bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive study of 1-Bit full adder cells: review, performance comparison and scalability analysis
Authors: Hasan Mehedi , Siddique Abdul Hasib , Mondol Abdal Hoque , Hossain Mainul , Zaman Hasan U. , Islam Sharnali
Published: May 2021

Full Adder (FA) circuits are integral components in the design of Arithmetic Logic Units (ALUs) of modern computing systems. Recently, there have been massive research interests in this area due to the growing need for low-power and high-performance computing systems. Researchers have proposed a variety of FA cells with diverse design techniques, each having its pros and cons. As a result, a systematic method for performance comparison of FA cells using a common simulation platform has become necessary. In this work, we present an extensive study of FA cells. We have compared the performance of thirty-three (33) existing 1-bit FA cells. The drive powers of these FA cells have been compared by applying a variety of load conditions. In addition, the 1-bit FA cells have been extended to 32-bit structures to test their scalability and to investigate their performance in wide-word structures. We have determined that twenty-one (21) of the thirty-three (33) FA cells cannot operate in a 32-bit structure, even though some of them exhibit excellent performance as a 1-bit cell. The main finding of this research is that the single-bit performance parameters of FA cells should not be considered as the main basis for performance comparison. Any FA cell should be analyzed in a multi-bit structure to determine its practical effectiveness.
Factors affecting the crop damage by wild boar (Sus scrofa) and effects of population control in the Ticino and Lake Maggiore Park (North-western Italy)
Authors: Cappa Fabrizio , Bani Luciano , Meriggi Alberto
Published: May 2021

Wild boar foraging impacts the crops, pastures, and meadows causing remarkable losses to agricultural income. Protected areas located in plains, such as the Ticino Valley Natural Park, are characterized by the coexistence of important natural habitats and intensive agricultural areas. In the Park, from 2010 to 2017, 49% of the complaints report an event of damage to maize and 43% to meadows. The total expense for reimbursements of the maize amounted to € 439,341.52, with damages concentrated in May, after sowing period and between August and September, during the milky stage of maize. For meadows reimbursements amounted to € 324,768.66, with damage events concentrated in February and March. To reduce damage to crops, the Park administration carried out lethal control of the wild boar population. From 2006 to 2017, the most used control method was culling from hunting hides. In our analysis, we did not find significant relationships between the number of shot boars and the damage amount. The factors that determine the decrease of damage probability to crops are mainly related to human disturbance and the characteristics of the fields. The predictive model of damage risk built comparing damaged and undamaged fields showed a good predictive ability. The population viability analyses showed that it is impossible to obtain a drastic reduction of population with the current harvest rate. By tripling it and focusing on the females and sub-adult a numerical reduction of 50% of the population would be achievable in 7 years and the probability of population survival would be halved in 3 years.
Lebesgue points of $$\ell _1$$-Cesàro summability of d-dimensional Fourier series
Authors: Weisz Ferenc
Published: May 2021

We generalize the classical Lebesgue’s theorem and prove that the $$\ell _1$$

ℓ
1

-Cesàro means of the Fourier series of the multi-dimensional function $$f\in L_1({{\mathbb {T}}}^d)$$

f
∈

L
1

(

T

d

)

converge to f at each strong $$\omega $$
ω
-Lebesgue point.
Suicide Prevention
Authors: Moutier Christine Yu , Pisani Anthony R. , Stahl Stephen M.
Published: May 2021

The current suicide public health crisis and advances in clinical practice have increased the need for clear, evidence-informed guidance on suicide prevention in healthcare. This clinical suicide prevention handbook is an essential resource for mental health and primary care professionals, and any practitioner aiming to ensure their practice is up-to-date, patient-centred and consistent with the most current standards of care. Starting with a summary of the science and public health model of suicide, the book offers quick tips for suicide screening, risk assessment, interventions, and follow-up communication. It discusses medicolegal risk management, how health systems can prevent suicide and provides highly specialized guidance for clinicians following the loss of a patient to suicide. Focused sections include incorporating social media into care plans, telemedicine, issues related to culture and race/ethnicity, and working with specific populations. It introduces an integrated, prevention-oriented approach to suicide prevention, incorporating realistic supports, foreseeable changes, and strategies.
Colonial Institutions and Civil War
Authors: Mukherjee Shivaji
Published: May 2021

What explains the peculiar spatial variation of Maoist insurgency in India? Mukherjee develops a novel typology of colonial indirect rule and land tenure in India, showing how they can lead to land inequality, weak state and Maoist insurgency. Using a multi-method research design that combines qualitative analysis of archival data on Chhattisgarh and Andhra Pradesh states, Mukherjee demonstrates path dependence of land/ethnic inequality leading to Maoist insurgency. This is nested within a quantitative analysis of a district level dataset which uses an instrumental variable analysis to address potential selection bias in colonial choice of princely states. The author also analyses various Maoist documents, and interviews with key human rights activists, police officers, and bureaucrats, providing rich contextual understanding of the motivations of agents. Furthermore, he demonstrates the generalizability of his theory to cases of colonial frontier indirect rule causing ​ethnic secessionist insurgency in Burma, and the Taliban insurgency in Pakistan.
Letting Climate Change
Authors: UNRUH CHARLOTTE FRANZISKA
Published: May 2021

Recent work by Ingmar Persson and Jason Hanna has posed an interesting new challenge for deontologists: How can they account for so-called cases of letting oneself do harm? In this article, I argue that cases of letting oneself do harm are structurally similar to real-world cases such as climate change, and that deontologists need an account of the moral status of these cases to provide moral guidance in real-world cases. I then explore different ways in which deontologists can solve this challenge and argue that the most promising way to conceive of cases of letting oneself do harm is as nonstandard cases of allowing harm, supplemented with an additional argument for the moral relevance of one's own agency. The upshot is that cases of letting oneself do harm are both more theoretically challenging and practically important than has been acknowledged.
The Guild of Our Lady of Ransom and Pilgrimage in England and Wales, c. 1890–1914
Authors: Hurlock Kathryn
Published: May 2021

The growth in Catholic pilgrimage in the late nineteenth and early twentieth century is widely acknowledged, but little attention has been paid to how and why many of the mass pilgrimages of the era began. This article will assess the contribution made by the Guild of Our Lady of Ransom to the growth of Catholic pilgrimage. After the Guild’s foundation in 1887, its leadership revived or restored pilgrimages to pre- and post-Reformation sites, and coordinated the movement of thousands of pilgrims across the country. This article offers an examination of how and why Guild leaders chose particular locations in the context of Marian Revivalism, papal interest in the English martyrs, defence of the Catholic faith, and late-nineteenth century medievalism. It argues that the Guild was pivotal in establishing some of England’s most famous post-Reformation pilgrimages. In doing so, it situates the work of the Guild in late nineteenth and early twentieth century religiosity, and demonstrates the pivotal nature of its work in establishing, developing, organising, and promoting some of the most important post-Reformation Catholic pilgrimages in Britain.
An overview of the process, progress, and outcomes of a National Center for Accelerated Innovation: The Boston Biomedical Innovation Center Experience
Authors: Antman Elliott M. , Freeman Mason W. , Golan David E. , Kitterman Roger , McKenna Erin , Parrish John , Vaughan Cheryl , Watts Lesley , Loscalzo Joseph
Published: May 2021

Implementation of clinically useful research discoveries in the academic environment is challenged by limited funding for early phase proof-of-concept studies and inadequate expertise in product development and commercialization. To address these limitations, the National Institutes of Health (NIH) established the National Centers for Accelerated Innovations (NCAI) program in 2013. Three centers competed successfully for awards through this mechanism. Here, we present the experience of one such center, the Boston Biomedical Innovation Center (B-BIC), and demonstrate its remarkable success at the translation of innovations to clinical application and commercialization, as well as skills development and education.
I. Pedagogy Toward Refusal
Authors: Flipper Joseph
Published: May 2021

Recognizing that thousands of people of color have suffered the many brutalities of racism, the editorial staff of Horizons marks the somber first anniversary of the tragic murder of George Floyd (May 25, 2020) with a pedagogical roundtable considering the possibility or impossibility of teaching antiracism in colleges and universities.
Shellfish Collection Practices of the First Inhabitants of Southwestern Puerto Rico: The Effects of Site Type and Paleoenvironment on Habitat Choice
Authors: Pestle William J. , Laguer-Díaz Carmen , Schneider M. Jesse , Carden Megan , Sherman Clark E. , Koski-Karell Daniel
Published: May 2021

After decades of study, much remains unknown about the foraging practices of the earliest inhabitants of Puerto Rico. Here, we present an analysis of the malacological assemblages of two neighboring and (partially) contemporary early sites from the island's southwest, finding intriguing intersite differences in shellfish collection practices. We attribute this diversity to differences in site type, chronology, or changes in local coastal configuration. This work not only provides insights into prehistoric Puerto Rican foraging dynamics but also demonstrates the importance of considering factors including intra-age chronology, site type, and changes in paleoenvironmental conditions when considering ancient foraging practices.
Three curious dogs in a Dunhuang manuscript: re-evaluating the identification of “yaks” in Pelliot chinois 2598
Authors: Granger Kelsey
Published: May 2021

A relatively understudied manuscript in the Pelliot collection, Pelliot chinois 2598, features a drawing on its verso of three animals tentatively identified as yaks. However, I would like to re-identify these as being a particular kind of dog which appeared suddenly in the early Tang 唐 (618–907) dynasty. This case will be built on the visual correlations between this image and other descriptions and depictions of such dogs. The manuscript and drawing as a whole will also be explored to contextualize this depiction, which may in turn lead us to hypothesize about the existence, visually or physically, of these dogs and their associated tropes in Dunhuang 敦煌.
Sex Effects on Mirror Overflow during Finger Tapping in Children with ADHD
Authors: Chen C. , Rosch K.S. , Seymour K.E. , Crocetti D. , Mahone E. M. , Mostofsky S.H.
Published: May 2021

Objectives:

The presence of excessive mirror overflow in children with Attention Deficit/Hyperactivity Disorder (ADHD) is discussed in numerous published reports. These reports, however, include a limited age range in their samples. The objective of this study is to examine the effects of diagnosis and sex on mirror overflow and standard deviation (SD) of tap time in children with and without ADHD across a larger age range (5–12 years) of children.

Methods:

One-hundred and forty-eight children with ADHD and 112 age- and sex-matched typically developing (TD) children completed a finger sequencing task. Mirror overflow, SD of tap time, and mean tap time were measured using finger twitch transducers.

Results:

Results reveal a significant diagnostic effect on mirror overflow such that boys and girls with ADHD demonstrate increased overflow compared to same-sex TD children. Boys with ADHD demonstrated more variable tap times compared to TD boys; no diagnostic effect was observed in the girls.

Conclusions:

Boys with ADHD exhibit anomalous motor variability; girls with ADHD show similar levels of variability as TD girls. Boys and girls with ADHD exhibit similar levels of excessive mirror overflow. This lack of sex differences on mirror overflow is distinct from reports finding sex effects on overflow and could result from an examination of a broader age range than is included in prior reports. Adolescent data would provide a greater understanding of the trajectory of anomalous mirror overflow across development. Examination of functional and structural connectivity would expand the current understanding of the neurobiological foundation of motor overflow.
Impacts of lockdown on dietary patterns among youths in China: the COVID-19 Impact on Lifestyle Change Survey
Authors: Yu Bin , Zhang Dong , Yu Wanqi , Luo Miyang , Yang Shujuan , Jia Peng
Published: May 2021

Objective:

To assess changes in dietary patterns among youths in China after COVID-19 lockdown.

Design:

This study was based on the COVID-19 Impact on Lifestyle Change Survey (COINLICS), a national retrospective survey established in early May 2020. The questionnaire was distributed through social media platforms. The sociodemographic information and routine dietary patterns before and after lockdown of participants were investigated. t tests and χ2 tests were used to compare the differences in consumption patterns of twelve major food groups and beverages between sex and across educational levels before and after lockdown. Factor analysis was employed to obtain the main dietary patterns.

Settings:

China.

Participants:

A total of 10 082 youths.

Results:

A significant decrease was observed in the average weekly frequency of rice intake, while significant increases were observed in the frequency of intake of wheat products, other staple foods, fish, eggs, fresh vegetables, preserved vegetables, fresh fruit and dairy products (all P values < 0·01). Heterogeneities of average weekly frequency existed between sex and across educational levels to different extents. The three main dietary patterns derived were loaded most heavily on dairy products, rice and wheat products, separately; the rice pattern became more dominant than the wheat products pattern after lockdown. The frequency of sugar-sweetened beverage consumption had decreased, while the frequency of other beverages had increased.

Conclusions:

Our timely survey would inform policymakers and health professionals of these significant changes in youths’ dietary patterns after lockdown, with heterogeneities observed to different extents between sex and across educational levels, for better policy-making and public health practice.
Oblique High Mach Number Heliospheric Shocks: The Role of α Particles
Authors: Ofman L. , Wilson L. B. , Koval A. , Szabo A.
Published: May 2021

Spacecraft observations of heliospheric shocks often find oscillations in the magnetic field and density both, upstream and downstream. The downstream magnetic oscillations of oblique collisionless shocks were detected by Wind with 10.9 samples s−1 and DSCOVR spacecraft with high temporal resolution of 50 samples s−1. The density oscillations associated with the shocks are also evident in proton and α particle density by Wind (with much lower temporal resolution). Recently, we have investigated low Mach number low‐β oblique shock oscillations using satellite data and 2.5D hybrid modeling with electrons modeled as fluid and ions modeled as particles and found that α particles—an important component of heliospheric plasma—may affect considerably the downstream oscillations and the shock structure. The objective of the present study is to investigate the effects of α particles on high Mach number heliospheric shocks dynamics, oscillations, nonstationarity, and shock‐front rippling. We extend the study to high Mach number shocks (M > 3), investigate several α particle typical densities, and compare the results for the various shock parameters. We model the effects of α particles on the shock ramp, wake, and downstream oscillation structure and the kinetic properties of proton and α particle velocity distributions at various locations downstream of the shocks. Using the 2.5D hybrid model we found that the modeled high Mach number quasi‐perpendicular shock magnetic and density structures are significantly affected by α particles with typical solar wind relative abundances, suggesting that the observed high Mach number shocks are similarly affected by α particles.
Variation of Snow Mass in a Regional Climate Model Downscaling Simulation Covering the Tianshan Mountains, Central Asia
Authors: Yang Tao , Li Qian , Chen Xi , Hamdi Rafiq , De Maeyer Philippe , Li Lanhai
Published: May 2021

Mountain snow is a fundamental freshwater supply in the arid regions. Climate warming alters the timing of snowmelt and shortens the snow cover duration, which greatly influences the regional climate and water management. However, a reliable estimation of snow mass in the Tianshan Mountains (TS) is still unclear due to the scarcity of extensive continuous surface observations and a complex spatial heterogeneity. Therefore, a long‐time snow simulation from 1982 to 2018 was performed in WRF/Noah‐MP to quantify snow mass in the TS, forced by ERA5 reanalysis data and real‐time updated leaf area index and green vegetation fraction. Meanwhile, March snow mass (close to the annual peak snow mass), snow cover fraction (SCF), and their associated trends were investigated in the TS. The results indicated a good accuracy of the simulated snow water equivalent (root mean square error [RMSE]: 7.82 mm/day) with a slight overestimation (2.84 mm/day). Compared with ERA5 data set, the RMSE and mean bias of the daily snow depth from WRF/Noah‐MP downscaling were significantly reduced by 95.74% and 93.02%, respectively. The climatological March snow mass measured 97.85 (±16.60) Gt in the TS and exhibited a negligible tendency during the study period. The total precipitation during the cold season controlled the variations of March snow mass. The increased precipitation in the high‐altitude regions contributed to an extensive snow mass, which could offset the loss in the TS lowland. In contrast, rapidly rising air temperature caused a significant reduction of March SCF, particularly in the Southern TS.
The Direct Radiative Forcing Impact of Agriculture‐Emitted Black Carbon Associated With India's Green Revolution
Authors: Liu Xinrui , Zhang Xiaodong , Huang Yufei , Chen Kaijie , Wang Linfei , Ma Jianmin , Huang Tao , Zhao Yuan , Gao Hong , Tao Shu , Liu Junfeng , Jian Xiaohu , Luo Jinmu
Published: May 2021

Biomass burning contributes considerably to black carbon (BC) emissions in South Asia, but such emissions have not been linked with the Green Revolution (GR) which has enabled substantial crop production growth in South Asian countries, India in particular. Here, we use an Earth system model to quantify climate change through the direct radiative forcing (DRF) by agriculture‐emitted BC associated with the GR in India. We show that the BC DRF in India has increased significantly since the GR, especially during the post‐GR period. The estimated BC DRF in India rose from +0.197 W/m2 in 1961 to +0.805 W/m2 in 2011; this represents a fourfold increase in DRF since the onset of the GR. The contribution of BC DRF by India's intensive agriculture to the global BC forcing also increased from 2.6% to 4.4% during the GR. Our results reveal that increasing BC emissions associated with the GR raises the importance of emission mitigation from agriculture source.
Whistler Wave Interactions With Superthermal Electrons on Martian Crustal Magnetic Fields: Bounce‐Averaged Diffusion Coefficients and Time Scales
Authors: Shane Alexander , Liemohn Michael
Published: May 2021

Pitch angle distributions of high‐energy superthermal electrons (> 100 eV) observed at Mars show evidence of a ubiquitous energization process occurring on dayside crustal magnetic fields. Wave–particle interactions have been put forth as one explanation and in this study we investigate if the conditions are right at Mars for this process to occur regularly. The resonant energy of electrons is dependent on not only the whistler wave frequency and normal angle but also the characteristic energy of the plasma environment. The characteristic energy is determined by the magnetic field strength and thermal electron density, both measured quantities by the Mars Atmosphere and Volatile EvolutioN mission. Bounce‐averaged diffusion coefficients are calculated using a typical characteristic energy profile and observed wave parameters. Time constants are also calculated and it is shown that wave–particle interactions are more efficient than Coulomb collisions. Low‐energy electrons have fast wave–particle interaction time scales and electrons can be scattered across the source cone and energized. High‐energy electrons have slow wave–particle interactions time scales and electrons energized to these energies will become trapped and modify the pitch angle distribution. Modeling the evolution of the electron distribution function will provide more insight into the process.
Identifying Outflow Regions of North American Monsoon Anticyclone‐Mediated Meridional Transport of Convectively Influenced Air Masses in the Lower Stratosphere
Authors: Clapp C. E. , Smith J. B. , Bedka K. M. , Anderson J. G.
Published: May 2021

We analyzed the effect of the North American monsoon anticyclone (NAMA) on the meridional transport of summertime cross‐tropopause convective outflow by applying a trajectory analysis to a climatology of convective overshooting tops (OTs) identified in GOES satellite images, which covers the domain from 29°S to 68°N and from 205°W to 1.25°W for the time period of May to September, 2013. From this analysis, we identify seasonal development of geographically distinct outflow regions of convectively influenced air masses (CIAMs) from the NAMA circulation to the global stratosphere and quantify the associated meridional displacement of CIAMs. We find that prior to the development of the NAMA, the majority of CIAMs exit the study area in a southeastern region between 5°N and 35°N at 45°W (75.5% in May). During July and August, when the NAMA is strongest, two additional outflow regions develop that constitute the majority of outflow: 68.1% in a northeastern region between 35°N and 60°N at 45°W and 13.4% in a southwestern region between 5°N and 35°N at 145°W. The shift in the location of most CIAM outflow from the pre‐NAMA southeastern region to NAMA‐dependent northeastern and southwestern regions corresponds to a change in average meridional displacement of CIAMs from 3.3° northward in May to 24.5° northward in July and August. Meridional transport of CIAMs through persistent outflow regions from the NAMA circulation to the global stratosphere has the potential to impact global stratospheric composition beyond convective source regions.
Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis
Authors: Gill Dipender , Zuber Verena , Dawson Jesse , Pearson-Stuttard Jonathan , Carter Alice R. , Sanderson Eleanor , Karhunen Ville , Levin Michael G. , Wootton Robyn E. , Klarin Derek , Tsao Philip S. , Tsilidis Konstantinos K. , Damrauer Scott M. , Burgess Stephen , Elliott Paul
Published: May 2021

Background

Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood.

Methods

Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.

Results

The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% −23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI −20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome.

Conclusions

Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
Does weight loss reduce the incidence of total knee and hip replacement for osteoarthritis?—A prospective cohort study among middle-aged and older adults with overweight or obesity
Authors: Jin Xingzhong , Gibson Alice A. , Gale Joanne , Schneuer Francisco , Ding Ding , March Lyn , Sainsbury Amanda , Nassar Natasha
Published: May 2021

Objective

This study aims to investigate the association between weight change and total knee or hip replacement (TKR or THR) for OA among middle-aged and older adults with overweight or obesity.

Method

Weight data were collected in 2006–2009 and in 2010 from the 45 and Up Study—a population-based cohort aged ≥45 years in New South Wales, Australia. Participants were included if they had a baseline body mass index (BMI) ≥ 25 kg/m2 and no history of TKR or THR. Weight change was categorised into four groups: >7.5% loss; >5–7.5% loss; stable (≤5% change) and >5% gain. Hospital admission data were linked to identify TKR and THR for OA, and multivariable Cox regression was used to assess risk of TKR and THR.

Results

Of 23,916 participants, 2139 lost >7.5% weight, 1655 lost 5–7.5% weight, and 4430 gained >5% weight. Over 5.2 years, 1009 (4.2%) underwent TKR and 483 (2.0%) THR. Compared to weight-stable, weight loss of >7.5% was associated with reduced risk of TKR after adjusting for age, sex, BMI, socioeconomic and lifestyle factors (hazard ratio 0.69, 95%CI 0.54–0.87), but had no association with THR. Weight loss of 5–7.5% was not associated with altered risk of either TKR or THR. Weight gain was associated with increased risk of THR after adjusting for confounders, but not TKR.

Conclusion

This study suggests that a weight loss target >7.5% is required to reduce the risk of TKR in adults with overweight or obesity. Weight gain should be avoided as it increases the risk of THR.
Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells
Authors: Wobus Manja , Mies Anna , Asokan Nandini , Oelschlägel Uta , Möbus Kristin , Winter Susann , Cross Michael , Weidner Heike , Rauner Martina , Hofbauer Lorenz C. , Bornhäuser Martin , Platzbecker Uwe
Published: May 2021

The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.
Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder
Authors: Sharma Akhil , Harutyunyan Arman , Schneider Bernard L. , Moszczynska Anna
Published: May 2021

There is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying “resilience” or vulnerability to METH use disorder and identify PARKIN as a novel potential drug target to treat heavy use of METH.
Assessing olfactory, memory, social and circadian phenotypes associated with schizophrenia in a genetic model based on Rim
Authors: Hidalgo Sergio , Campusano Jorge M. , Hodge James J. L.
Published: May 2021

Schizophrenia shows high heritability and several of the genes associated with this disorder are involved in calcium (Ca2+) signalling and synaptic function. One of these is theRab-3 interacting molecule-1(RIM1), which has recently been associated with schizophrenia by Genome Wide Association Studies (GWAS). However, its contribution to the pathophysiology of this disorder remains unexplored. In this work, we useDrosophilamutants of the orthologue ofRIM1,Rim, to model some aspects of the classical and non-classical symptoms of schizophrenia.Rimmutants showed several behavioural features relevant to schizophrenia including social distancing and altered olfactory processing. These defects were accompanied by reduced evoked Ca2+influx and structural changes in the presynaptic terminals sent by the primary olfactory neurons to higher processing centres. In contrast, expression ofRim-RNAiin the mushroom bodies (MBs), the main memory centre in flies, spared learning and memory suggesting a differential role of Rim in different synapses. Circadian deficits have been reported in schizophrenia. We observed circadian locomotor activity deficits inRimmutants, revealing a role of Rim in the pacemaker ventral lateral clock neurons (LNvs). These changes were accompanied by impaired day/night remodelling of dorsal terminal synapses from a subpopulation of LNvs and impaired day/night release of the circadian neuropeptide pigment dispersing factor (PDF) from these terminals. Lastly, treatment with the commonly used antipsychotic haloperidol rescuedRimlocomotor deficits to wildtype. This work characterises the role of Rim in synaptic functions underlying behaviours disrupted in schizophrenia.
Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies
Authors: Rögnvaldsson Sæmundur , Love Thorvardur Jon , Thorsteinsdottir Sigrun , Reed Elín Ruth , Óskarsson Jón Þórir , Pétursdóttir Íris , Sigurðardóttir Guðrún Ásta , Viðarsson Brynjar , Önundarson Páll Torfi , Agnarsson Bjarni A. , Sigurðardóttir Margrét , Þorsteinsdóttir Ingunn , Ólafsson Ísleifur , Þórðardóttir Ásdís Rósa , Eyþórsson Elías , Jónsson Ásbjörn , Björnsson Andri S. , Gunnarsson Gunnar Þór , Pálsson Runólfur , Indriðason Ólafur Skúli , Gíslason Gauti Kjartan , Ólafsson Andri , Hákonardóttir Guðlaug Katrín , Brinkhuis Manje , Halldórsdóttir Sara Lovísa , Ásgeirsdóttir Tinna Laufey , Steingrímsdóttir Hlíf , Danielsen Ragnar , Dröfn Wessman Inga , Kampanis Petros , Hultcrantz Malin , Durie Brian G. M. , Harding Stephen , Landgren Ola , Kristinsson Sigurður Yngvi
Published: May 2021

Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis
Authors: Maiti Guru P. , Sinha Sutapa , Mahmud Hasan , Boysen Justin , Mendez Mariana T. , Vesely Sara K. , Holter-Chakrabarty Jennifer , Kay Neil E. , Ghosh Asish K.
Published: May 2021

Mitochondrial metabolism is the key source for abundant ROS in chronic lymphocytic leukemia (CLL) cells. Here, we detected significantly lower superoxide anion (O2−) levels with increased accumulation of hydrogen peroxide (H2O2) in CLL cells vs. normal B-cells. Further analysis indicated that mitochondrial superoxide dismutase (SOD)2, which converts O2− into H2O2 remained deacetylated in CLL cells due to SIRT3 overexpression resulting its constitutive activation. In addition, catalase expression was also reduced in CLL cells suggesting impairment of H2O2-conversion into water and O2 which may cause H2O2-accumulation. Importantly, we identified two CpG-islands in the catalase promoter and discovered that while the distal CpG-island (−3619 to −3765) remained methylated in both normal B-cells and CLL cells, variable degrees of methylation were discernible in the proximal CpG-island (−174 to −332) only in CLL cells. Finally, treatment of CLL cells with a demethylating agent increased catalase mRNA levels. Functionally, ROS accumulation in CLL cells activated the AXL survival axis while upregulated SIRT3, suggesting that CLL cells rapidly remove highly reactive O2− to avoid its cytotoxic effect but maintain increased H2O2-level to promote cell survival. Therefore, abrogation of aberrantly activated cell survival pathways using antioxidants can be an effective intervention in CLL therapy in combination with conventional agents.
Long intergenic non-coding RNA 00473 promotes proliferation and migration of gastric cancer via the miR-16-5p/CCND2 axis and by regulating AQP3
Authors: Zhuo Shuaishuai , Sun Miaomiao , Bai Rumeng , Lu Die , Di Shihao , Ma Tianshi , Zou Zigui , Li Hongxia , Zhang Zhihong
Published: May 2021

Gastric cancer (GC) is one of the most common malignancies worldwide, but its molecular mechanisms remain unclear. Increasing evidence indicates that long non-coding RNAs (LncRNAs) play a pivotal role in various cancers recently. Our present study focused on exploring the function of long intergenic non-coding RNA 00473 (LINC00473) in GC. In this study, we found that LINC00473 expression was aberrantly increased in tumor tissues compared with the paired para-cancerous tissues. The expression of high LINC00473 in GC was notably correlated with a higher risk of lymphatic metastasis, a higher incidence of vascular cancer embolus, and advanced TNM stage. Further experiments showed that the overexpression of LINC00473 could promote the proliferation and metastasis of GC cells both in vitro and in vivo. The apoptosis of GC cells increased significantly by the decrease of LINC00473. Mechanistically, LINC00473 could sponge miR-16-5p in the cytoplasm and relieve its suppression of CCND2. Moreover, AQP3 was found to be a significant downstream target gene for LINC00473 through RNA transcriptome sequencing, as demonstrated by qRT-PCR and western blot. Overexpression of LINC00473 can partially reverse the effects of AQP3 decrease on GC proliferation and metastasis. LINC00473 regulated AQP3 expression through CREB was confirmed by western blot. Our research indicates that LINC00473/miR-16-5p/CCND2 axis plays a role in the proliferation of GC and modulates AQP3 to influence GC cell metastasis, making it a potential therapeutic target for GC.
Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice
Authors: Teufel Stefan , Köckemann Petra , Fabritius Christine , Wolff Lena I. , Bertrand Jessica , Pap Thomas , Hartmann Christine
Published: May 2021

Agonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.
N6-methyladenosine (m6A) methyltransferase KIAA1429 accelerates the gefitinib resistance of non-small-cell lung cancer
Authors: Tang Jun , Han Tianci , Tong Wei , Zhao Jian , Wang Wei
Published: May 2021

N6-methyladenosine (m6A) modification has been convincingly identified to be a critical regulator in human cancer. However, the contribution of m6A to NSCLC gefitinib resistance is still largely unknown. Here, we screened and identified that m6A methyltransferase KIAA1429 was highly expressed in gefitinib-resistant NSCLC cells (PC9-GR), tissues, and closely related to unfavorable survival. Functionally, KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro. Depletion of KIAA1429 repressed the tumor growth of PC9-GR cells in vivo. Mechanistically, KIAA1429 enhanced the mRNA stability of HOXA1 through targeting its 3′-untranslated regions (3′-UTR). Overall, our findings indicate that KIAA1429 plays essential oncogenic roles in NSCLC gefitinib resistance, which may provide a feasible therapeutic target for NSCLC.
Importance of circadian timing for aging and longevity
Authors: Acosta-Rodríguez Victoria A. , Rijo-Ferreira Filipa , Green Carla B. , Takahashi Joseph S.
Published: May 2021

Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.
Toxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage
Authors: Dass Sheena , Shunmugam Serena , Berry Laurence , Arnold Christophe-Sebastien , Katris Nicholas J. , Duley Samuel , Pierrel Fabien , Cesbron-Delauw Marie-France , Yamaryo-Botté Yoshiki , Botté Cyrille Y.
Published: May 2021

Apicomplexa are obligate intracellular parasites responsible for major human diseases. Their intracellular survival relies on intense lipid synthesis, which fuels membrane biogenesis. Parasite lipids are generated as an essential combination of fatty acids scavenged from the host and de novo synthesized within the parasite apicoplast. The molecular and metabolic mechanisms allowing regulation and channeling of these fatty acid fluxes for intracellular parasite survival are currently unknown. Here, we identify an essential phosphatidic acid phosphatase in Toxoplasma gondii, TgLIPIN, as the central metabolic nexus responsible for controlled lipid synthesis sustaining parasite development. Lipidomics reveal that TgLIPIN controls the synthesis of diacylglycerol and levels of phosphatidic acid that regulates the fine balance of lipids between storage and membrane biogenesis. Using fluxomic approaches, we uncover the first parasite host-scavenged lipidome and show that TgLIPIN prevents parasite death by ‘lipotoxicity’ through effective channeling of host-scavenged fatty acids to storage triacylglycerols and membrane phospholipids.
Observation of topological superconductivity in a stoichiometric transition metal dichalcogenide 2M-WS2
Authors: Li Y. W. , Zheng H. J. , Fang Y. Q. , Zhang D. Q. , Chen Y. J. , Chen C. , Liang A. J. , Shi W. J. , Pei D. , Xu L. X. , Liu S. , Pan J. , Lu D. H. , Hashimoto M. , Barinov A. , Jung S. W. , Cacho C. , Wang M. X. , He Y. , Fu L. , Zhang H. J. , Huang F. Q. , Yang L. X. , Liu Z. K. , Chen Y. L.
Published: May 2021

Topological superconductors (TSCs) are unconventional superconductors with bulk superconducting gap and in-gap Majorana states on the boundary that may be used as topological qubits for quantum computation. Despite their importance in both fundamental research and applications, natural TSCs are very rare. Here, combining state of the art synchrotron and laser-based angle-resolved photoemission spectroscopy, we investigated a stoichiometric transition metal dichalcogenide (TMD), 2M-WS2 with a superconducting transition temperature of 8.8 K (the highest among all TMDs in the natural form up to date) and observed distinctive topological surface states (TSSs). Furthermore, in the superconducting state, we found that the TSSs acquired a nodeless superconducting gap with similar magnitude as that of the bulk states. These discoveries not only evidence 2M-WS2 as an intrinsic TSC without the need of sensitive composition tuning or sophisticated heterostructures fabrication, but also provide an ideal platform for device applications thanks to its van der Waals layered structure.
Supervised dimensionality reduction for big data
Authors: Vogelstein Joshua T. , Bridgeford Eric W. , Tang Minh , Zheng Da , Douville Christopher , Burns Randal , Maggioni Mauro
Published: May 2021

To solve key biomedical problems, experimentalists now routinely measure millions or billions of features (dimensions) per sample, with the hope that data science techniques will be able to build accurate data-driven inferences. Because sample sizes are typically orders of magnitude smaller than the dimensionality of these data, valid inferences require finding a low-dimensional representation that preserves the discriminating information (e.g., whether the individual suffers from a particular disease). There is a lack of interpretable supervised dimensionality reduction methods that scale to millions of dimensions with strong statistical theoretical guarantees. We introduce an approach to extending principal components analysis by incorporating class-conditional moment estimates into the low-dimensional projection. The simplest version, Linear Optimal Low-rank projection, incorporates the class-conditional means. We prove, and substantiate with both synthetic and real data benchmarks, that Linear Optimal Low-Rank Projection and its generalizations lead to improved data representations for subsequent classification, while maintaining computational efficiency and scalability. Using multiple brain imaging datasets consisting of more than 150 million features, and several genomics datasets with more than 500,000 features, Linear Optimal Low-Rank Projection outperforms other scalable linear dimensionality reduction techniques in terms of accuracy, while only requiring a few minutes on a standard desktop computer.