bluuebunny/crossref_metadata_2025 huggingface dataset:
Glutamatergic dysfunction in Schizophrenia
Authors: Kruse Andreas O. , Bustillo Juan R.
Published: December 2022

The NMDA-R hypofunction model of schizophrenia started with the clinical observation of the precipitation of psychotic symptoms in patients with schizophrenia exposed to PCP or ketamine. Healthy volunteers exposed to acute low doses of ketamine experienced mild psychosis but also negative and cognitive type symptoms reminiscent of the full clinical picture of schizophrenia. In rodents, acute systemic ketamine resulted in a paradoxical increase in extracellular frontal glutamate as well as of dopamine. Similar increase in prefrontal glutamate was documented with acute ketamine in healthy volunteers with 1H-MRS. Furthermore, sub-chronic low dose PCP lead to reductions in frontal dendritic tree density in rodents. In post-mortem ultrastructural studies in schizophrenia, a broad reduction in dendritic complexity and somal volume of pyramidal cells has been repeatedly described. This most likely accounts for the broad, subtle progressive cortical thinning described with MRI in- vivo. Additionally, prefrontal reductions in the obligatory GluN1 subunit of the NMDA-R has been repeatedly found in post-mortem tissue. The vast 1H-MRS literature in schizophrenia has documented trait-like small increases in glutamate concentrations in striatum very early in the illness, before antipsychotic treatment (the same structure where increased pre-synaptic release of dopamine has been reported with PET). The more recent genetic literature has reliably detected very small risk effects for common variants involving several glutamate-related genes. The pharmacological literature has followed two main tracks, directly informed by the NMDA-R hypo model: agonism at the glycine site (as mostly add-on studies targeting negative and cognitive symptoms); and pre-synaptic modulation of glutamatergic release (as single agents for acute psychosis). Unfortunately, both approaches have failed so far. There is little doubt that brain glutamatergic abnormalities are present in schizophrenia and that some of these are related to the etiology of the illness. The genetic literature directly supports a non- specific etiological role for glutamatergic dysfunction. Whether NMDA-R hypofunction as a specific mechanism accounts for any important component of the illness is still not evident. However, a glutamatergic model still has heuristic value to guide future research in schizophrenia. New tools to jointly examine brain glutamatergic, GABA-ergic and dopaminergic systems in-vivo, early in the illness, may lay the ground for a next generation of clinical trials that go beyond dopamine D2 blockade.
Conjugated polymers based on selenophene building blocks
Authors: Marsh Adam V. , Heeney Martin
Published: December 2022

The intrinsic flexibility, solution processability, and optoelectronic properties of semiconducting conjugated polymers make them ideal candidates for use in a wide range of next-generation electronic devices. A virtually unlimited chemical design space has led to diverse polymeric architectures made from combinations of smaller molecular building blocks with desirable functionalities. Of these, thiophene is undoubtedly the most common due to its mixture of synthetic versatility, polymer backbone planarizing effects, and good optoelectronic characteristics. However, the success of thiophene has meant that other heterocycles, such as selenophene, remain relatively underexplored. This focus review discusses the challenges and material advantages of incorporating selenophene into conjugated polymer systems within the context of our contributions to the field. The early studies of poorly performing electrochemically synthesized polyselenophenes are outlined, progressing onto the model chemically synthesized alkylated homopolymers that revealed the key consequences of selenophene addition. We then review the various donor and donor-acceptor copolymer strategies that have exploited the properties of the selenium atom to enhance the performance of solar cells, transistors, and other organic electronic devices. Finally, we give our perspective on the state of the field and the fundamental material optimization studies required to realize the full potential of selenophene-containing conjugated polymers.
Loss of multipotency in adipose-derived stem cells after culture in temperature-responsive injectable polymer hydrogels
Authors: Mayumi Nozomi , Murase Nobuo , Yoshizaki Yuta , Kuzuya Akinori , Ohya Yuichi
Published: December 2022

Adipose-derived stem cells (AdSCs), a type of mesenchymal stem cell, are expected to be applicable to regenerative medicine and cellular delivery systems. The maintenance of cell multipotency and control of the differentiation direction are important for these applications. However, the differentiation direction of these cells is widely believed to depend on the physical properties of their scaffold. In this study, we explored whether the multipotency of AdSCs, that is, their ability to differentiate into multiple cells, is maintained when they are removed from injectable polymer (IP) hydrogels with various degrees of cross-linking and induced to differentiate into osteoblasts and adipocytes. We confirmed that AdSCs cultured in IP hydrogels maintained an undifferentiated state. However, their differentiation into osteoblasts and adipocytes cannot be ensured; specifically, the multipotency of AdSCs may decrease when they are cultured in IP hydrogels. When cultured in an IP hydrogel with extreme softness and poor cell adhesion properties, the AdSCs remained in an undifferentiated state, but their multipotency was reduced. These results provide important insights into stem cell delivery systems using IP hydrogels.
Mitochondrial genomes reveal mid-Pleistocene population divergence, and post-glacial expansion, in Australasian snapper (Chrysophrys auratus)
Authors: Oosting Tom , Martínez-García Lourdes , Ferrari Giada , Verry Alexander J. F. , Scarsbrook Lachie , Rawlence Nicolas J. , Wellenreuther Maren , Star Bastiaan , Ritchie Peter A.
Published: December 2022

Glacial cycles play important roles in determining the phylogeographic structure of terrestrial species, however, relatively little is known about their impacts on the distribution of marine biota. This study utilised modern (n = 350) and ancient (n = 26) mitochondrial genomes from Australasian snapper (Chrysophrys auratus) sampled in New Zealand to assess their demographic and phylogeographic history. We also tested for changes in genetic diversity using the up to 750-year-old mitochondrial genomes from pre-European archaeological sites to assess the potential impacts of human exploitation. Nucleotide diversity and haplotype diversity was high (π = 0.005, h = 0.972). There was no significant change in nucleotide diversity over the last 750 years (p = 0.343), with no detectable loss of diversity as a result of indigenous and industrial-scale fishing activity. While there was no evidence for contemporary population structure (AMOVA, p = 0.764), phylogeographic analyses identified two distinct mitochondrial clades that diverged approximately 650,000 years ago during the mid-Pleistocene, suggesting the species experienced barriers to gene flow when sea levels dropped over 120 m during previous glacial maxima. An exponential population increase was also observed around 8000 years ago consistent with a post-glacial expansion, which was likely facilitated by increased ocean temperatures and rising sea levels. This study demonstrates that glacial cycles likely played an important role in the demographic history of C. auratus and adds to our growing understanding of how dynamic climatic changes have influenced the evolution of coastal marine species.
Ultrafast light-induced dynamics in the microsolvated biomolecular indole chromophore with water
Authors: Onvlee Jolijn , Trippel Sebastian , Küpper Jochen
Published: December 2022

Interactions between proteins and their solvent environment can be studied in a bottom-up approach using hydrogen-bonded chromophore-solvent clusters. The ultrafast dynamics following UV-light-induced electronic excitation of the chromophores, potential radiation damage, and their dependence on solvation are important open questions. The microsolvation effect is challenging to study due to the inherent mix of the produced gas-phase aggregates. We use the electrostatic deflector to spatially separate different molecular species in combination with pump-probe velocity-map-imaging experiments. We demonstrate that this powerful experimental approach reveals intimate details of the UV-induced dynamics in the near-UV-absorbing prototypical biomolecular indole-water system. We determine the time-dependent appearance of the different reaction products and disentangle the occurring ultrafast processes. This approach ensures that the reactants are well-known and that detailed characteristics of the specific reaction products are accessible – paving the way for the complete chemical-reactivity experiment.
A quantitative model for the dynamics of target recognition and off-target rejection by the CRISPR-Cas Cascade complex
Authors: Rutkauskas Marius , Songailiene Inga , Irmisch Patrick , Kemmerich Felix E. , Sinkunas Tomas , Siksnys Virginijus , Seidel Ralf
Published: December 2022

CRISPR-Cas effector complexes recognise nucleic acid targets by base pairing with their crRNA which enables easy re-programming of the target specificity in rapidly emerging genome engineering applications. However, undesired recognition of off-targets, that are only partially complementary to the crRNA, occurs frequently and represents a severe limitation of the technique. Off-targeting lacks comprehensive quantitative understanding and prediction. Here, we present a detailed analysis of the target recognition dynamics by the Cascade surveillance complex on a set of mismatched DNA targets using single-molecule supercoiling experiments. We demonstrate that the observed dynamics can be quantitatively modelled as a random walk over the length of the crRNA-DNA hybrid using a minimal set of parameters. The model accurately describes the recognition of targets with single and double mutations providing an important basis for quantitative off-target predictions. Importantly the model intrinsically accounts for observed bias regarding the position and the proximity between mutations and reveals that the seed length for the initiation of target recognition is controlled by DNA supercoiling rather than the Cascade structure.
Engineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy
Authors: Zhu Junmeng , Ke Yaohua , Liu Qin , Yang Ju , Liu Fangcen , Xu Ruihan , Zhou Hang , Chen Aoxing , Xiao Jie , Meng Fanyan , Yu Lixia , Li Rutian , Wei Jia , Liu Baorui
Published: December 2022

In situ vaccination is a promising strategy to convert the immunosuppressive tumor microenvironment into an immunostimulatory one with limited systemic exposure and side effect. However, sustained clinical benefits require long-term and multidimensional immune activation including innate and adaptive immunity. Here, we develop a probiotic food-grade Lactococcus lactis-based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand. Intratumoural delivery of FOLactis contributes to local retention and sustained release of therapeutics to thoroughly modulate key components of the antitumour immune response, such as activation of natural killer cells, cytotoxic T lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. In addition, intratumoural administration of FOLactis induces a more robust tumor antigen-specific immune response and superior systemic antitumour efficacy in multiple poorly immune cell-infiltrated and anti-PD1-resistant tumors. Specific depletion of different immune cells reveals that CD8+ T and natural killer cells are crucial to the in situ vaccine-elicited tumor regression. Our results confirm that FOLactis displays an enhanced antitumour immunity and successfully converts the ‘cold’ tumors to ‘hot’ tumors.
Multi-angular polarimetric remote sensing to pinpoint global aerosol absorption and direct radiative forcing
Authors: Chen Cheng , Dubovik Oleg , Schuster Gregory L. , Chin Mian , Henze Daven K. , Lapyonok Tatyana , Li Zhengqiang , Derimian Yevgeny , Zhang Ying
Published: December 2022

Quantitative estimations of atmospheric aerosol absorption are rather uncertain due to the lack of reliable information about the global distribution. Because the information about aerosol properties is commonly provided by single-viewing photometric satellite sensors that are not sensitive to aerosol absorption. Consequently, the uncertainty in aerosol radiative forcing remains one of the largest in the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC AR5 and AR6). Here, we use multi-angular polarimeters (MAP) to provide constraints on emission of absorbing aerosol species and estimate global aerosol absorption optical depth (AAOD) and its climate effect. Our estimate of modern-era mid-visible AAOD is 0.0070 that is higher than IPCC by a factor of 1.3-1.8. The black carbon instantaneous direct radiative forcing (BC DRF) is +0.33 W/m2 [+0.17, +0.54]. The MAP constraint narrows the 95% confidence interval of BC DRF by a factor of 2 and boosts confidence in its spatial distribution.
Single-molecule characterization of subtype-specific β1 integrin mechanics
Authors: Jo Myung Hyun , Li Jing , Jaumouillé Valentin , Hao Yuxin , Coppola Jessica , Yan Jiabin , Waterman Clare M. , Springer Timothy A. , Ha Taekjip
Published: December 2022

Although integrins are known to be mechanosensitive and to possess many subtypes that have distinct physiological roles, single molecule studies of force exertion have thus far been limited to RGD-binding integrins. Here, we show that integrin α4β1 and RGD-binding integrins (αVβ1 and α5β1) require markedly different tension thresholds to support cell spreading. Furthermore, actin assembled downstream of α4β1 forms cross-linked networks in circularly spread cells, is in rapid retrograde flow, and exerts low forces from actin polymerization. In contrast, actin assembled downstream of αVβ1 forms stress fibers linking focal adhesions in elongated cells, is in slow retrograde flow, and matures to exert high forces (>54-pN) via myosin II. Conformational activation of both integrins occurs below 12-pN, suggesting that post-activation subtype-specific cytoskeletal remodeling imposes the higher threshold for spreading on RGD substrates. Multiple layers of single integrin mechanics for activation, mechanotransduction and cytoskeleton remodeling revealed here may underlie subtype-dependence of diverse processes such as somite formation and durotaxis.
Bead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration
Authors: Cao Yuanxiong , Tan Jiayi , Zhao Haoran , Deng Ting , Hu Yunxia , Zeng Junhong , Li Jiawei , Cheng Yifan , Tang Jiyuan , Hu Zhiwei , Hu Keer , Xu Bing , Wang Zitian , Wu Yaojiong , Lobie Peter E. , Ma Shaohua
Published: December 2022

Transplantation of mesenchymal stem cells (MSCs) holds promise to repair severe traumatic injuries. However, current transplantation practices limit the potential of this technique, either by losing the viable MSCs or reducing the performance of resident MSCs. Herein, we design a “bead-jet” printer, specialized for high-throughput intra-operative formulation and printing of MSCs-laden Matrigel beads. We show that high-density encapsulation of MSCs in Matrigel beads is able to augment MSC function, increasing MSC proliferation, migration, and extracellular vesicle production, compared with low-density bead or high-density bulk encapsulation of the equivalent number of MSCs. We find that the high-density MSCs-laden beads in sparse patterns demonstrate significantly improved therapeutic performance, by regenerating skeletal muscles approaching native-like cell density with reduced fibrosis, and regenerating skin with hair follicle growth and increased dermis thickness. MSC proliferation within 1-week post-transplantation and differentiation at 3 − 4 weeks post-transplantation are suggested to contribute therapy augmentation. We expect this “bead-jet” printing system to strengthen the potential of MSC transplantation.
A circuit from the ventral subiculum to anterior hypothalamic nucleus GABAergic neurons essential for anxiety-like behavioral avoidance
Authors: Yan Jing-Jing , Ding Xiao-Jing , He Ting , Chen Ai-Xiao , Zhang Wen , Yu Zi-Xian , Cheng Xin-Yu , Wei Chuan-Yao , Hu Qiao-Dan , Liu Xiao-Yao , Zhang Yan-Li , He Mengge , Xie Zhi-Yong , Zha Xi , Xu Chun , Cao Peng , Li Haohong , Xu Xiao-Hong
Published: December 2022

Behavioral observations suggest a connection between anxiety and predator defense, but the underlying neural mechanisms remain unclear. Here we examine the role of the anterior hypothalamic nucleus (AHN), a node in the predator defense network, in anxiety-like behaviors. By in vivo recordings in male mice, we find that activity of AHN GABAergic (AHNVgat+) neurons shows individually stable increases when animals approach unfamiliar objects in an open field (OF) or when they explore the open-arm of an elevated plus-maze (EPM). Moreover, object-evoked AHN activity overlap with predator cue responses and correlate with the object and open-arm avoidance. Crucially, exploration-triggered optogenetic inhibition of AHNVgat+ neurons reduces object and open-arm avoidance. Furthermore, retrograde viral tracing identifies the ventral subiculum (vSub) of the hippocampal formation as a significant input to AHNVgat+ neurons in driving avoidance behaviors in anxiogenic situations. Thus, convergent activation of AHNVgat+ neurons serves as a shared mechanism between anxiety and predator defense to promote behavioral avoidance.
A growth selection system for the directed evolution of amine-forming or converting enzymes
Authors: Wu Shuke , Xiang Chao , Zhou Yi , Khan Mohammad Saiful Hasan , Liu Weidong , Feiler Christian G. , Wei Ren , Weber Gert , Höhne Matthias , Bornscheuer Uwe T.
Published: December 2022

Fast screening of enzyme variants is crucial for tailoring biocatalysts for the asymmetric synthesis of non-natural chiral chemicals, such as amines. However, most existing screening methods either are limited by the throughput or require specialized equipment. Herein, we report a simple, high-throughput, low-equipment dependent, and generally applicable growth selection system for engineering amine-forming or converting enzymes and apply it to improve biocatalysts belonging to three different enzyme classes. This results in (i) an amine transaminase variant with 110-fold increased specific activity for the asymmetric synthesis of the chiral amine intermediate of Linagliptin; (ii) a 270-fold improved monoamine oxidase to prepare the chiral amine intermediate of Cinacalcet by deracemization; and (iii) an ammonia lyase variant with a 26-fold increased activity in the asymmetric synthesis of a non-natural amino acid. Our growth selection system is adaptable to different enzyme classes, varying levels of enzyme activities, and thus a flexible tool for various stages of an engineering campaign.
Non-classical ferroptosis inhibition by a small molecule targeting PHB2
Authors: Yang Wei , Mu Bo , You Jing , Tian Chenyu , Bin Huachao , Xu Zhiqiang , Zhang Liting , Ma Ronggang , Wu Ming , Zhang Guo , Huang Chong , Li Linli , Shao Zhenhua , Dai Lunzhi , Désaubry Laurent , Yang Shengyong
Published: December 2022

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.
Hemispheric lateralization of semantic processing before and after aripiprazole treatment in first-episode psychosis or ultra-high risk state
Authors: Hwang Tzung-Jeng , Chan Chia-Ta , Hsieh Cheng-Yu , Liu Chih-Min , Liu Chen-Chung , Chien Yi-Ling , Hsieh Ming H. , Lin Yi-Ting , Chou Tai-Li
Published: December 2022

Whether aberrant language-related lateralization can be improved after antipsychotic treatment in drug-free patients with first-episode psychosis or ultra-high risk state is little known. We aimed to investigate the improvement in lateralization of semantic processing after antipsychotic treatment and associated clinical and cognitive changes. Twenty-one drug-free patients with first-episode psychosis or ultra-high risk state underwent functional magnetic resonance imaging with a semantic task, neuropsychological testing, and clinical assessments with the Positive and Negative Syndrome Scale before and after 6 weeks of aripiprazole treatment. A lateralization index of the region of interest, i.e., inferior frontal gyrus, was calculated and correlated with the behavioral indices of the semantic task, Positive and Negative Syndrome Scale scores, and language-related neuropsychological test scores. After treatment, the lateralization index of the inferior frontal gyrus was significantly increased, which was related to reduced activation of the right inferior frontal gyrus. The increase in the lateralization index was significantly associated with the increase in verbal fluency score. A higher baseline accuracy of the semantic task was associated with a higher post-treatment lateralization index of the inferior frontal gyrus and greater improvement of the total score and positive subscore of the Positive and Negative Syndrome Scale. Our findings indicated aripiprazole treatment significantly increased semantic processing-related lateralization in the inferior frontal gyrus in drug-free patients with first-episode psychosis or ultra-high risk state. A higher baseline accuracy might predict a higher post-treatment lateralization index and greater symptom improvement.
Area of Habitat maps for the world’s terrestrial birds and mammals
Authors: Lumbierres Maria , Dahal Prabhat Raj , Soria Carmen D. , Di Marco Moreno , Butchart Stuart H. M. , Donald Paul F. , Rondinini Carlo
Published: December 2022

Area of Habitat (AOH) is “the habitat available to a species, that is, habitat within its range”. It complements a geographic range map for a species by showing potential occupancy and reducing commission errors. AOH maps are produced by subtracting areas considered unsuitable for the species from their range map, using information on each species’ associations with habitat and elevation. We present AOH maps for 5,481 terrestrial mammal and 10,651 terrestrial bird species (including 1,816 migratory bird species for which we present separate maps for the resident, breeding and non-breeding areas). Our maps have a resolution of 100 m. On average, AOH covered 66 ± 28% of the range maps for mammals and 64 ± 27% for birds. The AOH maps were validated independently, following a novel two-step methodology: a modelling approach to identify outliers and a species-level approach based on point localities. We used AOH maps to produce global maps of the species richness of mammals, birds, globally threatened mammals and globally threatened birds.
Chromosomal-level genome assembly of potato tuberworm, Phthorimaea operculella: a pest of solanaceous crops
Authors: Zhang Mengdi , Cheng Xinyue , Lin Runmao , Xie Bingyan , Nauen Ralf , Rondon Silvia I. , Zavala Jorge A. , Palli Subba Reddy , Li Suhua , Xiong Xingyao , Zhou Wenwu , Gao Yulin
Published: December 2022

The potato tuberworm, Phthorimaea operculella Zeller, is an oligophagous pest feeding on crops mainly belonging to the family Solanaceae. It is one of the most destructive pests of potato worldwide and attacks foliage and tubers in the field and in storage. However, the lack of a high-quality reference genome has hindered the association of phenotypic traits with their genetic basis. Here, we report on the genome assembly of P. operculella at the chromosomal level. Using Illumina, Nanopore and Hi-C sequencing, a 648.2 Mb genome was generated from 665 contigs, with an N50 length of 3.2 Mb, and 92.0% (596/648.2 Mb) of the assembly was anchored to 29 chromosomes. In total, 16619 genes were annotated, and 92.4% of BUSCO genes were fully represented. The chromosome-level genome of P. operculella will provide a significant resource for understanding the genetic basis for the biological study of this insect, and for promoting the integrative management of this pest in future.
Long-term High Resolution Image Dataset of Antarctic Coastal Benthic Fauna
Authors: Marini Simone , Bonofiglio Federico , Corgnati Lorenzo Paolo , Bordone Andrea , Schiaparelli Stefano , Peirano Andrea
Published: December 2022

Antarctica is a remote place, the continent is covered by ice and its surrounding coastal areas are frozen for the majority of the year. Due to its peculiarity the observation of the underwater organisms is particularly difficult, complicated by logistic factors. We present a long-term dataset consisting of 755 images acquired by using a non-invasive, autonomous imaging device and encompassing both the Antarctic daylight and dark periods, including the corresponding transition phases. All images have the same field of view showing the benthic fauna and part of the water column above, including fishes present in the monitored period. All the images are manually annotated after a visual inspection performed by expert biologists. The extended monitoring period and the annotated images make the dataset a valuable benchmark suitable for studying the dynamics of the long-term Antarctic underwater fauna as well as for developing and testing algorithms for automated image analysis focused on the recognition and classification of the Antarctic organisms and the automated analysis of their long-term dynamics.
High-resolution circa-2020 map of urban lakes in China
Authors: Song Chunqiao , Jiang Xingan , Fan Chenyu , Li Linsen
Published: December 2022

Urban lakes provide important ecological services to local communities, such as flood mitigation, biodiversity, and recreation. With rapid urbanization, urban lakes are significantly affected by socio-economic development and urgently need attention. Yet there is still a lack of datasets that include tiny urban lakes on a global or national scale. This study aims to produce a high-resolution circa-2020 map of urban lakes (≥0.001 km2) in China. The 10-m-resolution Sentinel-2 imagery and a simple but robust water extraction method was used to generate waterbodies. The accuracy of this national-scale dataset was evaluated by comparing it with manually sampled urban units, with the average accuracy of 81.85% in area and 93.35% in count. The database totally inventories 1.11 × 106 urban lakes in China, with a net area of ~2.13 × 103 km2. Overall, the spatial distribution of urban lakes in China showed strongly heterogeneous characteristics. This dataset will enhance our understanding of the distribution pattern of China’s urban lakes and contribute to better ecological and environmental management as well as sustainable urban development planning.
Introducing ligand GA, a genetic algorithm molecular tool for automated protein inhibitor design
Authors: Chalmers Gordon
Published: December 2022

Ligand GA is introduced in this work and approaches the problem of finding small molecules inhibiting protein functions by using the protein site to find close to optimal or optimal small molecule binders. Genetic algorithms (GA) are an effective means for approximating or solving computationally hard mathematics problems with large search spaces such as this one. The algorithm is designed to include constraints on the generated molecules from ADME restriction, localization in a binding site, specified hydrogen bond requirements, toxicity prevention from multiple proteins, sub-structure restrictions, and database inclusion. This algorithm and work is in the context of computational modeling, ligand design and docking to protein sites.
Excess iodine exposure acutely increases salivary iodide and antimicrobial hypoiodous acid concentrations in humans
Authors: Akiba Yasutada , Leung Angela M. , Bashir Muhammad-Tariq , Ebrahimi Ramin , Currier Jesse W. , Neverova Natalia , Kaunitz Jonathan D.
Published: December 2022

The lactoperoxidase (LPO)-hydrogen peroxide-halides reaction (LPO system) converts iodide and thiocyanate (SCN−) into hypoiodous acid (HOI) and hypothiocyanite (OSCN−), respectively. Since this system has been implicated in defense of the airways and oropharynx from microbial invasion, in this proof-of-concept study we measured the concentrations of these analytes in human saliva from a convenience clinical sample of 40 qualifying subjects before and after acute iodine administration via the iodinated contrast medium used in coronary angiography to test the hypothesis that an iodide load increases salivary iodide and HOI concentrations. Saliva was collected and salivary iodide, SCN−, HOI and OSCN− were measured using standard methodology. The large iodine load delivered by the angiographic dye, several 100-fold in excess of the U.S. Recommended Daily Allowance for iodine (150 µg/day), significantly increased salivary iodide and HOI levels compared with baseline levels, whereas there was no significant change in salivary SCN− and OSCN− levels. Iodine load and changes of salivary iodide and HOI levels were positively correlated, suggesting that higher iodide in the circulation increases iodide output and salivary HOI production. This first of its kind study suggests that a sufficient but safe iodide supplementation less than the Tolerable Upper Limit for iodine set by the U.S. Institute of Medicine (1,100 µg/day) may augment the generation of antimicrobial HOI by the salivary LPO system in concentrations sufficient to at least in theory protect the host against susceptible airborne microbial pathogens, including enveloped viruses such as coronaviruses and influenza viruses.
Hollow and porous TiO2 in PVA matrix nanocomposite green synthesis using ionic liquid micelle for Congo red removal from contaminated water
Authors: Shahabadi Arsalan , Golmohammadi Behrang , Shekaari Hemayat
Published: December 2022

A new green procedure has been applied to prepare TiO2 nanocomposite in polyvinyl alcohol (PVA) matrix using an aqueous micelle solution of ionic liquid 1-methyl-3-octylimidazolium bromide by determining critical micelle concentration (CMC). The COSMO-SAC model has been used to calculate the activity coefficient of water and understand the water molecules’ behavior in the synthesis mixture. The prepared nanocomposite was porous and layered that has been characterized using FT-IR, XRD, DSC, TGA, SEM, EDX, and elemental mapping. The prepared nanocomposite has been used to remove Congo red dye from contaminated water with the adsorption process. The Langmuir, Freundlich, and Temkin isotherms have been used for modeling equilibrium adsorption of dye removal. Also, the optimized process factors have been evaluated that could achieve 97% dye removal in the following conditions: pH = 12, T = 25 ℃, and t = 45 min using 0.2 g TiO2@PVA (Mesh 100)/L of 10 ppm Congo red aqueous solution. Also, the efficiency of the nanocomposite was 88% after 5 recovery cycles from the optimized condition.
Age-specific serum thyrotropin reference range for the diagnosis of subclinical hypothyroidism and its association with lipid profiles in the elderly population
Authors: Ni Wenjing , Zhang Mengjie , Wang Xiaowei , Li Xingjia , Wang Qifeng , Wang Yan , Chen Guofang , Shen Tonggao , Fan Kuanlu , Yao Xiaoming , Sun Yu , Liu Chao , Xu Shuhang
Published: December 2022

The overdiagnosis of subclinical hypothyroidism (SCH) in the elderly has driven researchers to establish age-specific thyroid stimulating hormone (TSH) intervals to precisely evaluate the prevalence of SCH. Moreover, abnormal lipid profiles, an insidious manifestation of SCH, show various impacts on different age groups. This study aimed to establish an age-specific TSH reference range to clarify the spectrum of SCH in the elderly. The prevalence of dyslipidemia and the age-specific association between TSH and lipid profiles were analyzed to elucidate the relationship between SCH and dyslipidemia. This cross-sectional study enrolled 2460 participants aged ≥ 65 years via cluster sampling. All participants received physical, laboratory tests and thyroid ultrasound examination and completed the questionnaire. The chi-square test was used to analyze variations of dyslipidemia prevalence among different groups. The Cochran-Armitage trend test was applied for testing the linear trends of age-specific prevalence of dyslipidemia among different TSH intervals in each age group. After adjusting for confounding factors, the age-specific association between TSH and lipid profiles was identified using multi-variate linear regression analysis. The TSH reference ranges in the 65–70 age group, 71–80 age group and > 80 age group were 0.65–5.51 mIU/L, 0.85–5.89 mIU/L and 0.78–6.70 mIU/L, respectively. Using these age-specific reference ranges, the prevalence of SCH in the whole population was 3.74%, which was significantly lower than the prevalence based on the laboratory reference range (10.28%). In the 65–70 age group, only the prevalence of high total cholesterol (TC) increased significantly with the age-specific TSH intervals, and TSH was positively associated with TC and low-density lipoprotein cholesterol (LDL-C). In the 71–80 and > 80 age groups, the prevalence of high TC, high triglycerides (TGs), and high LDL-C increased significantly with elevated TSH reference ranges. The levels of TC, TGs, and LDL-C were also positively associated with TSH level in 71–80 age group. However, such an association disappeared in > 80 age group. An age-specific reference range for TSH can effectively prevent the overdiagnosis of SCH in the elderly. Aging could somewhat attenuate the impact of TSH on lipid profiles.
The effect of the COVID-19 pandemic on deceased and living organ donors in the United States of America
Authors: Hantouche Mireille , Lara Carrion Libia , Porcu Emilio , Bramstedt Katrina A.
Published: December 2022

A life-saving treatment, solid organ transplantation (SOT) has transformed the survival and quality of life of patients with end-organ dysfunction. The coronavirus disease (COVID-19) pandemic has impacted the practice of deceased and living donations worldwide by various resource shifting, including healthcare personnel and equipment such as ventilators and bed space. Our work explores the COVID-19 pandemic and global transplant data to create a statistical model for deducing the impact of COVID-19 on living donor and deceased donor transplants in the United States of America (USA). In severely impacted regions, transplant centers need to carefully balance the risks and benefits of performing a transplant during the COVID-19 pandemic. In our statistical model, the COVID cases are used as an explanatory variable (input) to living or deceased donor transplants (output). The model is shown to be statistically accurate for both estimation of the correlation structure, and prediction of future donors. The provided predictions are to be taken as probabilistic assertions, so that for each instant where the prediction is calculated, a statistical measure of accuracy (confidence interval) is provided. The method is tested on both low and high frequency data, that notoriously exhibit a different behavior.
Diabetes medication recommendation system using patient similarity analytics
Authors: Tan Wei Ying , Gao Qiao , Oei Ronald Wihal , Hsu Wynne , Lee Mong Li , Tan Ngiap Chuan
Published: December 2022

Type-2 diabetes mellitus (T2DM) is a medical condition in which oral medications avail to patients to curb their hyperglycaemia after failed dietary therapy. However, individual responses to the prescribed pharmacotherapy may differ due to their clinical profiles, comorbidities, lifestyles and medical adherence. One approach is to identify similar patients within the same community to predict their likely response to the prescribed diabetes medications. This study aims to present an evidence-based diabetes medication recommendation system (DMRS) underpinned by patient similarity analytics. The DMRS was developed using 10-year electronic health records of 54,933 adult patients with T2DM from six primary care clinics in Singapore. Multiple clinical variables including patient demographics, comorbidities, laboratory test results, existing medications, and trajectory patterns of haemoglobin A1c (HbA1c) were used to identify similar patients. The DMRS was evaluated on four groups of patients with comorbidities such as hyperlipidaemia (HLD) and hypertension (HTN). Recommendations were assessed using hit ratio which represents the percentage of patients with at least one recommended sets of medication matches exactly the diabetes prescriptions in both the type and dosage. Recall, precision, and mean reciprocal ranking of the recommendation against the diabetes prescriptions in the EHR records were also computed. Evaluation against the EHR prescriptions revealed that the DMRS recommendations can achieve hit ratio of 81% for diabetes patients with no comorbidity, 84% for those with HLD, 78% for those with HTN, and 75% for those with both HLD and HTN. By considering patients’ clinical profiles and their trajectory patterns of HbA1c, the DMRS can provide an individualized recommendation that resembles the actual prescribed medication and dosage. Such a system is useful as a shared decision-making tool to assist clinicians in selecting the appropriate medications for patients with T2DM.
Modified DNA vaccine confers improved humoral immune response and effective virus protection against SARS-CoV-2 delta variant
Authors: Hayashi Hiroki , Sun Jiao , Yanagida Yuka , Otera Takako , Sasai Miwa , Chang Chin Yang , Tai Jiayu A. , Nishikawa Tomoyuki , Yamashita Kunihiko , Sakaguchi Naoki , Yoshida Shota , Baba Satoshi , Shimamura Munehisa , Okamoto Sachiko , Amaishi Yasunori , Chono Hideto , Mineno Junichi , Rakugi Hiromi , Morishita Ryuichi , Yamamoto Masahiro , Nakagami Hironori
Published: December 2022

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. New technologies have been utilized to develop several types of vaccines to prevent the spread of SARS-CoV-2 infection, including mRNA vaccines. Our group previously developed an effective DNA-based vaccine. However, emerging SARS-CoV-2 variants of concern (VOCs), such as the delta variant, have escaped mutations against vaccine-induced neutralizing antibodies. This suggests that modified vaccines accommodating VOCs need to be developed promptly. Here, we first modified the current DNA vaccine to enhance antigenicity. Compared with the parental DNA vaccine, the modified version (GP∆-DNA vaccine) induced rapid antibody production. Next, we updated the GP∆-DNA vaccine to spike glycoprotein of the delta variant (GP∆-delta DNA vaccine) and compared the efficacy of different injection routes, namely intramuscular injection using a needle and syringe and intradermal injection using a pyro-drive jet injector (PJI). We found that the levels of neutralizing antibodies induced by the intradermal PJI injection were higher than intramuscular injection. Furthermore, the PJI-injected GP∆-delta DNA vaccine effectively protected human angiotensin-converting enzyme 2 (hACE2) knock-in mice from delta-variant infection. These results indicate that the improved DNA vaccine was effective against emerging VOCs and was a potential DNA vaccine platform for future VOCs or global pandemics.
Hypergraph geometry reflects higher-order dynamics in protein interaction networks
Authors: Murgas Kevin A. , Saucan Emil , Sandhu Romeil
Published: December 2022

Protein interactions form a complex dynamic molecular system that shapes cell phenotype and function; in this regard, network analysis is a powerful tool for studying the dynamics of cellular processes. Current models of protein interaction networks are limited in that the standard graph model can only represent pairwise relationships. Higher-order interactions are well-characterized in biology, including protein complex formation and feedback or feedforward loops. These higher-order relationships are better represented by a hypergraph as a generalized network model. Here, we present an approach to analyzing dynamic gene expression data using a hypergraph model and quantify network heterogeneity via Forman-Ricci curvature. We observe, on a global level, increased network curvature in pluripotent stem cells and cancer cells. Further, we use local curvature to conduct pathway analysis in a melanoma dataset, finding increased curvature in several oncogenic pathways and decreased curvature in tumor suppressor pathways. We compare this approach to a graph-based model and a differential gene expression approach.
Natural reservoir Rousettus aegyptiacus bat host model of orthonairovirus infection identifies potential zoonotic spillover mechanisms
Authors: Schuh Amy J. , Amman Brian R. , Guito Jonathan C. , Graziano James C. , Sealy Tara K. , Kirejczyk Shannon G. M. , Towner Jonathan S.
Published: December 2022

The human-pathogenic Kasokero virus (KASV; genus Orthonairovirus) has been isolated from the sera of Egyptian rousette bats (ERBs; Rousettus aegyptiacus) captured in Uganda and unengorged Ornithodoros (Reticulinasus) faini ticks collected from the rock crevices of ERB colonies in South Africa and Uganda. Although evidence suggests that KASV is maintained in an enzootic transmission cycle between O. (R.) faini ticks and ERBs with potential for incidental virus spillover to humans through the bite of an infected tick, the vertebrate reservoir status of ERBs for KASV has never been experimentally evaluated. Furthermore, the potential for bat-to-bat and bat-to-human transmission of KASV is unknown. Herein, we inoculate two groups of ERBs with KASV; one group of bats is serially sampled to assess viremia, oral, fecal, and urinary shedding and the second group of bats is serially euthanized to assess virus-tissue tropism. Throughout the study, none of the bats exhibit overt signs of clinical disease. Following the detection of high KASV loads of long duration in blood, oral, fecal, and urine specimens collected from ERBs in the serial sampling group, all bats seroconvert to KASV. ERBs from the serial euthanasia group exhibit high KASV loads indicative of virus replication in the skin at the inoculation site, spleen, and inguinal lymph node tissue, and histopathology and in situ hybridization reveal virus replication in the liver and self-limiting, KASV-induced lymphohistiocytic hepatitis. The results of this study suggest that ERBs are competent, natural vertebrate reservoir hosts for KASV that can sustain viremias of appropriate magnitude and duration to support virus maintenance through bat-tick-bat transmission cycles. Viral shedding data suggests that KASV might also be transmitted bat-to-bat and highlights the potential for KASV spillover to humans through contact with infectious oral secretions, feces, or urine.
Effect of biofertilizers on leaf yield, nitrate amount, mineral content and antioxidants of basil (Ocimum basilicum L.) in a floating culture
Authors: Dasgan Hayriye Yildiz , Aldiyab Abdullah , Elgudayem Farah , Ikiz Boran , Gruda Nazim S.
Published: December 2022

Hydroponics is one of the systems in agriculture which reinforce productivity by controlling environmental and growing conditions. In this study, we evaluated the effect of three bio-fertilizers, namely bacteria, micro-algae, and mycorrhiza, on basil leaf yield and quality (Ocimum basilicum L.) in a floating culture system. Soil has rich amounts of beneficial microorganisms, supporting plant nutrition, producing phytohormones, controlling phytopathogens, and improving soil structure. However, soilless culture usually contains no beneficial microorganisms if we do not include them in the system. This study aims to evaluate the response of three bio-fertilizers where mineral fertilizers are reduced by 50%. Considering the total harvest data, bacteria, mycorrhiza, and micro-algae treatments increased basil yield compared to 50% control by about 18.94%, 13.94%, and 5.72%, respectively. The maximum total yield and leaf area were recorded using bacteria with 2744 g m−2 and 1528 cm2 plant−1. Plants with mycorrhiza achieved the highest number of leaves and branches, with 94.3 leaves plant−1 and 24.50 branches plant−1, respectively. It was observed that this bio-fertilizer increased the formation of lateral branches in the basil plant without thickening its stems. In addition, bacteria and mycorrhiza induced the highest percentage of dry matter and total soluble solids. The effect of bio-fertilizers on basil leaf EC and pH was insignificant for all the treatments at different harvest periods (p < 0.05). Using bio-fertilizers enhanced the intake of nutrients N (nitrogen), P (phosphorus), K (potassium), Ca (calcium), Mg (magnesium), Fe (iron), Mn (manganese), Zn (zinc), and Cu (copper). Using bio-fertilizers represents a promising and environmentally friendly approach to increasing crop yields and ameliorating quality and antioxidant compounds with fewer resources. An application of bio-fertilizers in hydroponic cultivation of basil cv. ‘Dino’ reduced the need for mineral fertilizers. At the same time, bio-fertilizers affected an increased plant yield and improved product quality. Furthermore, the bacteria had a pronounced enhancing effect on the increase of phenol and flavonoids in the leaves of basil plants.