bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing respiratory virus surveillance networks using uncertainty propagation
Authors: Pei Sen , Teng Xian , Lewis Paul , Shaman Jeffrey
Published: January 2021

Infectious disease prevention, control and forecasting rely on sentinel observations; however, many locations lack the capacity for routine surveillance. Here we show that, by using data from multiple sites collectively, accurate estimation and forecasting of respiratory diseases for locations without surveillance is feasible. We develop a framework to optimize surveillance sites that suppresses uncertainty propagation in a networked disease transmission model. Using influenza outbreaks from 35 US states, the optimized system generates better near-term predictions than alternate systems designed using population and human mobility. We also find that monitoring regional population centers serves as a reasonable proxy for the optimized network and could direct surveillance for diseases with limited records. The  proxy method is validated using model simulations for 3,108 US counties and historical data for two other respiratory pathogens – human metapneumovirus and seasonal coronavirus – from 35 US states and can be used to guide systemic allocation of surveillance efforts.
Ultraviolet radiation drives mutations in a subset of mucosal melanomas
Authors: Mundra Piyushkumar A. , Dhomen Nathalie , Rodrigues Manuel , Mikkelsen Lauge Hjorth , Cassoux Nathalie , Brooks Kelly , Valpione Sara , Reis-Filho Jorge S. , Heegaard Steffen , Stern Marc-Henri , Roman-Roman Sergio , Marais Richard
Published: January 2021

Although identified as the key environmental driver of common cutaneous melanoma, the role of ultraviolet radiation (UVR)-induced DNA damage in mucosal melanoma is poorly defined. We analyze 10 mucosal melanomas of conjunctival origin by whole genome sequencing and our data shows a predominance of UVR-associated single base substitution signature 7 (SBS7) in the majority of the samples. Our data shows mucosal melanomas with SBS7 dominance have similar genomic patterns to cutaneous melanomas and therefore this subset should not be excluded from treatments currently used for common cutaneous melanoma.
Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections
Authors: Zhang Chao , Wang Yifan , Zhu Yuanfei , Liu Caixuan , Gu Chenjian , Xu Shiqi , Wang Yalei , Zhou Yu , Wang Yanxing , Han Wenyu , Hong Xiaoyu , Yang Yong , Zhang Xueyang , Wang Tingfeng , Xu Cong , Hong Qin , Wang Shutian , Zhao Qiaoyu , Qiao Weihua , Zang Jinkai , Kong Liangliang , Wang Fangfang , Wang Haikun , Qu Di , Lavillette Dimitri , Tang Hong , Deng Qiang , Xie Youhua , Cong Yao , Huang Zhong
Published: January 2021

The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen–antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections.
Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model
Authors: Shibata Tomonori , Nagano Konami , Ueyama Morio , Ninomiya Kensuke , Hirose Tetsuro , Nagai Yoshitaka , Ishikawa Kinya , Kawai Gota , Nakatani Kazuhiko
Published: January 2021

Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here we report our discovery that naphthyridine carbamate dimer (NCD) targets disease-causing r(UGGAA)nrepeat RNAs in spinocerebellar ataxia type 31 (SCA31). Structural analysis of the NCD-UGGAA/UGGAA complex by nuclear magnetic resonance (NMR) spectroscopy clarifies the mode of binding that recognizes four guanines in the UGGAA/UGGAA pentad by hydrogen bonding with four naphthyridine moieties of two NCD molecules. Biological studies show that NCD disrupts naturally occurring RNA foci built on r(UGGAA)nrepeat RNA known as nuclear stress bodies (nSBs) by interfering with RNA–protein interactions resulting in the suppression of nSB-mediated splicing events. Feeding NCD to larvae of theDrosophilamodel of SCA31 alleviates the disease phenotype induced by toxic r(UGGAA)nrepeat RNA. These studies demonstrate that small molecules targeting toxic repeat RNAs are a promising chemical tool for studies on repeat expansion diseases.
Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML
Authors: Oki Toshihiko , Mercier Francois , Kato Hiroki , Jung Yookyung , McDonald Thomas O. , Spencer Joel A. , Mazzola Michael C. , van Gastel Nick , Lin Charles P. , Michor Franziska , Kitamura Toshio , Scadden David T.
Published: January 2021

Acute myeloid leukemia (AML) is a high remission, high relapse fatal blood cancer. Although mTORC1 is a master regulator of cell proliferation and survival, its inhibitors have not performed well as AML treatments. To uncover the dynamics of mTORC1 activity in vivo, fluorescent probes are developed to track single cell proliferation, apoptosis and mTORC1 activity of AML cells in the bone marrow of live animals and to quantify these activities in the context of microanatomical localization and intra-tumoral heterogeneity. When chemotherapy drugs commonly used clinically are given to mice with AML, apoptosis is rapid, diffuse and not preferentially restricted to anatomic sites. Dynamic measurement of mTORC1 activity indicated a decline in mTORC1 activity with AML progression. However, at the time of maximal chemotherapy response, mTORC1 signaling is high and positively correlated with a leukemia stemness transcriptional profile. Cell barcoding reveals the induction of mTORC1 activity rather than selection of mTORC1 high cells and timed inhibition of mTORC1 improved the killing of AML cells. These data define the real-time dynamics of AML and the mTORC1 pathway in association with AML growth, response to and relapse after chemotherapy. They provide guidance for timed intervention with pathway-specific inhibitors.
High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
Authors: Kumar Anil , Sundaram Kumaran , Mu Jingyao , Dryden Gerald W. , Sriwastva Mukesh K. , Lei Chao , Zhang Lifeng , Qiu Xiaolan , Xu Fangyi , Yan Jun , Zhang Xiang , Park Juw Won , Merchant Michael L. , Bohler Henry C. L. , Wang Baomei , Zhang Shuangqin , Qin Chao , Xu Ziying , Han Xianlin , McClain Craig J. , Teng Yun , Zhang Huang-Ge
Published: January 2021

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.
Antibody neutralization of SARS-CoV-2 through ACE2 receptor mimicry
Authors: Ge Jiwan , Wang Ruoke , Ju Bin , Zhang Qi , Sun Jing , Chen Peng , Zhang Senyan , Tian Yuling , Shan Sisi , Cheng Lin , Zhou Bing , Song Shuo , Zhao Juanjuan , Wang Haiyan , Shi Xuanling , Ding Qiang , Liu Lei , Zhao Jincun , Zhang Zheng , Wang Xinquan , Zhang Linqi
Published: January 2021

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.
The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus
Authors: Huisman Christian , Kim Young A. , Jeon Shin , Shin Bongjin , Choi Jeonghoon , Lim Su Jeong , Youn Sung Min , Park Younjung , K. C. Medha , Kim Sangsoo , Lee Soo-Kyung , Lee Seunghee , Lee Jae W.
Published: January 2021

In humans, inactivating mutations inMLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our twoMll4mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency ofMll4results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production inMll4mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice.
Excited-state vibration-polariton transitions and dynamics in nitroprusside
Authors: Grafton Andrea B. , Dunkelberger Adam D. , Simpkins Blake S. , Triana Johan F. , Hernández Federico J. , Herrera Felipe , Owrutsky Jeffrey C.
Published: January 2021

Strong cavity coupling to molecular vibrations creates vibration-polaritons capable of modifying chemical reaction kinetics, product branching ratios, and charge transfer equilibria. However, the mechanisms impacting these molecular processes remain elusive. Furthermore, even basic elements determining the spectral properties of polaritons, such as selection rules, transition moments, and lifetimes are poorly understood. Here, we use two-dimensional infrared and filtered pump–probe spectroscopy to report clear spectroscopic signatures and relaxation dynamics of excited vibration-polaritons formed from the cavity-coupled NO band of nitroprusside. We apply an extended multi-level quantum Rabi model that predicts transition frequencies and strengths that agree well with our experiment. Notably, the polariton features decay ~3–4 times slower than the polariton dephasing time, indicating that they support incoherent population, a consequence of their partial matter character.
NIR-excitable heterostructured upconversion perovskite nanodots with improved stability
Authors: Ruan Longfei , Zhang Yong
Published: January 2021

There is a great need to develop heterostructured nanocrystals which combine two or more different materials into single nanoparticles with combined advantages. Lead halide perovskite quantum dots (QDs) have attracted much attention due to their excellent optical properties but their biological applications have not been much explored due to their poor stability and short penetration depth of the UV excitation light in tissues. Combining perovskite QDs with upconversion nanoparticles (UCNP) to form hybrid nanocrystals that are stable, NIR excitable and emission tunable is important, however, this is challenging because hexagonal phase UCNP can not be epitaxially grown on cubic phase perovskite QDs directly or vice versa. In this work, one-pot synthesis of perovskite-UCNP hybrid nanocrystals consisting of cubic phase perovskite QDs and hexagonal phase UCNP is reported, to form a watermelon-like heterostructure using cubic phase UCNP as an intermediate transition phase. The nanocrystals are NIR-excitable with much improved stability.
Reduced immune responses to hepatitis B primary vaccination in obese individuals with nonalcoholic fatty liver disease (NAFLD)
Authors: Joshi Shivali S. , Davis Rachelle P. , Ma Mang M. , Tam Edward , Cooper Curtis L. , Ramji Alnoor , Kelly Erin M. , Jayakumar Saumya , Swain Mark G. , Jenne Craig N. , Coffin Carla S.
Published: January 2021

Obesity and cirrhosis are associated with poor hepatitis B virus (HBV) vaccine responses, but vaccine efficacy has not been assessed in nonalcoholic fatty liver disease (NAFLD). Sixty-eight HBV-naïve adults with NAFLD were enrolled through the Canadian HBV network and completed three-dose HBV or HBV/HAV vaccine (Engerix-B®, or Twinrix®, GlaxoSmithKline). Anti-HBs titers were measured at 1–3 months post third dose. In 31/68 subjects enrolled at the coordinating-site, T-cell proliferation and follicular T-helper cells (pTFH) were assessed using PBMC. Immune response was also studied in NAFLD mice. NAFLD patients were stratified as low-risk-obesity, BMI < 35 (N = 40) vs. medium-high-risk obesity, BMI > 35 (N = 28). Anti-HBs titers were lower in medium/high-risk obesity, 385 IU/L ± 79 vs. low-risk obesity class, 642 IU/L ± 68.2, p = 0.02. High-risk obesity cases, N = 14 showed lower vaccine-specific-CD3+ CD4+ T-cell response compared to low-risk obesity patients, N = 17, p = 0.02. Low vaccine responders showed dysfunctional pTFH. NAFLD mice showed lower anti-HBs levels and T-cell response vs. controls. In conclusion, we report here that obese individuals with NAFLD exhibit decreased HBV vaccine-specific immune responses.
A dataset of EEG and EOG from an auditory EOG-based communication system for patients in locked-in state
Authors: Jaramillo-Gonzalez Andres , Wu Shizhe , Tonin Alessandro , Rana Aygul , Ardali Majid Khalili , Birbaumer Niels , Chaudhary Ujwal
Published: January 2021

The dataset presented here contains recordings of electroencephalogram (EEG) and electrooculogram (EOG) from four advanced locked-in state (LIS) patients suffering from ALS (amyotrophic lateral sclerosis). These patients could no longer use commercial eye-trackers, but they could still move their eyes and used the remnant oculomotor activity to select letters to form words and sentences using a novel auditory communication system. Data were recorded from four patients during a variable range of visits (from 2 to 10), each visit comprised of 3.22 ± 1.21 days and consisted of 5.57 ± 2.61 sessions recorded per day. The patients performed a succession of different sessions, namely, Training, Feedback, Copy spelling, and Free spelling. The dataset provides an insight into the progression of ALS and presents a valuable opportunity to design and improve assistive and alternative communication technologies and brain-computer interfaces. It might also help redefine the course of progression in ALS, thereby improving clinical judgement and treatment.
Impact of Cattaneo-Christov heat flux model on MHD hybrid nano-micropolar fluid flow and heat transfer with viscous and joule dissipation effects
Authors: Tassaddiq Asifa
Published: January 2021

Review of literature reveals that hybrid nanofluids are more effective for heat transmission as compared to the conventional fluids. Nevertheless, the knowledge of developed techniques for the enhancement of heat transmission in hybrid nanofluids has many gaps and, subsequently, an extensive study for such fluids is vital. In this article, the author investigates the effect of hybrid nanoparticles on the thermal efficiency of nano-structured nanoparticles (micropolar fluid) by using the Cattaneo-Christov heat flux model. The magnetic field is pragmatic normal to the hybrid nanofluid flow direction. In order to investigate the influence of physical parameters, the proposed model has been converted to a set of ordinary differential equations (ODEs) by means of involved variables. Furthermore, the analytical and numerical approaches are compared by using different techniques to comprehend the significance of this research. It is found that macro-velocity field reduces with micropolar factor and Hartmann number. A significant result is found in micro-velocity field for the cases when$$n = 0.5$$n=0.5and$$n = 0$$n=0. Also an escalating conduct in thermal field is observed against the increasing estimations of Hartmann number, micropolar parameter, Eckert number, and material parameter.
Tensile deformation behavior of twist grain boundaries in CoCrFeMnNi high entropy alloy bicrystals
Authors: Lee Hyunsoo , Shabani Mitra , Pataky Garrett J. , Abdeljawad Fadi
Published: January 2021

High entropy alloys (HEA) are a class of materials that consist of multiple elemental species in similar concentrations. The use of elements in far from dilute concentrations introduces a multi-dimensional composition design space by which the properties of metallic systems can be tailored. While the mechanical behavior of HEAs has been the subject of active research recently, the role of grain boundaries (GBs) in their deformation behavior remains poorly understood. Motivated by recent experiments on HEAs demonstrating that GBs act as nucleation sites for deformation twins, herein, we leverage atomistic simulations to construct a series of equiatomic CoCrFeMnNi HEA bicrystals with $$\langle 110 \rangle$$

⟨
110
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and $$\langle 111 \rangle$$

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111
⟩

symmetric twist GBs and examine their tensile behavior and underlying deformation mechanisms at 77 K. Simulation results reveal that plastic deformation proceeds by the nucleation of partial dislocations from GBs, which then grow with further loading by bowing into the bulk crystals leaving behind stacking faults. Variations in the nucleation stress exist as function of GB character, defined in this work by the twist angle. Our results provide future avenues to explore GBs as a microstructure design tool to develop HEAs with tailored properties.
Auditory cues reveal intended movement information in middle frontal gyrus neuronal ensemble activity of a person with tetraplegia
Authors: Hosman Tommy , Hynes Jacqueline B. , Saab Jad , Wilcoxen Kaitlin G. , Buchbinder Bradley R. , Schmansky Nicholas , Cash Sydney S. , Eskandar Emad N. , Simeral John D. , Franco Brian , Kelemen Jessica , Vargas-Irwin Carlos E. , Hochberg Leigh R.
Published: January 2021

Intracortical brain-computer interfaces (iBCIs) allow people with paralysis to directly control assistive devices using neural activity associated with the intent to move. Realizing the full potential of iBCIs critically depends on continued progress in understanding how different cortical areas contribute to movement control. Here we present the first comparison between neuronal ensemble recordings from the left middle frontal gyrus (MFG) and precentral gyrus (PCG) of a person with tetraplegia using an iBCI. As expected, PCG was more engaged in selecting and generating intended movements than in earlier perceptual stages of action planning. By contrast, MFG displayed movement-related information during the sensorimotor processing steps preceding the appearance of the action plan in PCG, but only when the actions were instructed using auditory cues. These results describe a previously unreported function for neurons in the human left MFG in auditory processing contributing to motor control.
An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum
Authors: Nasamu Armiyaw S. , Falla Alejandra , Pasaje Charisse Flerida A. , Wall Bridget A. , Wagner Jeffrey C. , Ganesan Suresh M. , Goldfless Stephen J. , Niles Jacquin C.
Published: January 2021

Establishing robust genome engineering methods in the malarial parasite, Plasmodium falciparum, has the potential to substantially improve the efficiency with which we gain understanding of this pathogen’s biology to propel treatment and elimination efforts. Methods for manipulating gene expression and engineering the P. falciparum genome have been validated. However, a significant barrier to fully leveraging these advances is the difficulty associated with assembling the extremely high AT content DNA constructs required for modifying the P. falciparum genome. These are frequently unstable in commonly-used circular plasmids. We address this bottleneck by devising a DNA assembly framework leveraging the improved reliability with which large AT-rich regions can be efficiently manipulated in linear plasmids. This framework integrates several key functional genetics outcomes via CRISPR/Cas9 and other methods from a common, validated framework. Overall, this molecular toolkit enables P. falciparum genetics broadly and facilitates deeper interrogation of parasite genes involved in diverse biological processes.
Investigating the optical clearing effects of 50% glycerol in ex vivo human skin by harmonic generation microscopy
Authors: Lai Jia-Hong , Liao En-Yu , Liao Yi-Hua , Sun Chi-Kuang
Published: January 2021

Imaging depth and quality of optical microscopy can be enhanced by optical clearing. Here we investigate the optical clearing of the ex vivo human skin by 50% glycerol topical application, which is allowed for cosmetic usage. Harmonic generation microscopy, by combining second and third harmonic generation (THG) modalities, was utilized to examine the clearing effect. The THG image intensity is sensitive to the improved optical homogeneity after optical clearing, and the second harmonic generation (SHG) image intensity in the dermis could serve as a beacon to confirm the reduction of the scattering in the epidermis layer. As a result, our study supports the OC effect through 50% glycerol topical application. Our study further indicates the critical role of stratum corneum shrinkage for the observed SHG and THG signal recovery.
Cancer associated talin point mutations disorganise cell adhesion and migration
Authors: Azizi Latifeh , Cowell Alana R. , Mykuliak Vasyl V. , Goult Benjamin T. , Turkki Paula , Hytönen Vesa P.
Published: January 2021

Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. We analysed talin-1 mutations reported in the Catalogue of Somatic Mutations in Cancer database and developed a bioinformatics pipeline to predict the severity of each mutation. These predictions were then assessed using biochemistry and cell biology experiments. With this approach we were able to identify several talin-1 mutations affecting integrin activity, actin recruitment and Deleted in Liver Cancer 1 localization. We explored potential changes in talin-1 signalling responses by assessing impact on migration, invasion and proliferation. Altogether, this study describes a pipeline approach of experiments for crude characterization of talin-1 mutants in order to evaluate their functional effects and potential pathogenicity. Our findings suggest that cancer related point mutations in talin-1 can affect cell behaviour and so may contribute to cancer progression.
Clinical application of the experimental ADL test for patients with cognitive impairment: pilot study
Authors: Lim Yong-Hyun , Baek Yookyeong , Kang Soon Ju , Kang Kyunghun , Lee Ho-Won
Published: January 2021

We employed a hospital-based Internet of Things (IoT) platform to validate the role of real-time activities of daily living (ADL) measurement as a digital biomarker for cognitive impairment in a hospital setting. Observational study. 12 patients with dementia, 11 patients with mild cognitive impairment (MCI), and 15 cognitively normal older adults. The results of 13 experimental ADL tasks were categorized into success or fail. The total number of successful task and the average success proportion of each group was calculated. Time to complete the total tasks was also measured. Patients with dementia, patients with MCI, and cognitively normal older adults performed 13 experimental ADL tasks in a hospital setting. Significant differences in the average success rate of 13 tasks were found among groups. Dementia group showed the lowest success proportion (49.3%) compared with MCI group (78.3%) and normal group (97.4%). Correlation between classical ADL scales and the number of completed ADL tasks was statistically significant. In particular, instrumental ADL (I-ADL) had stronger relationship with the number of completed ADL tasks than Barthel’s ADL (B-ADL). Dementia group required more time to accomplish the tasks when compared to MCI and normal groups. This study demonstrated that there is a clear relationship between the performance of experimental ADL tasks and the severity of cognitive impairment. The evaluation of ADLs involving the IoTs platform in an ecological setting allows accurate assessment and quantification of the patient’s functional level.
Asymptotic entropy of the Gibbs state of complex networks
Authors: Glos Adam , Krawiec Aleksandra , Pawela Łukasz
Published: January 2021

In this work we study the entropy of the Gibbs state corresponding to a graph. The Gibbs state is obtained from the Laplacian, normalized Laplacian or adjacency matrices associated with a graph. We calculated the entropy of the Gibbs state for a few classes of graphs and studied their behavior with changing graph order and temperature. We illustrate our analytical results with numerical simulations for Erdős–Rényi, Watts–Strogatz, Barabási–Albert and Chung–Lu graph models and a few real-world graphs. Our results show that the behavior of Gibbs entropy as a function of the temperature differs for a choice of real networks when compared to the random Erdős–Rényi graphs.
The relationship between reflex eye realignment and the percept of single vision in young children
Authors: Meier Kimberly , Lundell Deanna L. , Seemiller Eric S. , Giaschi Deborah , Wilcox Laurie M. , Candy T. Rowan
Published: January 2021

Effective binocular vision is dependent on both motor and perceptual function. Young children undergo development of both components while interacting with their dynamic three-dimensional environment. When this development fails, eye misalignment and double vision may result. We compared the range of image disparities over which young children display reflex motor realignment of their eyes with the range over which they report a single versus double percept. In response to step changes in the disparity of a 2.2° wide stimulus, 5-year-olds generated an adult-like reflex vergence velocity tuning function peaking at 2° of disparity, with a mean latency of 210 ms. On average, they reported double vision for stimulus disparities of 3° and larger, compared to 1° in adult reports. Three-year-olds also generated reflex vergence tuning functions peaking at approximately 2° of disparity, but their percepts could not be assessed. These data suggest that, by age 5, reflex eye realignment responses and percepts driven by these brief stimuli are tightly coordinated in space and time to permit robust binocular function around the point of fixation. Importantly, the plastic neural processes maintaining this tight coordination during growth control the stability of visual information driving learning during childhood.
Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukaemia using patient similarity networks
Authors: Mikulkova Zuzana , Manukyan Gayane , Turcsanyi Peter , Kudelka Milos , Urbanova Renata , Savara Jakub , Ochodkova Eliska , Brychtova Yvona , Molinsky Jan , Simkovic Martin , Starostka David , Novak Jan , Janca Ondrej , Dihel Martin , Ryznerova Pavlina , Mohammad Lekaa , Papajik Tomas , Kriegova Eva
Published: January 2021

The tissue microenvironment in chronic lymphocytic leukaemia (CLL) plays a key role in the pathogenesis of CLL, but the complex blood microenvironment in CLL has not yet been fully characterised. Therefore, immunophenotyping of circulating immune cells in 244 CLL patients and 52 healthy controls was performed using flow cytometry and analysed by multivariate Patient Similarity Networks (PSNs). Our study revealed high inter-individual heterogeneity in the distribution and activation of bystander immune cells in CLL, depending on the bulk of the CLL cells. High CLL counts were associated with low activation on circulating monocytes and T cells and vice versa. The highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. PSNs revealed a low activation of immune cells in CLL progression, irrespective of IgHV status, Binet stage and TP53 disruption. Patients with high intermediate monocytes (> 5.4%) with low activation were 2.5 times more likely (95% confidence interval 1.421–4.403, P = 0.002) to had shorter time-to-treatment than those with low monocyte counts. Our study demonstrated the association between the activation of circulating immune cells and the bulk of CLL cells. The highest activation of bystander immune cells was detected in patients with slow disease course and in those treated with novel agents. The subset of intermediate monocytes showed predictive value for time-to-treatment in CLL.
Efficient embedded sleep wake classification for open-source actigraphy
Authors: Banfi Tommaso , Valigi Nicolò , di Galante Marco , d’Ascanio Paola , Ciuti Gastone , Faraguna Ugo
Published: January 2021

This study presents a thorough analysis of sleep/wake detection algorithms for efficient on-device sleep tracking using wearable accelerometric devices. It develops a novel end-to-end algorithm using convolutional neural network applied to raw accelerometric signals recorded by an open-source wrist-worn actigraph. The aim of the study is to develop an automatic classifier that: (1) is highly generalizable to heterogenous subjects, (2) would not require manual features’ extraction, (3) is computationally lightweight, embeddable on a sleep tracking device, and (4) is suitable for a wide assortment of actigraphs. Hereby, authors analyze sleep parameters, such as total sleep time, waking after sleep onset and sleep efficiency, by comparing the outcomes of the proposed algorithm to the gold standard polysomnographic concurrent recordings. The relatively substantial agreement (Cohen’s kappa coefficient, median, equal to 0.78 ± 0.07) and the low-computational cost (2727 floating-point operations) make this solution suitable for an on-board sleep-detection approach.
Early prediction of live birth for assisted reproductive technology patients: a convenient and practical prediction model
Authors: Gao Hong , Liu Dong-e , Li Yumei , Wu Xinrui , Tan Hongzhuan
Published: January 2021

Live birth is the most important concern for assisted reproductive technology (ART) patients. Therefore, in the medical reproductive centre, obstetricians often need to answer the following question: “What are the chances that I will have a healthy baby after ART treatment?” To date, our obstetricians have no reference on which to base the answer to this question. Our research aimed to solve this problem by establishing prediction models of live birth for ART patients. Between January 1, 2010, and May 1, 2017, we conducted a retrospective cohort study of women undergoing ART treatment at the Reproductive Medicine Centre, Xiangya Hospital of Central South University, Hunan, China. The birth of at least one live-born baby per initiated cycle or embryo transfer procedure was defined as a live birth, and all other pregnancy outcomes were classified as no live birth. A live birth prediction model was established by stepwise multivariate logistic regression. All eligible subjects were randomly allocated to two groups: group 1 (80% of subjects) for the establishment of the prediction models and group 2 (20% of subjects) for the validation of the established prediction models. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each prediction model at different cut-off values were calculated. The prediction model of live birth included nine variables. The area under the ROC curve was 0.743 in the validation group. The sensitivity, specificity, PPV, and NPV of the established model ranged from 97.9–24.8%, 7.2–96.3%, 44.8–83.8% and 81.7–62.5%, respectively, at different cut-off values. A stable, reliable, convenient, and satisfactory prediction model for live birth by ART patients was established and validated, and this model could be a useful tool for obstetricians to predict the live rate of ART patients. Meanwhile, it is also a reference for obstetricians to create good conditions for infertility patients in preparation for pregnancy.
Model selection for inferential models with high dimensional data: synthesis and graphical representation of multiple techniques
Authors: Lima Eliana , Hyde Robert , Green Martin
Published: January 2021

Inferential research commonly involves identification of causal factors from within high dimensional data but selection of the ‘correct’ variables can be problematic. One specific problem is that results vary depending on statistical method employed and it has been argued that triangulation of multiple methods is advantageous to safely identify the correct, important variables. To date, no formal method of triangulation has been reported that incorporates both model stability and coefficient estimates; in this paper we develop an adaptable, straightforward method to achieve this. Six methods of variable selection were evaluated using simulated datasets of different dimensions with known underlying relationships. We used a bootstrap methodology to combine stability matrices across methods and estimate aggregated coefficient distributions. Novel graphical approaches provided a transparent route to visualise and compare results between methods. The proposed aggregated method provides a flexible route to formally triangulate results across any chosen number of variable selection methods and provides a combined result that incorporates uncertainty arising from between-method variability. In these simulated datasets, the combined method generally performed as well or better than the individual methods, with low error rates and clearer demarcation of the true causal variables than for the individual methods.
CircRNA GFRA1 promotes hepatocellular carcinoma progression by modulating the miR-498/NAP1L3 axis
Authors: Lv Shuai , Li Yingxia , Ning Hanbing , Zhang Meihui , Jia Qiaoyu , Wang Xijuan
Published: January 2021

Circular RNAs (circRNAs) play essential roles in tumorigenesis and tumor progression. CircRNA GFRA1 (circGFRA1) was dysregulated in many cancer samples and acted as an independent marker for prediction of survivals in various cancer patients. However, the functions and molecular mechanisms of circGFRA1 in hepatocellular carcinoma (HCC) remain unclear. We collected 62 HCC tissues and normal adjacent tissues to evaluate the expression of circGFRA1 and the relationship between circGFRA1 expression and HCC patients’ survival. We carried out a list of characterization experiments to investigate the roles and underling mechanisms of circGFRA1 and miR-498 in HCC progressions. CircGFRA1 was greatly increased in HCC tissues and cells, and the over-expression of circGFRA1 was intimately related with the advanced clinical stage and poor survival of HCC patients. The expression of circGFRA1 was negatively correlated with the expression of miR-498, but a positive correlation was found between circGFRA1 and NAP1L3 expression in HCC tissues. Silencing circGFRA1 inhibited the growth and invasion of hepatocellular carcinoma. Moreover, miR-498 over-expression or NAP1L3 inhibition could abrogate the oncogene role of circGFRA1 in HCC in vivo. Our findings indicated that circGFRA1 contributed to HCC progression by modulating the miR-498/NAP1L3 axis in HCC.
Polysaccharide hydrogel based 3D printed tumor models for chemotherapeutic drug screening
Authors: Gebeyehu Aragaw , Surapaneni Sunil Kumar , Huang John , Mondal Arindam , Wang Vivian Ziwen , Haruna Nana Fatima , Bagde Arvind , Arthur Peggy , Kutlehria Shallu , Patel Nil , Rishi Arun K. , Singh Mandip
Published: January 2021

A series of stable and ready-to-use bioinks have been developed based on the xeno-free and tunable hydrogel (VitroGel) system. Cell laden scaffold fabrication with optimized polysaccharide-based inks demonstrated that Ink H4 and RGD modified Ink H4-RGD had excellent rheological properties. Both bioinks were printable with 25–40 kPa extrusion pressure, showed 90% cell viability, shear-thinning and rapid shear recovery properties making them feasible for extrusion bioprinting without UV curing or temperature adjustment. Ink H4-RGD showed printability between 20 and 37 °C and the scaffolds remained stable for 15 days at temperature of 37 °C. 3D printed non-small-cell lung cancer (NSCLC) patient derived xenograft cells (PDCs) showed rapid spheroid growth of size around 500 µm in diameter and tumor microenvironment formation within 7 days. IC50 values demonstrated higher resistance of 3D spheroids to docetaxel (DTX), doxorubicin (DOX) and erlotinib compared to 2D monolayers of NSCLC-PDX, wild type triple negative breast cancer (MDA-MB-231 WT) and lung adenocarcinoma (HCC-827) cells. Results of flow property, shape fidelity, scaffold stability and biocompatibility of H4-RGD suggest that this hydrogel could be considered for 3D cell bioprinting and also for in-vitro tumor microenvironment development for high throughput screening of various anti-cancer drugs.
Circulating adiponectin and leptin and risk of overall and aggressive prostate cancer: a systematic review and meta-analysis
Authors: Burton Anya J. , Gilbert Rebecca , Tilling Kate , Langdon Ryan , Donovan Jenny L. , Holly Jeff M. P. , Martin Richard M.
Published: January 2021

Obesity is associated with an increased risk of advanced, recurrent and fatal prostate cancer. Adipokines may mediate this relationship. We conducted a systematic review and meta-analysis of associations of leptin and adiponectin with overall and aggressive prostate cancer. Bibliographic databases were systematically searched up to 1st April 2017. Log Odds Ratios (ORs) per 2.5 unit increase in adiponectin or leptin levels were derived and pooled. All analyses were stratified by study type (cross-sectional/prospective). 746 papers were retrieved, 34 eligible studies identified, 31 of these could be included in the meta-analysis. Leptin was not consistently associated with overall prostate cancer (pooled OR 1.00, 95%CI 0.98–1.02, per 2.5 ng/ml increase, prospective study OR 0.97, 95%CI 0.95–0.99, cross-sectional study OR 1.19, 95%CI 1.13–1.26) and there was weak evidence of a positive association with aggressive disease (OR 1.03, 95%CI 1.00–1.06). There was also weak evidence of a small inverse association of adiponectin with overall prostate cancer (OR 0.96, 95%CI 0.93–0.99, per 2.5 µg/ml increase), but less evidence of an association with aggressive disease (OR 0.98, 95%CI 0.94–1.01). The magnitude of any effects are small, therefore levels of circulating adiponectin or leptin alone are unlikely to be useful biomarkers of risk or prognosis.
Spatiotemporal variation in cell proliferation patterns during arthropod axial elongation
Authors: Cepeda Rodrigo E. , Terraza John B. , Pardo Renato V. , Núñez-Pascual Valentina , Mundaca-Escobar Marco , Sarrazin Andres F.
Published: January 2021

An elongated and segmented body plan is a common morphological characteristic of all arthropods and is probably responsible for their high adaptation ability to diverse environments. Most arthropods form their bodies by progressively adding segments, resembling vertebrate somitogenesis. This sequential segmentation relies on a molecular clock that operates in the posterior region of the elongating embryo that combines dynamically with cellular behaviors and tissue rearrangements, allowing the extension of the developing body along its main embryonic axis. Even though the molecular mechanisms involved in elongation and segment formation have been found to be conserved in a considerable degree, cellular processes such as cell division are quite variable between different arthropods. In this study, we show that cell proliferation in the beetleTribolium castaneumhas a nonuniform spatiotemporal patterning during axial elongation. We found that dividing cells are preferentially oriented along the anterior–posterior axis, more abundant and posteriorly localized during thoracic segments formation and that this cell proliferation peak was triggered at the onset of axis elongation. This raise in cell divisions, in turn, was correlated with an increase in the elongation rate, but not with changes in cell density. When DNA synthesis was inhibited over this period, both the area and length of thoracic segments were significantly reduced but not of the first abdominal segment. We discuss the variable participation that different cell division patterns and cell movements may have on arthropod posterior growth and their evolutionary contribution.
Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens
Authors: Kashima Yukie , Togashi Yosuke , Fukuoka Shota , Kamada Takahiro , Irie Takuma , Suzuki Ayako , Nakamura Yoshiaki , Shitara Kohei , Minamide Tatsunori , Yoshida Taku , Taoka Naofumi , Kawase Tatsuya , Wada Teiji , Inaki Koichiro , Chihara Masataka , Ebisuno Yukihiko , Tsukamoto Sakiyo , Fujii Ryo , Ohashi Akihiro , Suzuki Yutaka , Tsuchihara Katsuya , Nishikawa Hiroyoshi , Doi Toshihiko
Published: January 2021

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.
Topological data analysis (TDA) enhances bispectral EEG (BSEEG) algorithm for detection of delirium
Authors: Yamanashi Takehiko , Kajitani Mari , Iwata Masaaki , Crutchley Kaitlyn J. , Marra Pedro , Malicoat Johnny R. , Williams Jessica C. , Leyden Lydia R. , Long Hailey , Lo Duachee , Schacher Cassidy J. , Hiraoka Kazuaki , Tsunoda Tomoyuki , Kobayashi Ken , Ikai Yoshiaki , Kaneko Koichi , Umeda Yuhei , Kadooka Yoshimasa , Shinozaki Gen
Published: January 2021

Current methods for screening and detecting delirium are not practical in clinical settings. We previously showed that a simplified EEG with bispectral electroencephalography (BSEEG) algorithm can detect delirium in elderly inpatients. In this study, we performed a post-hoc BSEEG data analysis using larger sample size and performed topological data analysis to improve the BSEEG method. Data from 274 subjects included in the previous study were analyzed as a 1st cohort. Subjects were enrolled at the University of Iowa Hospitals and Clinics (UIHC) between January 30, 2016, and October 30, 2017. A second cohort with 265 subjects was recruited between January 16, 2019, and August 19, 2019. The BSEEG score was calculated as a power ratio between low frequency to high frequency using our newly developed algorithm. Additionally, Topological data analysis (TDA) score was calculated by applying TDA to our EEG data. The BSEEG score and TDA score were compared between those patients with delirium and without delirium. Among the 274 subjects from the first cohort, 102 were categorized as delirious. Among the 206 subjects from the second cohort, 42 were categorized as delirious. The areas under the curve (AUCs) based on BSEEG score were 0.72 (1st cohort, Fp1-A1), 0.76 (1st cohort, Fp2-A2), and 0.67 (2nd cohort). AUCs from TDA were much higher at 0.82 (1st cohort, Fp1-A1), 0.84 (1st cohort, Fp2-A2), and 0.78 (2nd cohort). When sensitivity was set to be 0.80, the TDA drastically improved specificity to 0.66 (1st cohort, Fp1-A1), 0.72 (1st cohort, Fp2-A2), and 0.62 (2nd cohort), compared to 0.48 (1st cohort, Fp1-A1), 0.54 (1st cohort, Fp2-A2), and 0.46 (2nd cohort) with BSEEG. BSEEG has the potential to detect delirium, and TDA is helpful to improve the performance.
Exploring the biological role of postzygotic and germinal de novo mutations in ASD
Authors: Alonso-Gonzalez A. , Calaza M. , Amigo J. , González-Peñas J. , Martínez-Regueiro R. , Fernández-Prieto M. , Parellada M. , Arango C. , Rodriguez-Fontenla Cristina , Carracedo A.
Published: January 2021

De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined ASD cohort (N = 2171 trios) was created using previously published data by the Autism Sequencing Consortium (ASC). New plausible candidate genes for ASD such as FMR1 and NFIA were found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk.