-deficient cells. In the present work, we report that the contribution of APP-CTFs accumulation is associated with mitochondrial dysfunction and mitophagy failure in AD patient-iNSCs as well as PSEN KO-iNSCs.
Novel prognostic marker LINC00205 promotes tumorigenesis and metastasis by competitively suppressing miRNA-26a in gastric cancer
Authors: Huangfu Longtao , Fan Biao , Wang Gangjian , Gan Xuejun , Tian Shanshan , He Qifei , Yao Qian , Shi Jinyao , Li Xiaomei , Du Hong , Gao Xiangyu , Xing Xiaofang , Ji Jiafu
Published: January 2022

Rapid proliferation and metastasis of gastric cancer (GC) resulted in a poor prognosis in the clinic. Previous studies elucidated that long non-coding RNA (LncRNA) LINC00205 was upregulated in various tumors and participated in tumor progression. The aim of our study was to investigate the regulating role of LINC00205 in tumorigenesis and metastasis of GC. Both public datasets and our data showed that the LINC00205 was highly expressed in GC tissues and several cell lines. Notably, GC patients with high level of LINC00205 had a poor prognosis in our cohort. Mechanistically, knockdown of LINC00205 by shRNAs suppressed GC cells proliferation, migration, invasion remarkably, and induced cell cycle arrest. Based on bioinformatics prediction, we found that LINC00205 might act as a competitive endogenous RNA (ceRNA) through targeting miR-26a. The level of miR-26a had negatively correlated with LINC00205 expression and was decreased among GC cell lines, tissues, and serum samples. Our results for the first time confirmed that miR-26a was a direct target of LINC00205 and might have the potential to become a plasma marker for clinical tumor diagnosis. Indeed, LINC00205 knockdown resulted in the dramatic promotion of miR-26a expression as well as inhibition of miR-26a potential downstream targets, such as HMGA2, EZH2, and USP15. These targets were essential for cell survival and epithelial-mesenchymal transition. Importantly, LINC00205 was able to remodel the miR-26a-mediated downstream silence, which identified a new mechanism of malignant transformation of GC cells. In conclusion, this study revealed the regulating role of the LINC00205/miR-26a axis in GC progression and provided a new potential therapeutic strategy for GC treatment.
tRNA-derived fragment TRF365 regulates the metabolism of anterior cruciate ligament cells by targeting IKBKB
Authors: Long Dianbo , Xu Yiyang , Mao Guping , Xin Ruobing , Deng Zengfa , Liao Hongyi , Li Zhiwen , Yang Zhi , Yu Baoxi , Yang Zhijian , He Aishan , Zhang Ziji , Kang Yan
Published: January 2022

tRNA-derived fragments (tRFs) are new noncoding RNAs, and recent studies have shown that tRNAs and tRFs have important functions in cell metabolism via posttranscriptional regulation of gene expression. However, whether tRFs regulate cellular metabolism of the anterior cruciate ligament (ACL) remains elusive. The aim of this study was to investigate the role and action mechanism of tRFs in ACL cell metabolism. A tRF array was used to determine tRF expression profiles in different human ACL cells, and quantitative real-time polymerase chain reaction and fluorescence in situ hybridisation were used to determine TRF365 expression. ACL cells were transfected with a TRF365 mimic or a TRF365 inhibitor to determine whether TRF365 regulates IKBKB expression. A rescue experiment and dual-luciferase reporter assay were conducted to determine whether the 3′-untranslated region (UTR) of IKBKB has a TRF365-binding site. TRF365 was weakly expressed in osteoarthritis (OA) ACL and interleukin-1β-treated ACL cells. IKBKB was highly expressed in OA ACL and interleukin-1β-treated ACL cells; transfection with the TRF365 mimic suppressed IKBKB expression, whereas transfection with the TRF365 inhibitor had the opposite effect. A dual-luciferase reporter assay showed that TRF365 silenced the expression of IKBKB by binding to its 3′-UTR. Thus, TRF365 regulates the metabolism of ACL cells by targeting IKBKB. In summary, TRF365 may provide a new direction for the study of ACL degeneration and on the pathophysiological process of OA.
Crystal structure and functional implication of bacterial STING
Authors: Ko Tzu-Ping , Wang Yu-Chuan , Yang Chia-Shin , Hou Mei-Hui , Chen Chao-Jung , Chiu Yi-Fang , Chen Yeh
Published: January 2022

Mammalian innate immune sensor STING (STimulator of INterferon Gene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase (cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in β-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2’3’-cGAMP-dependent signaling in eukaryotes.
Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression
Authors: Cheung Phyllis F. , Yang JiaJin , Fang Rui , Borgers Arianna , Krengel Kirsten , Stoffel Anne , Althoff Kristina , Yip Chi Wai , Siu Elaine H. L. , Ng Linda W. C. , Lang Karl S. , Cham Lamin B. , Engel Daniel R. , Soun Camille , Cima Igor , Scheffler Björn , Striefler Jana K. , Sinn Marianne , Bahra Marcus , Pelzer Uwe , Oettle Helmut , Markus Peter , Smeets Esther M. M. , Aarntzen Erik H. J. G. , Savvatakis Konstantinos , Liffers Sven-Thorsten , Lueong Smiths S. , Neander Christian , Bazarna Anna , Zhang Xin , Paschen Annette , Crawford Howard C. , Chan Anthony W. H. , Cheung Siu Tim , Siveke Jens T.
Published: January 2022

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.
Mini-batch optimization enables training of ODE models on large-scale datasets
Authors: Stapor Paul , Schmiester Leonard , Wierling Christoph , Merkt Simon , Pathirana Dilan , Lange Bodo M. H. , Weindl Daniel , Hasenauer Jan
Published: January 2022

Quantitative dynamic models are widely used to study cellular signal processing. A critical step in modelling is the estimation of unknown model parameters from experimental data. As model sizes and datasets are steadily growing, established parameter optimization approaches for mechanistic models become computationally extremely challenging. Mini-batch optimization methods, as employed in deep learning, have better scaling properties. In this work, we adapt, apply, and benchmark mini-batch optimization for ordinary differential equation (ODE) models, thereby establishing a direct link between dynamic modelling and machine learning. On our main application example, a large-scale model of cancer signaling, we benchmark mini-batch optimization against established methods, achieving better optimization results and reducing computation by more than an order of magnitude. We expect that our work will serve as a first step towards mini-batch optimization tailored to ODE models and enable modelling of even larger and more complex systems than what is currently possible.