bluuebunny/crossref_metadata_2025 huggingface dataset:
MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma
Authors: Fu Dechen , Pfannenstiel Luke , Demelash Abeba , Phoon Yee Peng , Mayell Cameron , Cabrera Claudia , Liu Caini , Zhao Junjie , Dermawan Josephine , Patil Deepa , DeVecchio Jennifer , Kalady Matthew , Souers Andrew J. , Phillips Darren C. , Li Xiaoxia , Gastman Brian
Published: January 2022

Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2 family members is a well-studied means by which this protein confers resistance to multiple anti-cancer therapies. We found that specific DNA damaging chemotherapies promote nuclear MCL1 translocation in CRC models. In p53null CRC, this process is associated with resistance to chemotherapeutic agents, the mechanism of which is distinct from the classical mitochondrial protection. We previously reported that MCL1 has a noncanonical chemoresistance capability, which requires a novel loop domain that is distinct from the BH3-binding domain associated with anti-apoptotic function. Herein we disclose that upon treatment with specific DNA-damaging chemotherapy, this loop domain binds directly to alpha-enolase which in turn binds to calmodulin; we further show these protein−protein interactions are critical in MCL1’s nuclear import and chemoresistance. We additionally observed that in chemotherapy-treated p53−/− CRC models, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors, which has significant translational relevance given the co-expression of these proteins in CRC patient samples. Together these findings indicate that chemotherapy-induced MCL1 translocation represents a novel resistance mechanism in CRC, while also exposing an inherent and targetable Bcl-xL co-dependency in these cancers. The combination of chemotherapy and Bcl-xL inhibitors may thus represent a rational means of treating p53−/− CRC via exploitation of this unique MCL1-based chemoresistance mechanism.
Make it easier: 3-word strategies to help children with cerebral visual impairment use their vision more effectively
Authors: Pilling Rachel F.
Published: January 2022

Introduction

Cerebral Visual Impairment (CVI) is the most common cause of visual impairment in children in the United Kingdom. Management relies on identifying strategies and adaptations which enable the child to use their vision effectively and efficiently. The majority of published strategies involve lengthy inventories used in a specialist setting. Feedback from parent support groups cite the provision of immediate advice on strategies at the time of diagnosis as a key indicator of good care. The aim of the study was to use the Delphi technique to construct a set of three-word phrases to succinctly describe strategies for common visual dysfunctions in children with CVI.

Method

A panel of twelve experts across health, education and those with lived experience was recruited. Four rounds of questionnaires were used to reach consensus on candidates symptoms and suggestions for 3-word-phrases. Consensus was defined as 70% agreement.

Results

Response rates were 92, 67, 92 and 91% for each round respectively. The 3-word phrases reaching consensus were: Big Bold Bright; Keep it Still; Eyes or Ears; Show It High; Better on Left/Right; Clear the Clutter; Keep It Short; Give Me Time, My Vision Varies, Just One Thing.

Conclusion

The intention is for the phrases presented to act as a ‘starter’ at the point of diagnosis and are appropriate for children of any developmental or visual ability. The real-life validation of this set of expert-consensus phrases will require further studies, evaluating both their effectiveness in terms of mapping to an intervention and impact on visual development.
Lack of TRPV1 aggravates obesity-associated hypertension through the disturbance of mitochondrial Ca2+ homeostasis in brown adipose tissue
Authors: Li Li , Ma Liqun , Luo Zhidan , Wei Xiao , Zhao Yu , Zhou Cui , Mou Aidi , Lu Zongshi , You Mei , He Chengkang , Ma Huan , Zhou Qing , Wang Lijuan , Cao Tingbing , Gu Yucun , Gao Peng , Zhu Zhiming
Published: January 2022

The combination of obesity and hypertension is associated with high morbidity and mortality; however, the mechanism underlying obesity-induced hypertension remains unclear. In this study, we detected the possible effects of TRPV1, a previously identified antihypertensive calcium (Ca2+) channel in adipose tissue, on the occurrence of obesity and hypertension in mice lacking UCP1, a spontaneously genetically manipulated obesity model, by generating TRPV1 and UCP1 double knockout mice. In these mice, obesity and hypertension appeared earlier and were more severe than in mice with the knockout of UCP1 or TRPV1 alone. The knockout of TRPV1 in UCP1 knockout mice further reduced functional brown adipose tissue (BAT) generation; decreased resting oxygen consumption, heat production, and locomotor activities; and was accompanied by severe mitochondrial respiratory dysfunction in BAT. Mechanistically, TRPV1, UCP1, and LETM1 acted as a complex to maintain an appropriate mitochondrial Ca2+ level, and TRPV1 knockout caused a compensatory increase in mitochondrial Ca2+ uptake via LETM1 activation. However, the compensatory response was blocked in UCP1−/− mice, resulting in dramatically reduced mitochondrial Ca2+ uptake and higher production of ATP and oxidative stress. This study provides in vivo evidence for the critical role of BAT mitochondrial Ca2+ homeostasis in obesity-associated hypertension and indicates that the TRPV1/UCP1/LETM1 complex may be an alternative intervention target.
Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2
Authors: Garcia-Flores Valeria , Romero Roberto , Xu Yi , Theis Kevin R. , Arenas-Hernandez Marcia , Miller Derek , Peyvandipour Azam , Bhatti Gaurav , Galaz Jose , Gershater Meyer , Levenson Dustyn , Pusod Errile , Tao Li , Kracht David , Florova Violetta , Leng Yaozhu , Motomura Kenichiro , Para Robert , Faucett Megan , Hsu Chaur-Dong , Zhang Gary , Tarca Adi L. , Pique-Regi Roger , Gomez-Lopez Nardhy
Published: January 2022

Pregnant women represent a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Here we show that SARS-CoV-2 infection during pregnancy primarily induces unique inflammatory responses at the maternal-fetal interface, which are largely governed by maternal T cells and fetal stromal cells. SARS-CoV-2 infection during pregnancy is also associated with humoral and cellular immune responses in the maternal blood, as well as with a mild cytokine response in the neonatal circulation (i.e., umbilical cord blood), without compromising the T-cell repertoire or initiating IgM responses. Importantly, SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and emphasizes the rarity of placental infection.
Learning in continuous action space for developing high dimensional potential energy models
Authors: Manna Sukriti , Loeffler Troy D. , Batra Rohit , Banik Suvo , Chan Henry , Varughese Bilvin , Sasikumar Kiran , Sternberg Michael , Peterka Tom , Cherukara Mathew J. , Gray Stephen K. , Sumpter Bobby G. , Sankaranarayanan Subramanian K. R. S.
Published: January 2022

Reinforcement learning (RL) approaches that combine a tree search with deep learning have found remarkable success in searching exorbitantly large, albeit discrete action spaces, as in chess, Shogi and Go. Many real-world materials discovery and design applications, however, involve multi-dimensional search problems and learning domains that have continuous action spaces. Exploring high-dimensional potential energy models of materials is an example. Traditionally, these searches are time consuming (often several years for a single bulk system) and driven by human intuition and/or expertise and more recently by global/local optimization searches that have issues with convergence and/or do not scale well with the search dimensionality. Here, in a departure from discrete action and other gradient-based approaches, we introduce a RL strategy based on decision trees that incorporates modified rewards for improved exploration, efficient sampling during playouts and a “window scaling scheme" for enhanced exploitation, to enable efficient and scalable search for continuous action space problems. Using high-dimensional artificial landscapes and control RL problems, we successfully benchmark our approach against popular global optimization schemes and state of the art policy gradient methods, respectively. We demonstrate its efficacy to parameterize potential models (physics based and high-dimensional neural networks) for 54 different elemental systems across the periodic table as well as alloys. We analyze error trends across different elements in the latent space and trace their origin to elemental structural diversity and the smoothness of the element energy surface. Broadly, our RL strategy will be applicable to many other physical science problems involving search over continuous action spaces.
Ice front retreat reconfigures meltwater-driven gyres modulating ocean heat delivery to an Antarctic ice shelf
Authors: Yoon Seung-Tae , Lee Won Sang , Nam SungHyun , Lee Choon-Ki , Yun Sukyoung , Heywood Karen , Boehme Lars , Zheng Yixi , Lee Inhee , Choi Yeon , Jenkins Adrian , Jin Emilia Kyung , Larter Robert , Wellner Julia , Dutrieux Pierre , Bradley Alexander T.
Published: January 2022

Pine Island Ice Shelf (PIIS) buttresses the Pine Island Glacier, the key contributor to sea-level rise. PIIS has thinned owing to ocean-driven melting, and its calving front has retreated, leading to buttressing loss. PIIS melting depends primarily on the thermocline variability in its front. Furthermore, local ocean circulation shifts adjust heat transport within Pine Island Bay (PIB), yet oceanic processes underlying the ice front retreat remain unclear. Here, we report a PIB double-gyre that moves with the PIIS calving front and hypothesise that it controls ocean heat input towards PIIS. Glacial melt generates cyclonic and anticyclonic gyres near and off PIIS, and meltwater outflows converge into the anticyclonic gyre with a deep-convex-downward thermocline. The double-gyre migrated eastward as the calving front retreated, placing the anticyclonic gyre over a shallow seafloor ridge, reducing the ocean heat input towards PIIS. Reconfigurations of meltwater-driven gyres associated with moving ice boundaries might be crucial in modulating ocean heat delivery to glacial ice.
Hierarchically encapsulating enzymes with multi-shelled metal-organic frameworks for tandem biocatalytic reactions
Authors: Man Tiantian , Xu Caixia , Liu Xiao-Yuan , Li Dan , Tsung Chia-Kuang , Pei Hao , Wan Ying , Li Li
Published: January 2022

Biocatalytic transformations in living organisms, such as multi-enzyme catalytic cascades, proceed in different cellular membrane-compartmentalized organelles with high efficiency. Nevertheless, it remains challenging to mimicking biocatalytic cascade processes in natural systems. Herein, we demonstrate that multi-shelled metal-organic frameworks (MOFs) can be used as a hierarchical scaffold to spatially organize enzymes on nanoscale to enhance cascade catalytic efficiency. Encapsulating multi-enzymes with multi-shelled MOFs by epitaxial shell-by-shell overgrowth leads to 5.8~13.5-fold enhancements in catalytic efficiencies compared with free enzymes in solution. Importantly, multi-shelled MOFs can act as a multi-spatial-compartmental nanoreactor that allows physically compartmentalize multiple enzymes in a single MOF nanoparticle for operating incompatible tandem biocatalytic reaction in one pot. Additionally, we use nanoscale Fourier transform infrared (nano-FTIR) spectroscopy to resolve nanoscale heterogeneity of vibrational activity associated to enzymes encapsulated in multi-shelled MOFs. Furthermore, multi-shelled MOFs enable facile control of multi-enzyme positions according to specific tandem reaction routes, in which close positioning of enzyme-1-loaded and enzyme-2-loaded shells along the inner-to-outer shells could effectively facilitate mass transportation to promote efficient tandem biocatalytic reaction. This work is anticipated to shed new light on designing efficient multi-enzyme catalytic cascades to encourage applications in many chemical and pharmaceutical industrial processes.
Asymmetric synthesis of N-bridged [3.3.1] ring systems by phosphonium salt/Lewis acid relay catalysis
Authors: Tan Jian-Ping , Li Kehan , Shen Boming , Zhuang Cheng , Liu Zanjiao , Xiao Kai , Yu Peiyuan , Yi Bing , Ren Xiaoyu , Wang Tianli
Published: January 2022

Optically pure pseudo-natural products (PNPs), particularly exemplified by azabicyclo[3.3.1]nonane molecules and their analogs provide an attractive platform for structure−activity relationship studies, and also lead new compound discovery in drug development. However, there are currently no examples of guiding catalytic asymmetric strategies available to construct such important PN-scaffolds, thus limiting their broad use. Here, we report a general and modular method for constructing these pseudo-natural N-bridged [3.3.1] ring systems via cascade process by bifunctional phosphonium salt/Lewis acid relay catalysis. A wide variety of substrates bearing an assortment of functional groups (59 examples) are compatible with this protocol. Other features include a [3 + 2] cyclization/ring-opening/Friedel-Crafts cascade pathway, excellent reactivities and stereoselectivities, easily available starting materials, step economy and scalability. The obtained enantioenriched products showed potential of preliminary anticancer activities. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging even unprecedented chiral PNPs, offering new opportunities for bioactive small-molecule discovery.
Iridium-catalyzed enantioconvergent hydrogenation of trisubstituted olefins
Authors: Peters Bram B. C. , Zheng Jia , Birke Norman , Singh Thishana , Andersson Pher G.
Published: January 2022

Asymmetric hydrogenation of olefins constitutes a practical and efficient method to introduce chirality into prochiral substrates. However, the absolute majority of the developed methodologies is enantiodivergent and thus require isomerically pure olefins which is a considerable drawback since most olefination strategies produce (E/Z)-mixtures. Although some advances have been reported, a general enantioconvergent hydrogenation featuring a broad functional group tolerance remains elusive. Here, we report the development of a general iridium-catalyzed enantioconvergent hydrogenation of a broad range of functionalized trisubstituted olefins. The substitution pattern around the olefin is critical; whereas α-prochiral olefins can undergo an enantioconvergent hydrogenation, β-prochiral olefins react in an enantiodivergent manner. The presented methodology hydrogenates α-prochiral substrates with excellent control of enantioselection and high isolated yields. Most importantly, both isomerically pure alkenes as well as isomeric mixtures can be hydrogenated to yield the same major enantiomer in excellent enantiomeric excesses which is unusual in transition-metal catalyzed asymmetric hydrogenations.
The 21-gene recurrence score in early non-ductal breast cancer: a National Cancer Database analysis
Authors: Makower Della , Qin Jiyue , Lin Juan , Xue Xiaonan , Sparano Joseph A.
Published: January 2022

The 21-gene recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit in early estrogen receptor-positive (ER +) HER2-negative (HER2-) breast cancer (BCA). We evaluated clinicopathologic characteristics, RS and chemotherapy benefit in invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and carcinomas of mixed histologies (ductal + lobular (DLC), ductal + other (DOC), lobular + other (LOC)). Women diagnosed between 1/1/2010 and 1/1/2014 with ER + HER2- BCA, measuring <5 cm, with 0–3 involved axillary nodes, surgery as first treatment, and available RS, were identified from the NCDB. Associations between categorical variables were examined using chi-square test. Cox proportional hazards model was used to examine overall survival (OS) differences among histology subtypes. IDC was associated with smaller size, high grade, and RS > 26. ILC was associated with larger size, and least likely to be high grade (p < 0.0001). Lobular histology was associated with lower incidence of RS > 26. IDC patients (pts) were more likely to receive chemotherapy than pts with other histologies (p < 0.0001). OS for IDC, ILC and DOC were similar. DLC was associated with improved OS (HR 0.82, p = 0.02). Adjuvant chemotherapy was associated with improved OS in IDC (HR = 0.76, p < 0.0001) but not in ILC (HR = 0.99, p = 0.93), DLC (HR = 1.04, p = 0.86), DOC (HR = 0.87, p = 0.71), or LOC (HR = 2.91, p = 0.10). Lobular and mixed BCA histologies have distinct clinicopathologic features compared with IDC, and are less likely to have high RS. OS is similar for IDC and ILC. Although chemotherapy benefit was seen only in IDC, benefit for ILC with RS > 26 cannot be excluded.
Comparative transcriptional analyses of preclinical models and patient samples reveal MYC and RELA driven expression patterns that define the molecular landscape of IBC
Authors: Rypens Charlotte , Bertucci François , Finetti Pascal , Robertson Fredika , Fernandez Sandra V. , Ueno Naoto , Woodward Wendy A. , Van Golen Kenneth , Vermeulen Peter , Dirix Luc , Viens Patrice , Birnbaum Daniel , Devi Gayathri R. , Cristofanilli Massimo , Van Laere Steven
Published: January 2022

Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.
Design of soft magnetic materials
Authors: Renuka Balakrishna Ananya , James Richard D.
Published: January 2022

We present a strategy for the design of ferromagnetic materials with exceptionally low magnetic hysteresis, quantified by coercivity. In this strategy, we use a micromagnetic algorithm that we have developed in previous research and which has been validated by its success in solving the “Permalloy Problem”—the well-known difficulty of predicting the composition 78.5% Ni of the lowest coercivity in the Fe–Ni system—and by the insight it provides into the “Coercivity Paradox” of W. F. Brown. Unexpectedly, the design strategy predicts that cubic materials with large saturation magnetization ms and large magnetocrystalline anisotropy constant κ1 will have low coercivity on the order of that of Permalloy, as long as the magnetostriction constants λ100, λ111 are tuned to special values. The explicit prediction for a cubic material with low coercivity is the dimensionless number $$({c}_{11}-{c}_{12}){\lambda }_{100}^{2}/(2{\kappa }_{1})=81$$

(

c

11

−

c

12

)

λ

100

2

/

(

2

κ

1

)

=
81
for 〈100〉 easy axes. The results would seem to have broad potential application, especially to magnetic materials of interest in energy research.
Unconventional superconductivity in magic-angle twisted trilayer graphene
Authors: Fischer Ammon , Goodwin Zachary A. H. , Mostofi Arash A. , Lischner Johannes , Kennes Dante M. , Klebl Lennart
Published: January 2022

Magic-angle twisted trilayer graphene (MATTG) recently emerged as a highly tunable platform for studying correlated phases of matter, such as correlated insulators and superconductivity. Superconductivity occurs in a range of doping levels that is bounded by van Hove singularities, which stimulates the debate of the origin and nature of superconductivity in this material. In this work, we discuss the role of spin-fluctuations arising from atomic-scale correlations in MATTG for the superconducting state. We show that in a phase diagram as a function of doping (ν) and temperature, nematic superconducting regions are surrounded by ferromagnetic states and that a superconducting dome with Tc ≈ 2 K appears between the integer fillings ν = −2 and ν = −3. Applying a perpendicular electric field enhances superconductivity on the electron-doped side which we relate to changes in the spin-fluctuation spectrum. We show that the nematic unconventional superconductivity leads to pronounced signatures in the local density of states detectable by scanning tunneling spectroscopy measurements.
Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa
Authors: Viana Raquel , Moyo Sikhulile , Amoako Daniel G. , Tegally Houriiyah , Scheepers Cathrine , Althaus Christian L. , Anyaneji Ugochukwu J. , Bester Phillip A. , Boni Maciej F. , Chand Mohammed , Choga Wonderful T. , Colquhoun Rachel , Davids Michaela , Deforche Koen , Doolabh Deelan , du Plessis Louis , Engelbrecht Susan , Everatt Josie , Giandhari Jennifer , Giovanetti Marta , Hardie Diana , Hill Verity , Hsiao Nei-Yuan , Iranzadeh Arash , Ismail Arshad , Joseph Charity , Joseph Rageema , Koopile Legodile , Kosakovsky Pond Sergei L. , Kraemer Moritz U. G. , Kuate-Lere Lesego , Laguda-Akingba Oluwakemi , Lesetedi-Mafoko Onalethatha , Lessells Richard J. , Lockman Shahin , Lucaci Alexander G. , Maharaj Arisha , Mahlangu Boitshoko , Maponga Tongai , Mahlakwane Kamela , Makatini Zinhle , Marais Gert , Maruapula Dorcas , Masupu Kereng , Matshaba Mogomotsi , Mayaphi Simnikiwe , Mbhele Nokuzola , Mbulawa Mpaphi B. , Mendes Adriano , Mlisana Koleka , Mnguni Anele , Mohale Thabo , Moir Monika , Moruisi Kgomotso , Mosepele Mosepele , Motsatsi Gerald , Motswaledi Modisa S. , Mphoyakgosi Thongbotho , Msomi Nokukhanya , Mwangi Peter N. , Naidoo Yeshnee , Ntuli Noxolo , Nyaga Martin , Olubayo Lucier , Pillay Sureshnee , Radibe Botshelo , Ramphal Yajna , Ramphal Upasana , San James E. , Scott Lesley , Shapiro Roger , Singh Lavanya , Smith-Lawrence Pamela , Stevens Wendy , Strydom Amy , Subramoney Kathleen , Tebeila Naume , Tshiabuila Derek , Tsui Joseph , van Wyk Stephanie , Weaver Steven , Wibmer Constantinos K. , Wilkinson Eduan , Wolter Nicole , Zarebski Alexander E. , Zuze Boitumelo , Goedhals Dominique , Preiser Wolfgang , Treurnicht Florette , Venter Marietje , Williamson Carolyn , Pybus Oliver G. , Bhiman Jinal , Glass Allison , Martin Darren P. , Rambaut Andrew , Gaseitsiwe Simani , von Gottberg Anne , de Oliveira Tulio
Published: January 2022

The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively1–3. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function4. Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.
Comprehensive diffusion MRI dataset for in vivo human brain microstructure mapping using 300 mT/m gradients
Authors: Tian Qiyuan , Fan Qiuyun , Witzel Thomas , Polackal Maya N. , Ohringer Ned A. , Ngamsombat Chanon , Russo Andrew W. , Machado Natalya , Brewer Kristina , Wang Fuyixue , Setsompop Kawin , Polimeni Jonathan R. , Keil Boris , Wald Lawrence L. , Rosen Bruce R. , Klawiter Eric C. , Nummenmaa Aapo , Huang Susie Y.
Published: January 2022

Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling.
Landscape Dynamics (landDX) an open-access spatial-temporal database for the Kenya-Tanzania borderlands
Authors: Tyrrell Peter , Amoke Irene , Betjes Koen , Broekhuis Femke , Buitenwerf Robert , Carroll Sarah , Hahn Nathan , Haywood Daniel , Klaassen Britt , Løvschal Mette , Macdonald David , Maiyo Karen , Mbithi Hellen , Mwangi Nelson , Ochola Churchil , Odire Erick , Ondrusek Victoria , Ratemo Junior , Pope Frank , Russell Samantha , Sairowua Wilson , Sigilai Kiptoo , Stabach Jared A. , Svenning Jens-Christian , Stone Elizabeth , du Toit Johan T. , Western Guy , Wittemyer George , Wall Jake
Published: January 2022

The savannas of the Kenya-Tanzania borderland cover >100,000 km2and is one of the most important regions globally for biodiversity conservation, particularly large mammals. The region also supports >1 million pastoralists and their livestock. In these systems, resources for both large mammals and pastoralists are highly variable in space and time and thus require connected landscapes. However, ongoing fragmentation of (semi-)natural vegetation by smallholder fencing and expansion of agriculture threatens this social-ecological system. Spatial data on fences and agricultural expansion are localized and dispersed among data owners and databases. Here, we synthesized data from several research groups and conservation NGOs and present the first release of the Landscape Dynamics (landDX) spatial-temporal database, covering ~30,000 km2of southern Kenya. The data includes 31,000 livestock enclosures, nearly 40,000 kilometres of fencing, and 1,500 km2of agricultural land. We provide caveats and interpretation of the different methodologies used. These data are useful to answer fundamental ecological questions, to quantify the rate of change of ecosystem function and wildlife populations, for conservation and livestock management, and for local and governmental spatial planning.
Mendelian randomisation analyses of UK Biobank and published data suggest that increased adiposity lowers risk of breast and prostate cancer
Authors: Amin Hasnat A. , Kaewsri Pimpika , Yiorkas Andrianos M. , Cooke Heather , Blakemore Alexandra I. , Drenos Fotios
Published: January 2022

Breast (BCa) and prostate (PrCa) cancer are the first and second most common types of cancer in women and men, respectively. We aimed to explore the causal effect of adiposity on BCa and PrCa risk in the UK Biobank and published data. We used Mendelian randomisation (MR) to assess the causal effect of body mass index (BMI), body fat percentage (BFP), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) on BCa and PrCa risk. We found that increased BMI, WC and HC decreased the risk of breast cancer (OR 0.70 per 5.14 kg/m2 [0.59–0.85, p = 2.1 × 10–4], 0.76 per 12.49 cm [60–0.97, p = 0.028] and 0.73 per 10.31 cm [0.59–0.90, p = 3.7 × 10–3], respectively) and increased WC and BMI decreased the risk of prostate cancer (0.68 per 11.32 cm [0.50–0.91, p = 0.01] and 0.76 per 10.23 kg/m2 [0.61–0.95, p = 0.015], respectively) in UK Biobank participants. We confirmed our results with a two-sample-MR of published data. In conclusion, our results suggest a protective effect of adiposity on the risk of BCa and PrCa highlighting the need to re-evaluate the role of adiposity as cancer risk factor.
A neural network-based method for exhaustive cell label assignment using single cell RNA-seq data
Authors: Li Ziyi , Feng Hao
Published: January 2022

The fast-advancing single cell RNA sequencing (scRNA-seq) technology enables researchers to study the transcriptome of heterogeneous tissues at a single cell level. The initial important step of analyzing scRNA-seq data is usually to accurately annotate cells. The traditional approach of annotating cell types based on unsupervised clustering and marker genes is time-consuming and laborious. Taking advantage of the numerous existing scRNA-seq databases, many supervised label assignment methods have been developed. One feature that many label assignment methods shares is to label cells with low confidence as “unassigned.” These unassigned cells can be the result of assignment difficulties due to highly similar cell types or caused by the presence of unknown cell types. However, when unknown cell types are not expected, existing methods still label a considerable number of cells as unassigned, which is not desirable. In this work, we develop a neural network-based cell annotation method called NeuCA (Neural network-based Cell Annotation) for scRNA-seq data obtained from well-studied tissues. NeuCA can utilize the hierarchical structure information of the cell types to improve the annotation accuracy, which is especially helpful when data contain closely correlated cell types. We show that NeuCA can achieve more accurate cell annotation results compared with existing methods. Additionally, the applications on eight real datasets show that NeuCA has stable performance for intra- and inter-study annotation, as well as cross-condition annotation. NeuCA is freely available as an R/Bioconductor package at https://bioconductor.org/packages/NeuCA.
Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity
Authors: Bharti Hina , Singal Aakriti , Saini Manisha , Cheema Pradeep Singh , Raza Mohsin , Kundu Suman , Nag Alo
Published: January 2022

Malaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.
Effect of nano-SiO2 and nano-CaCO3 on the static and dynamic properties of concrete
Authors: Wang Zhi-hang , Bai Er-lei , Xu Jin-yu , Du Yu-hang , Zhu Jing-sai
Published: January 2022

Three kinds of nano-concrete, i.e., 2.0% nano-SiO2 doped, 2.0% nano-CaCO3 doped and 1.0% nano-SiO2-1.0% nano-CaCO3 co-doped concretes (NS, NC, NSC) were prepared for a study on static property and dynamic property under different strain rates (50–130 s−1) using HYY series hydraulic servo test system and Φ100 mm split Hopkinson pressure bar test system, and a comparison with plain concrete (PC) as well. The results have shown that under static load, as compared with PC, NC has both strength and elastic modulus increased obviously, while NS has strength decreased and elastic modulus increased, and under dynamic load, there is an obvious strain rate effect for the dynamic compressive strength, impact toughness, energy dissipation and impact failure mode of concrete. Under the same strain rate, the dynamic compressive strength, peak strain, impact toughness and energy dissipation of NC are significantly increased, while its dynamic elastic modulus is decreased. Compared with PC, NS has dynamic compressive strength, peak strain, impact toughness and energy dissipation decreased, and dynamic elastic modulus increased, NC has static and dynamic mechanical properties improved, NS has static and dynamic mechanical properties weakened, and NSC is between PC and NC in static and dynamic mechanical properties, but generally improved. Doped with nano-CaCO3, NC has compactness improved, weak areas reduced, and pore size distribution optimized, while doped with nano-SiO2, NS has obvious internal weak areas, with pore structure degraded.
A case–control study of the causes of acute respiratory infection among hospitalized patients in Northeastern Laos
Authors: Phommasone Koukeo , Xaiyaphet Xaipasong , Garcia-Rivera Jose A. , Hontz Robert D. , Pathavongsa Viengmone , Keomoukda Patsalin , Vongsouvath Malavanh , Mayxay Mayfong , Vongsouvath Manivanh , Newton Paul N. , Ashley Elizabeth A. , Dubot-Pérès Audrey
Published: January 2022

With the advent of highly sensitive real-time PCR, multiple pathogens have been identified from nasopharyngeal swabs of patients with acute respiratory infections (ARIs). However, the detection of microorganisms in the upper respiratory tract does not necessarily indicate disease causation. We conducted a matched case–control study, nested within a broader fever aetiology project, to facilitate determination of the aetiology of ARIs in hospitalised patients in Northeastern Laos. Consenting febrile patients of any age admitted to Xiengkhuang Provincial Hospital were included if they met the inclusion criteria for ARI presentation (at least one of the following: cough, rhinorrhoea, nasal congestion, sore throat, difficulty breathing, and/or abnormal chest auscultation). One healthy control for each patient, matched by sex, age, and village of residence, was recruited for the study. Nasopharyngeal swabs were collected from participants and tested for 33 pathogens by probe-based multiplex real-time RT-PCR (FastTrack Diagnostics Respiratory pathogen 33 kit). Attributable fraction of illness for a given microorganism was calculated by comparing results between patients and controls (= 100 * [OR − 1]/OR) (OR = odds ratio). Between 24th June 2019 and 24th June 2020, 205 consenting ARI patients and 205 matching controls were recruited. After excluding eight pairs due to age mismatch, 197 pairs were included in the analysis. Males were predominant with sex ratio 1.2:1 and children < 5 years old accounted for 59% of participants. At least one potential pathogen was detected in 173 (88%) patients and 175 (89%) controls. ARI in admitted patients were attributed to influenza B virus, influenza A virus, human metapneumovirus (HMPV), and respiratory syncytial virus (RSV) in 17.8%, 17.2%, 7.5%, and 6.5% of participants, respectively. SARS-CoV-2 was not detected in any cases or controls. Determining ARI aetiology in individual patients remains challenging. Among hospitalised patients with ARI symptoms presenting to a provincial hospital in Northeastern Laos, half were determined to be caused by one of several respiratory viruses, in particular influenza A virus, influenza B virus, HMPV, and RSV.
Distinct spatio-temporal and spectral brain patterns for different thermal stimuli perception
Authors: Tayeb Zied , Dragomir Andrei , Lee Jin Ho , Abbasi Nida Itrat , Dean Emmanuel , Bandla Aishwarya , Bose Rohit , Sundar Raghav , Bezerianos Anastasios , Thakor Nitish V. , Cheng Gordon
Published: January 2022

Understanding the human brain’s perception of different thermal sensations has sparked the interest of many neuroscientists. The identification of distinct brain patterns when processing thermal stimuli has several clinical applications, such as phantom-limb pain prediction, as well as increasing the sense of embodiment when interacting with neurorehabilitation devices. Notwithstanding the remarkable number of studies that have touched upon this research topic, understanding how the human brain processes different thermal stimuli has remained elusive. More importantly, very intense thermal stimuli perception dynamics, their related cortical activations, as well as their decoding using effective features are still not fully understood. In this study, using electroencephalography (EEG) recorded from three healthy human subjects, we identified spatial, temporal, and spectral patterns of brain responses to different thermal stimulations ranging from extremely cold and hot stimuli (very intense), moderately cold and hot stimuli (intense), to a warm stimulus (innocuous). Our results show that very intense thermal stimuli elicit a decrease in alpha power compared to intense and innocuous stimulations. Spatio-temporal analysis reveals that in the first 400 ms post-stimulus, brain activity increases in the prefrontal and central brain areas for very intense stimulations, whereas for intense stimulation, high activity of the parietal area was observed post-500 ms. Based on these identified EEG patterns, we successfully classified the different thermal stimulations with an average test accuracy of 84% across all subjects. En route to understanding the underlying cortical activity, we source localized the EEG signal for each of the five thermal stimuli conditions. Our findings reveal that very intense stimuli were anticipated and induced early activation (before 400 ms) of the anterior cingulate cortex (ACC). Moreover, activation of the pre-frontal cortex, somatosensory, central, and parietal areas, was observed in the first 400 ms post-stimulation for very intense conditions and starting 500 ms post-stimuli for intense conditions. Overall, despite the small sample size, this work presents novel findings and a first comprehensive approach to explore, analyze, and classify EEG-brain activity changes evoked by five different thermal stimuli, which could lead to a better understanding of thermal stimuli processing in the brain and could, therefore, pave the way for developing a real-time withdrawal reaction system when interacting with prosthetic limbs. We underpin this last point by benchmarking our EEG results with a demonstration of a real-time withdrawal reaction of a robotic prosthesis using a human-like artificial skin.
Cardiac troponin I and T for ruling out coronary artery disease in suspected chronic coronary syndrome
Authors: Tveit Sjur H. , Myhre Peder L. , Hanssen Tove Aminda , Forsdahl Signe Helene , Iqbal Amjid , Omland Torbjørn , Schirmer Henrik
Published: January 2022

To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD50) in patients with suspected chronic coronary syndrome (CCS). A total of 706 patients with suspected CCS, referred for Coronary Computed Tomography Angiography, were included. cTn concentrations were measured using the Singulex hs-cTnI (limit of detection [LoD] 0.08 ng/L) and Roche hs-cTnT (LoD 3 ng/L) assays. Obstructive coronary artery disease (CAD50) was defined as ≥ 50% coronary stenosis. Cardiovascular risk was determined by the NORRISK2-score. Median age of the patients was 65 (range 28–87) years, 35% were women. All patients had hs-cTnI concentrations above the LoD (median 1.9 [Q1-3 1.2–3.6] ng/L), 72% had hs-cTnT above the LoD (median 5 [Q1-3 2–11] ng/L). There was a graded relationship between hs-cTn concentrations and coronary artery calcium. Only hs-cTnI remained associated with CAD50 in adjusted analyses (OR 1.20 95% Confidence Interval [1.05–1.38]), p = 0.009). The C-statistics for hs-cTnI and hs-cTnT were 0.65 (95% CI [0.60–0.69]) and 0.60 (0.56–0.64). The highest specificity and negative predictive values for CAD50 were in the lowest NORRISK2-tertile. hs-cTn concentrations provide diagnostic information in patients with suspected CCS, with superior performance of hs-cTnI compared to hs-cTnT in regard to CAD50. The diagnostic performance appeared best in those with low cardiovascular risk.
Feasibility analysis of an ultrasound on line diagnostic approach for oral and bone surgery
Authors: Cutolo Maria Alessandra , Cafiero Carlo , Califano Luigi , Giaquinto Martino , Cusano Andrea , Cutolo Antonello
Published: January 2022

During implant surgery procedures, surgical precision is an essential prerequisite for the functional and aesthetic success of the prosthetic crown to be placed on the dental implant. A modern implant surgical approach should be standardized as much as possible to guarantee extreme precision in the insertion of the implant into the upper and lower bone jaws. Among the most common surgical errors during implant surgery there is the over-preparation of the surgical alveolus with possible damage to the contiguous anatomical structures. To avoid this problem, in the recent years, there has been an increasing attention to the development of new control techniques. In this paper, we describe an innovative ultrasound approach, which exploits the integration of an electro-acoustic transducer with the surgical drill used for realizing the alveolus in the bone that will host the implant. Specifically, he proposed approach is based on the “time-of-flight” detection technique for measuring the thickness of the residual bone subjected to the drilling. In order to demonstrate the feasibility of the proposed approach, here we report on a detailed numerical analysis aimed at studying the propagation of ultrasonic waves through the drill-bit and through the involved tissues. The obtained results confirm the validity of our approach, and enable for a future first prototype implementation of a hi-tech surgical drill-bit, which in general is suitable not only for dental implant surgery but also for other uses in oral surgery, maxillofacial surgery and for bone surgery.
Response of soil structure and crop yield to soft rock in Mu Us sandy land, China
Authors: Zhang Jian , Guo Zhen
Published: January 2022

The sandy land leaks water and fertilizer, and is seriously degraded, while the soft rock has a special depression structure, which plays a role in retaining water and fertilizer. The application of soft rock new material to sand reclamation can improve the ecological environment and ensure the quality of basic cultivated land. The soft rock and sand were mixed in different volume ratios (1:0, 11:1, 5:1, 4:1, 3:1, 2:1, 7:5, 1:1, 5:7, 1:2, 1:3, 1:4, 1:5, 1:11, 0:1) to prepare the composite soil, and its Raman spectrum characteristics, microstructure, texture composition and potato yield were studied. The results show that there are more silt and clay particles in the soft rock and more coarse particles in the sand. The peak position of the sand is 464.5 cm−1. With the increase of the content of the soft rock, the peak position decreases gradually. When the content of the soft rock accounts for more than 50%, the soil structure collapses and also becomes compact, at the same time the compressive stress is generated between the soil particles. When the ratio of soft rock to sand is 1:1, the soil texture is loam. The potato yield of the soil with the ratio of 1:5 of soft rock and sand cover increases significantly by 4.89–37.31% and 4.08–35.95% compared with that of 1:1 and 1:2 compound soils. Under the condition of 1:1 and 1:2 compounded ratio of soft rock and sand, there are more cementitious materials between the soil particles generated. The compounded ratio 1:5 is most suitable ratio for potato growth of local economic crop. The results confirmed that the Raman spectroscopy characteristics of SiO2 molecules can be used to study the cementation force between composite soil particles. When the compound ratio is 1:5, the soil improvement of Mu Us sandy land and the high yield of potatoes can be achieved, which could also provides a theoretical basis for sandy land remediation.
Bacteriophage EK99P-1 alleviates enterotoxigenic Escherichia coli K99-induced barrier dysfunction and inflammation
Authors: Kim Narae , Gu Min Jeong , Kye Yoon-Chul , Ju Young-Jun , Hong Rira , Ju Do Bin , Pyung Young Jin , Han Seung Hyun , Park Byung-Chul , Yun Cheol-Heui
Published: January 2022

Bacteriophages, simply phages, have long been used as a potential alternative to antibiotics for livestock due to their ability to specifically kill enterotoxigenic Escherichia coli (ETEC), which is a major cause of diarrhea in piglets. However, the control of ETEC infection by phages within intestinal epithelial cells, and their relationship with host immune responses, remain poorly understood. In this study, we evaluated the effect of phage EK99P-1 against ETEC K99-infected porcine intestinal epithelial cell line (IPEC-J2). Phage EK99P-1 prevented ETEC K99-induced barrier disruption by attenuating the increased permeability mediated by the loss of tight junction proteins such as zonula occludens-1 (ZO-1), occludin, and claudin-3. ETEC K99-induced inflammatory responses, such as interleukin (IL)-8 secretion, were decreased by treatment with phage EK99P-1. We used a IPEC-J2/peripheral blood mononuclear cell (PBMC) transwell co-culture system to investigate whether the modulation of barrier disruption and chemokine secretion by phage EK99P-1 in ETEC K99-infected IPEC-J2 would influence immune cells at the site of basolateral. The results showed that phage EK99P-1 reduced the mRNA expression of ETEC K99-induced pro-inflammatory cytokines, IL-1β and IL-8, from PBMC collected on the basolateral side. Together, these results suggest that phage EK99P-1 prevented ETEC K99-induced barrier dysfunction in IPEC-J2 and alleviated inflammation caused by ETEC K99 infection. Reinforcement of the intestinal barrier, such as regulation of permeability and cytokines, by phage EK99P-1 also modulates the immune cell inflammatory response.