bluuebunny/crossref_metadata_2025 huggingface dataset:
Developments in scalable strategies for detecting early markers of cognitive decline
Authors: Whelan Robert , Barbey Florentine M. , Cominetti Marcia R. , Gillan Claire M. , Rosická Anna M.
Published: November 2022

Effective strategies for early detection of cognitive decline, if deployed on a large scale, would have individual and societal benefits. However, current detection methods are invasive or time-consuming and therefore not suitable for longitudinal monitoring of asymptomatic individuals. For example, biological markers of neuropathology associated with cognitive decline are typically collected via cerebral spinal fluid, cognitive functioning is evaluated from face-to-face assessments by experts and brain measures are obtained using expensive, non-portable equipment. Here, we describe scalable, repeatable, relatively non-invasive and comparatively inexpensive strategies for detecting the earliest markers of cognitive decline. These approaches are characterized by simple data collection protocols conducted in locations outside the laboratory: measurements are collected passively, by the participants themselves or by non-experts. The analysis of these data is, in contrast, often performed in a centralized location using sophisticated techniques. Recent developments allow neuropathology associated with potential cognitive decline to be accurately detected from peripheral blood samples. Advances in smartphone technology facilitate unobtrusive passive measurements of speech, fine motor movement and gait, that can be used to predict cognitive decline. Specific cognitive processes can be assayed using ‘gamified’ versions of standard laboratory cognitive tasks, which keep users engaged across multiple test sessions. High quality brain data can be regularly obtained, collected at-home by users themselves, using portable electroencephalography. Although these methods have great potential for addressing an important health challenge, there are barriers to be overcome. Technical obstacles include the need for standardization and interoperability across hardware and software. Societal challenges involve ensuring equity in access to new technologies, the cost of implementation and of any follow-up care, plus ethical issues.
PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer
Authors: Propper David J. , Gao Fangfei , Saunders Mark P. , Sarker Debashis , Hartley John A. , Spanswick Victoria J. , Lowe Helen L. , Hackett Louise D. , Ng Tony T. , Barber Paul R. , Weitsman Gregory E. , Pearce Sarah , White Laura , Lopes Andre , Forsyth Sharon , Hochhauser Daniel
Published: November 2022

Background

Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC).

Methods

Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage.

Results

Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed.

Conclusions

The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure.

Trial registration number

ClinicalTrials.gov number: NCT01862003.
Mitochondrial glutamine transporter SLC1A5_var, a potential target to suppress astrocyte reactivity in Parkinson’s Disease
Authors: Liu Yang , Cao Lei , Song Yuting , Kang Zhengwei , Liu Ting , Ding Jianhua , Hu Gang , Lu Ming
Published: November 2022

SLC1A5 variant (SLC1A5_var) is identified as a mitochondrial glutamine transporter in cancer cells recently. However, the role of SLC1A5_var in Parkinson’s disease (PD) is completely unknown. Here, we found the significant downregulation of SLC1A5_var in astrocytes and midbrain of mice treated with MPTP/MPP+ and LPS. Importantly, overexpression of SLC1A5_var ameliorated but knockdown of SLC1A5_var exacerbated MPTP/MPP+- and LPS-induced mitochondrial dysfunction. Consequently, SLC1A5_var provided beneficial effects on PD pathology including improvement of PD-like motor symptoms and rescue of dopaminergic (DA) neuron degeneration through maintaining mitochondrial energy metabolism. Moreover, SLC1A5_var reduced astrocyte reactivity via inhibition of A1 astrocyte conversion. Further investigation demonstrated that SLC1A5_var restrained the secretion of astrocytic pro-inflammatory cytokines by blunting TLR4-mediated downstream pathways. This is the first study to prove that astrocytic SLC1A5_var inhibits neuroinflammation, and rescues the loss of DA neurons and motor symptoms involved in PD progression, which provides a novel target for PD treatment.
Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism
Authors: Katona Máté , Bartók Ádám , Nichtova Zuzana , Csordás György , Berezhnaya Elena , Weaver David , Ghosh Arijita , Várnai Péter , Yule David I. , Hajnóczky György
Published: November 2022

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when ‘parked’, mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.
Simultaneous atmospheric water production and 24-hour power generation enabled by moisture-induced energy harvesting
Authors: Li Tingxian , Wu Minqiang , Xu Jiaxing , Du Ruxue , Yan Taisen , Wang Pengfei , Bai Zhaoyuan , Wang Ruzhu , Wang Siqi
Published: November 2022

Water and electricity scarcity are two global challenges, especially in arid and remote areas. Harnessing ubiquitous moisture and sunlight for water and power generation is a sustainable route to address these challenges. Herein, we report a moisture-induced energy harvesting strategy to realize efficient sorption-based atmospheric water harvesting (SAWH) and 24-hour thermoelectric power generation (TEPG) by synergistically utilizing moisture-induced sorption/desorption heats of SAWH, solar energy in the daytime and radiative cooling in the nighttime. Notably, the synergistic effects significantly improve all-day thermoelectric power density (~346%) and accelerate atmospheric water harvesting compared with conventional designs. We further demonstrate moisture-induced energy harvesting for a hybrid SAWH-TEPG device, exhibiting high water production of 750 g m−2, together with impressive thermoelectric power density up to 685 mW m−2 in the daytime and 21 mW m−2 in the nighttime. Our work provides a promising approach to realizing sustainable water production and power generation at anytime and anywhere.
Southern Ocean biogenic blooms freezing-in Oligocene colder climates
Authors: Hochmuth Katharina , Whittaker Joanne M. , Sauermilch Isabel , Klocker Andreas , Gohl Karsten , LaCasce Joseph H.
Published: November 2022

Crossing a key atmospheric CO2threshold triggered a fundamental global climate reorganisation ~34 million years ago (Ma) establishing permanent Antarctic ice sheets. Curiously, a more dramatic CO2decline (~800–400 ppm by the Early Oligocene(~27 Ma)), postdates initial ice sheet expansion but the mechanisms driving this later, rapid drop in atmospheric carbon during the early Oligocene remains elusive and controversial. Here we use marine seismic reflection and borehole data to reveal an unprecedented accumulation of early Oligocene strata (up to 2.2 km thick over 1500 × 500 km) with a major biogenic component in the Australian Southern Ocean. High-resolution ocean simulations demonstrate that a tectonically-driven, one-off reorganisation of ocean currents, caused a unique period where current instability coincided with high nutrient input from the Antarctic continent. This unrepeated and short-lived environment favoured extreme bioproductivity and enhanced sediment burial. The size and rapid accumulation of this sediment package potentially holds ~1.067 × 1015 kg of the ‘missing carbon’ sequestered during the decline from an Eocene high CO2-world to a mid-Oligocene medium CO2-world, highlighting the exceptional role of the Southern Ocean in modulating long-term climate.
The composition and structure of the ubiquitous hydrocarbon contamination on van der Waals materials
Authors: Pálinkás András , Kálvin György , Vancsó Péter , Kandrai Konrád , Szendrő Márton , Németh Gergely , Németh Miklós , Pekker Áron , Pap József S. , Petrik Péter , Kamarás Katalin , Tapasztó Levente , Nemes-Incze Péter
Published: November 2022

The behavior of single layer van der Waals (vdW) materials is profoundly influenced by the immediate atomic environment at their surface, a prime example being the myriad of emergent properties in artificial heterostructures. Equally significant are adsorbates deposited onto their surface from ambient. While vdW interfaces are well understood, our knowledge regarding atmospheric contamination is severely limited. Here we show that the common ambient contamination on the surface of: graphene, graphite, hBN and MoS2 is composed of a self-organized molecular layer, which forms during a few days of ambient exposure. Using low-temperature STM measurements we image the atomic structure of this adlayer and in combination with infrared spectroscopy identify the contaminant molecules as normal alkanes with lengths of 20-26 carbon atoms. Through its ability to self-organize, the alkane layer displaces the manifold other airborne contaminant species, capping the surface of vdW materials and possibly dominating their interaction with the environment.
Anti-Jahn-Teller effect induced ultrafast insulator to metal transition in perovskite BaBiO3
Authors: Feng Nan , Han Jian , Lin Changpeng , Ai Zhengwei , Lan Chuwen , Bi Ke , Lin Yuanhua , Xue Kan-Hao , Xu Ben
Published: November 2022

The Jahn-Teller (JT) effect involves the ions M with a degenerate electronic state distorting the corner-sharing MO6octahedra to lift the degeneracy, inducing strong coupling of electrons to lattice, and mediating the exotic properties in perovskite oxides. Conversely, the anti-Jahn–Teller (AJT) effect refers to the deformation against the Jahn-Teller-distorted MO6octahedra. However, it is difficult to experimentally execute both effects descending from the fine-tuning of crystal structures. We propose the AJT can be introduced by THz laser illumination at 11.71 THz in a candidate superconducting perovskite material BaBiO3near room temperature. The illumination coherently drives the infrared-active phonon that excites the Raman breathing mode through the quadratic-linear nonlinear interaction. The process is characterized by the emergence of an AJT effect, accompanied by an insulator-to-metal transition occurring on the picosecond timescale. This study underlines the important role of crystal structure engineering by coherent phonon excitation in designing optoelectronic devices.
A way forward for fundamental physics in space
Authors: Bassi A. , Cacciapuoti L. , Capozziello S. , Dell’Agnello S. , Diamanti E. , Giulini D. , Iess L. , Jetzer P. , Joshi S. K. , Landragin A. , Poncin-Lafitte C. Le , Rasel E. , Roura A. , Salomon C. , Ulbricht H.
Published: November 2022

Space-based research can provide a major leap forward in the study of key open questions in the fundamental physics domain. They include the validity of Einstein’s Equivalence principle, the origin and the nature of dark matter and dark energy, decoherence and collapse models in quantum mechanics, and the physics of quantum many-body systems. Cold-atom sensors and quantum technologies have drastically changed the approach to precision measurements. Atomic clocks and atom interferometers as well as classical and quantum links can be used to measure tiny variations of the space-time metric, elusive accelerations, and faint forces to test our knowledge of the physical laws ruling the Universe. In space, such instruments can benefit from unique conditions that allow improving both their precision and the signal to be measured. In this paper, we discuss the scientific priorities of a space-based research program in fundamental physics.
Path probability selection in nature and path integral
Authors: Wang Chao , Li Min-Lan , Wang Rui-Wu
Published: November 2022

Understanding of any biological evolutions, such as speciation, adaptation behavior and biodiversity pattern, is based on a fundamental concept of fitness, in which natural selection implies the improvement and progress of fitness in either direct/indirect benefit or genetic transmission to the next generation. However, this basic idea of biological evolution, which is mathematically described by Price equation or its related models, has not fully considered feedback effects from the environment or other generations. They lost the global dynamics of the evolutions consequently. Drawing on the idea of modern physics, we introduce the path integral by iterating the Price equation step by step to characterize the evolutionary path in which the stationary fitness is replaced by the path probability. The evolutionary selection therefore will depend on path probability instead of fitness advantage. In such a framework of the evolutionary path, the intermediate process of evolution is not always pointing to the fitness-maximizing equilibrium and multiple evolutionary paths could thus coexist without fitness advantage discrimination. This mechanism could potentially explain evolutionary strategies with the diversified fitness (e.g., coexistence of altruism and selfishness) and thus species diversity.
Lithium-sensing riboswitch classes regulate expression of bacterial cation transporter genes
Authors: White Neil , Sadeeshkumar Harini , Sun Anna , Sudarsan Narasimhan , Breaker Ronald R.
Published: November 2022

Lithium is rare in Earth’s crust compared to the biologically relevant alkali metal cations sodium and potassium but can accumulate to toxic levels in some environments. We report the experimental validation of two distinct bacterial riboswitch classes that selectively activate gene expression in response to elevated Li+ concentrations. These RNAs commonly regulate the expression of nhaA genes coding for ion transporters that weakly discriminate between Na+ and Li+. Our findings demonstrated that the primary function of Li+ riboswitches and associated NhaA transporters is to prevent Li+ toxicity, particularly when bacteria are living at high pH. Additional riboswitch-associated genes revealed how some cells defend against the deleterious effects of Li+ in the biosphere, which might become more problematic as its industrial applications increase.
Associations between digital media use and brain surface structural measures in preschool-aged children
Authors: Hutton John S. , Dudley Jonathan , DeWitt Thomas , Horowitz-Kraus Tzipi
Published: November 2022

The American Academy of Pediatrics recommends limits on digital media use (“screen time”), citing cognitive-behavioral risks. Media use in early childhood is ubiquitous, though few imaging-based studies have been conducted to quantify impacts on brain development. Cortical morphology changes dynamically from infancy through adulthood and is associated with cognitive-behavioral abilities. The current study involved 52 children who completed MRI and cognitive testing at a single visit. The MRI protocol included a high-resolution T1-weighted anatomical scan. The child’s parent completed the ScreenQ composite measure of media use. MRI measures included cortical thickness (CT) and sulcal depth (SD) across the cerebrum. ScreenQ was applied as a predictor of CT and SD first in whole-brain regression analyses and then for regions of interest (ROIs) identified in a prior study of screen time involving adolescents, controlling for sex, age and maternal education. Higher ScreenQ scores were correlated with lower CT in right-lateralized occipital, parietal, temporal and fusiform areas, and also lower SD in right-lateralized inferior temporal/fusiform areas, with substantially greater statistical significance in ROI-based analyses. These areas support primary visual and higher-order processing and align with prior findings in adolescents. While differences in visual areas likely reflect maturation, those in higher-order areas may suggest under-development, though further studies are needed.
A systematic review and meta-analysis on alcohol consumption and risk of endometriosis: an update from 2012
Authors: Li Piani Letizia , Chiaffarino Francesca , Cipriani Sonia , Viganò Paola , Somigliana Edgardo , Parazzini Fabio
Published: November 2022

Endometriosis is a complex and chronic disease, whose multifactorial nature has encouraged a deep investigation on the role of lifestyle factors. A strong association between alcohol intake and endometriosis risk has already been shown. We aimed to confirm this association, considering the updated literature. 23 eligible studies were identified through comprehensive literature search of PubMed and EMBASE (May 2012–October 2021). A borderline statistical significance was found comparing any alcohol consumption with no consumption (unadjusted OR 1.14; 95% CI: 0.99–1.31, p = 0.06), in contrast with a previous meta-analysis. However, we confirmed the significant association between moderate alcohol intake and endometriosis (unadjusted OR 1.22, 95% CI: 1.03–1.45, p = 0.02), also performing a sensitivity analysis (unadjusted OR 1.27, 95% CI: 1.04–1.54). Our partly divergent evidence reflects the tough challenge of isolating the impact of specific factors on the natural history of multifactorial diseases. Indeed, on one hand alcohol could be adopted by patients as a self-management therapy and on the other, it could favor the disease, promoting positive feedback with inflammatory mediators and oxidative stress. Our study encourages further investigation on the role of modifiable lifestyle factors and highlights the opportunity to adopt them to prevent or at least limit endometriosis progression.
Assessment of a mass balance equation for estimating community-level prevalence of COVID-19 using wastewater-based epidemiology in a mid-sized city
Authors: Rainey Andrew L. , Loeb Julia C. , Robinson Sarah E. , Davis Paul , Liang Song , Lednicky John A. , Coker Eric S. , Sabo-Attwood Tara , Bisesi Joseph H. , Maurelli Anthony T.
Published: November 2022

Wastewater-based epidemiology (WBE) has emerged as a valuable epidemiologic tool to detect the presence of pathogens and track disease trends within a community. WBE overcomes some limitations of traditional clinical disease surveillance as it uses pooled samples from the entire community, irrespective of health-seeking behaviors and symptomatic status of infected individuals. WBE has the potential to estimate the number of infections within a community by using a mass balance equation, however, it has yet to be assessed for accuracy. We hypothesized that the mass balance equation-based approach using measured SARS-CoV-2 wastewater concentrations can generate accurate prevalence estimates of COVID-19 within a community. This study encompassed wastewater sampling over a 53-week period during the COVID-19 pandemic in Gainesville, Florida, to assess the ability of the mass balance equation to generate accurate COVID-19 prevalence estimates. The SARS-CoV-2 wastewater concentration showed a significant linear association (Parameter estimate = 39.43, P value < 0.0001) with clinically reported COVID-19 cases. Overall, the mass balance equation produced accurate COVID-19 prevalence estimates with a median absolute error of 1.28%, as compared to the clinical reference group. Therefore, the mass balance equation applied to WBE is an effective tool for generating accurate community-level prevalence estimates of COVID-19 to improve community surveillance.
Development and evaluation of a new assistive device for low back load reduction in caregivers: an experimental study
Authors: Omura Yuka , Hirata Masayuki , Yoshimine Toshiki , Nakatani Eiji , Inoue Tomoko
Published: November 2022

Low back pain among healthcare professionals is associated with the manual handling of patients. Some bed features for turning and repositioning have been developed; however, the load during patient care remains heavy. We developed a device to reduce low back load in caregivers during patient bedside care and evaluated it objectively and subjectively from a caregiver’s perspective using a randomised crossover study. Overall, 28 clinical nurses and care workers were randomly assigned to two interventional groups: administering care with (Device method) and without (Manual method) the device in an experimental room. We measured the caregiver’s trunk flexion angle using inertial measurement units and video recording during care and then defined a trunk flexion angle of > 45° as the threshold; the variables were analysed using linear mixed models. Subsequently, participants responded to a survey regarding the usability of the device. Trunk flexion time and percentage of time were 26.5 s (95% confidence interval: 14.1 s, 38.9 s) (p < 0.001) and 23.0% (95% confidence interval: 16.4%, 29.6%) (p < 0.001) lower, respectively, in the Device group than in the Manual group. Furthermore, caregivers evaluated the care they could administer with the device as being better than that associated with manual care.
Seminal extracellular vesicles subsets modulate gene expression in cumulus cells of porcine in vitro matured oocytes
Authors: Mateo-Otero Yentel , Yeste Marc , Roca Jordi , Llavanera Marc , Bucci Diego , Galeati Giovanna , Spinaci Marcella , Barranco Isabel
Published: November 2022

Seminal plasma (SP), a fluid composed mainly by secretions from accessory sex glands, contains a heterogenous population of extracellular vesicles (EVs), involved in several reproductive physiological processes. Seminal plasma has been found to modulate ovary function, in terms of hormone secretion and immune regulation. This study evaluated the potential effect of SP-EV-subsets on the modulation of cumulus-oocyte-complex (COCs) physiology during in vitro maturation (IVM). Two SP-EV-subsets, small-EVs (S-EVs) and large-EVs (L-EVs), were isolated from pig SP by size-exclusion-chromatography. Next, COCs were IVM in the absence (control) or presence of each SP-EV-subset to evaluate their uptake by COCs (PKH67-EVs labelling) and their effect on oocyte and cumulus cells (CCs) (gene expression, and progesterone and estradiol-17β levels). S-EVs and L-EVs were able to bind CCs but not oocytes. Supplementation with L-EVs induced changes (P ≤ 0.05) in the transcript levels of oocyte maturation- (HAS2) and steroidogenesis-related genes (CYP11A1 and HSD3B1) in CCs. No effect on nuclear oocyte maturation and progesterone and estradiol-17β levels was observed when COCs were IVM with any of the two SP-EV-subsets. In conclusion, while SP-EV-subsets can be integrated by CCs during IVM, they do not affect oocyte maturation and only L-EVs are able to modulate CCs function, mainly modifying the expression of steroidogenesis-related genes.
Generation of bright autobioluminescent bacteria by chromosomal integration of the improved lux operon ilux2
Authors: Gregor Carola
Published: November 2022

The bacterial bioluminescence system enables the generation of light by living cells without the requirement of an external luciferin. Due to the relatively low light emission, many applications of bioluminescence imaging would benefit from an increase in brightness of this system. In this report, a new approach of mutagenesis and screening of the involved proteins is described that is based on the identification of mutants with improved properties under rate-limiting reaction conditions. Multiple rounds of screening in Escherichia coli resulted in the operon ilux2 that contains 26 new mutations in the fatty acid reductase complex which provides the aldehyde substrate for the bioluminescence reaction. Chromosomal integration of ilux2 yielded an autonomously bioluminescent E. coli strain with sixfold increased brightness compared to the previously described ilux operon. The ilux2 strain produces sufficient signal for the robust detection of individual cells and enables highly sensitive long-term imaging of bacterial propagation without a selection marker.
LncDC: a machine learning-based tool for long non-coding RNA detection from RNA-Seq data
Authors: Li Minghua , Liang Chun
Published: November 2022

Long non-coding RNAs (lncRNAs) play an essential role in diverse biological processes and disease development. Accurate classification of lncRNAs and mRNAs is important for the identification of tissue- or disease-specific lncRNAs. Here, we present our tool LncDC (Long non-coding RNA detection) that is able to accurately predict lncRNAs with an XGBoost model using features extracted from RNA sequences, secondary structures, and translated proteins. Benchmarking experiments showed that LncDC consistently outperformed six state-of-the-art tools in distinguishing lncRNAs from mRNAs. Notably, the use of sequence and secondary structure (SASS) k-mer score features and flexible ORF features improved the classification capability of LncDC. We anticipate that LncDC will definitely promote the discovery of more and novel disease-specific lncRNAs. LncDC is implemented in Python and freely available at https://github.com/lim74/LncDC.
Empagliflozin suppresses urinary mitochondrial DNA copy numbers and interleukin-1β in type 2 diabetes patients
Authors: Lee Haekyung , Kim Hyoungnae , Jeon Jin Seok , Noh Hyunjin , Park Rojin , Byun Dong Won , Kim Hye Jeong , Suh Kyoil , Park Hyeong Kyu , Kwon Soon Hyo
Published: November 2022

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes in type 2 diabetes mellitus (T2DM) patients. However, the mechanisms by which SGLT2 inhibitors improve the clinical outcomes remain elusive. We evaluated whether empagliflozin, an SGLT2 inhibitor, ameliorates mitochondrial dysfunction and inflammatory milieu of the kidneys in T2DM patients. We prospectively measured copy numbers of urinary and serum mitochondrial DNA (mtDNA) nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND-1) and cytochrome-c oxidase 3 (mtCOX-3) and urinary interleukin-1β (IL-1β) in healthy volunteers (n = 22), in SGLT2 inhibitor-naïve T2DM patients (n = 21) at baseline, and in T2DM patients after 3 months of treatment with empagliflozin (10 mg, n = 17 or 25 mg, n = 4). Both urinary mtDNA copy numbers and IL-1β levels were higher in the T2DM group than in healthy volunteers. Baseline copy numbers of serum mtCOX-3 in the T2DM group were lower than those in healthy volunteers. Empagliflozin induced marked reduction in both urinary and serum mtND-1 and mtCOX-3 copy numbers, as well as in urinary IL-1β. Empagliflozin could attenuate mitochondrial damage and inhibit inflammatory response in T2DM patients. This would explain the beneficial effects of SGLT2 inhibitors on cardiovascular and renal outcomes.
The sleep EEG envelope is a novel, neuronal firing-based human biomarker
Authors: Ujma Péter P. , Dresler Martin , Simor Péter , Fabó Dániel , Ulbert István , Erőss Loránd , Bódizs Róbert
Published: November 2022

Sleep EEG reflects voltage differences relative to a reference, while its spectrum reflects its composition of various frequencies. In contrast, the envelope of the sleep EEG reflects the instantaneous amplitude of oscillations, while its spectrum reflects the rhythmicity of the occurrence of these oscillations. The sleep EEG spectrum is known to relate to demographic, psychological and clinical characteristics, but the envelope spectrum has been rarely studied. In study 1, we demonstrate in human invasive data from cortex-penetrating microelectrodes and subdural grids that the sleep EEG envelope spectrum reflects neuronal firing. In study 2, we demonstrate that the scalp EEG envelope spectrum is stable within individuals. A multivariate learning algorithm could predict age (r = 0.6) and sex (r = 0.5) from the EEG envelope spectrum. With age, oscillations shifted from a 4–5 s rhythm to faster rhythms. Our results demonstrate that the sleep envelope spectrum is a promising biomarker of demographic and disease-related phenotypes.
Discovery of potential natural dihydroorotate dehydrogenase inhibitors and their synergism with brequinar via integrated molecular docking, dynamic simulations and in vitro approach
Authors: Khairy Asmaa , Hammoda Hala M. , Celik Ismail , Zaatout Hala H. , Ibrahim Reham S.
Published: November 2022

The critical function of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis attracted a great interest throughout beyond decades. Inhibitors of human DHODH (hDHODH) have validated efficacy for remedy of many immunological diseases. Brequinar and leflunomide are examples of such compounds. However, most of such immunosuppressive medications suffer from a lot of side effects and accompanied by adverse metabolic disturbances and toxicities. So that, immunomodulation utilizing natural products received the attention of many researchers. In this study, computer-aided molecular docking, molecular dynamic (MD) simulations and biochemical testing were utilized to find new pharmacologically active chemical entities from natural sources to combat immunosuppressive diseases. More specifically, Glide docking was used for a structure-based virtual screening of in-house 3D database of compounds retrieved from some traditionally known immunomodulatory plants surveyed from literature. The top five scored plants were found to be Zingiber officinale, Curcuma longa, Glycyrrhiza glabra, Allium sativum and Olea europaea. In vitro hDHODH inhibitory assays illustrated the ability of Allium sativum and silymarin standard hits; specifically, silibinin, to significantly inhibit the hDHODH enzyme. Molecular docking and MD simulations revealed a strong binding of the discovered hits within the active site. Following that, the most promising hits were tested separately with brequinar in a fixed-ratio combination setting to assess their combined effects on hDHODH catalytic inhibition. The binary combination of silibinin and brequinar revealed that in this combination, brequinar could be utilized at a dose 9.33-fold less when compared to its single-use to produce 99% inhibition for hDHODH enzyme. These findings confirmed that this binary mixture is an excellent combination providing better therapeutic effects and lower side effects.
Convalescent plasma treatment for SARS-CoV-2 infected high-risk patients: a matched pair analysis to the LEOSS cohort
Authors: Freise Noemi F. , Gliga Smaranda , Fischer Johannes , Lübke Nadine , Lutterbeck Matthias , Schöler Miriam , Bölke Edwin , Orth Hans Martin , Feldt Torsten , Roemmele Christoph , Wilke Dominik , Schneider Jochen , Wille Kai , Hohmann Christian , Strauss Richard , Hower Martin , Ruf Andreas , Schubert Joerg , Isberner Nora , Stecher Melanie , Pilgram Lisa , Vehreschild Jörg J. ,   LEOSS Study Group, de With Katja , Spinner Christoph , Lanznaster Julia , Beutel Gernot , Jung Norma , Göpel Siri , Westhoff Timm , Hohenstein Bernd , Rothfuss Katja , Rieg Siegbert , Ruethrich Maria Madeleine , Rupp Jan , Hanses Frank , Luedde Tom , Jensen Björn
Published: November 2022

Establishing the optimal treatment for COVID-19 patients remains challenging. Specifically, immunocompromised and pre-diseased patients are at high risk for severe disease course and face limited therapeutic options. Convalescent plasma (CP) has been considered as therapeutic approach, but reliable data are lacking, especially for high-risk patients. We performed a retrospective analysis of 55 hospitalized COVID-19 patients from University Hospital Duesseldorf (UKD) at high risk for disease progression, in a substantial proportion due to immunosuppression from cancer, solid organ transplantation, autoimmune disease, dialysis. A matched-pairs analysis (1:4) was performed with 220 patients from the Lean European Open Survey on SARS-CoV-2-infected Patients (LEOSS) who were treated or not treated with CP. Both cohorts had high mortality (UKD 41.8%, LEOSS 34.1%). A matched-pairs analysis showed no significant effect on mortality. CP administration before the formation of pulmonary infiltrates showed the lowest mortality in both cohorts (10%), whereas mortality in the complicated phase was 27.8%. CP administration during the critical phase revealed the highest mortality: UKD 60.9%, LEOSS 48.3%. In our cohort of COVID-19 patients with severe comorbidities CP did not significantly reduce mortality in a retrospective matched-pairs analysis. However, our data supports the concept that a reduction in mortality is achievable by early CP administration.
A short exposure to a semi-natural habitat alleviates the honey bee hive microbial imbalance caused by agricultural stress
Authors: Gorrochategui-Ortega June , Muñoz-Colmenero Marta , Kovačić Marin , Filipi Janja , Puškadija Zlatko , Kezić Nikola , Parejo Melanie , Büchler Ralph , Estonba Andone , Zarraonaindia Iratxe
Published: November 2022

Honeybee health and the species’ gut microbiota are interconnected. Also noteworthy are the multiple niches present within hives, each with distinct microbiotas and all coexisting, which we termed “apibiome”. External stressors (e.g. anthropization) can compromise microbial balance and bee resilience. We hypothesised that (1) the bacterial communities of hives located in areas with different degrees of anthropization differ in composition, and (2) due to interactions between the multiple microbiomes within the apibiome, changes in the community of a niche would impact the bacteria present in other hive sections. We characterised the bacterial consortia of different niches (bee gut, bee bread, hive entrance and internal hive air) of 43 hives from 3 different environments (agricultural, semi-natural and natural) through 16S rRNA amplicon sequencing. Agricultural samples presented lower community evenness, depletion of beneficial bacteria, and increased recruitment of stress related pathways (predicted via PICRUSt2). The taxonomic and functional composition of gut and hive entrance followed an environmental gradient. Arsenophonus emerged as a possible indicator of anthropization, gradually decreasing in abundance from agriculture to the natural environment in multiple niches. Importantly, after 16 days of exposure to a semi-natural landscape hives showed intermediate profiles, suggesting alleviation of microbial dysbiosis through reduction of anthropization.
Inclusion of bimetallic Fe0.75Cu0.25-BDC MOFs into Alginate-MoO3/GO as a novel nanohybrid for adsorptive removal of hexavalent chromium from water
Authors: Mahmoud Mohamed E. , Amira Mohamed F. , Azab Mayar M. H. M. , Abdelfattah Amir M.
Published: November 2022

Metal–organic frameworks (MOFs) as porous materials have recently attracted research works in removal of toxic pollutants from water. Cr(VI) is well-known as one of the most toxic forms of chromium and the selection of efficient and effective Cr(VI)-remediation technology must be focused on a number of important parameters. Therefore, the objective of this work is to fabricate a novel nanohybrid adsorbent for removal of Cr(VI) by using assembled bimetallic MOFs (Fe0.75Cu0.25-BDC)-bound- Alginate-MoO3/Graphene oxide (Alg-MoO3/GO) via simple solvothermal process. The aimed Fe0.75Cu0.25-BDC@Alg-MoO3/GO nanohybrid was confirmed by FTIR, SEM, TEM, XRD and TGA. Adsorptive extraction of Cr(VI) from aqueous solution was aimed by various optimized experimental parameters providing optimum pH = 3, dosage = 5–10 mg, starting concentration of Cr(VI) = 5–15 mg L−1, shaking time = 5–10 min. The point of zero charge (pHPzc) was 3.8. For Cr(VI) removal by Fe0.75Cu0.25-BDC@Alg-MoO3/GO, four isotherm models were estimated: Langmuir, Freundlich, Temkin and Dubinin-Radushkevich (D-R) with calculated correlation coefficient (R2 = 0.9934) for Langmuir model which was higher than others. The collected results from the kinetic study clarified that pseudo-second order model is the most convenient one for describing the adsorption behavior of Cr(VI) and therefore, the adsorption process was suggested to rely on a chemisorption mechanism. Thermodynamic parameters referred that the adsorption mechanism is based on a spontaneous and exothermic process. Finally, the emerged Fe0.75Cu0.25-BDC@Alg-MoO3/GO nanohybrid was confirmed as an effective adsorbent for extraction of hexavalent chromium from real water specimens (tap, sea water and wastewater) with percentage recovery values > 98%.
Craniofacial and three-dimensional palatal analysis in cleft lip and palate patients treated in Spain
Authors: Viñas María José , Galiotto-Barba Francesca , Cortez-Lede María Gabriela , Rodríguez-González María Ángeles , Moral Ignacio , Delso Elena , González-Meli Beatriz , Lobo Fernando , López-Cedrún José Luis , Neagu David , Garatea Joaquín , Garatea Amaia , Berenguer Beatriz , Lorca-García Concepción , Delgado María Dolores , Martí Eunate , Gutiérrez José Manuel , Hernández Carlos , Murillo-González Jorge , Martínez-Álvarez Concepción , Martínez-Sanz Elena
Published: November 2022

Growth alterations have been described in patients operated on for oral clefts. The purpose of this work was to analyze the craniofacial and palate morphology and dimensions of young adults operated on for oral clefts in early childhood in Spain. Eighty-three patients from eight different hospitals were divided into four groups based on their type of cleft: cleft lip (CL, n = 6), unilateral cleft lip and palate (UCLP, n = 37), bilateral cleft lip and palate (BCLP, n = 16), and cleft palate only (CPO, n = 24). A control group was formed of 71 individuals. Three-dimensional (3D) digital models were obtained from all groups with an intraoral scanner, together with cephalometries and frontal, lateral, and submental facial photographs. Measurements were obtained and analyzed statistically. Our results showed craniofacial alterations in the BCLP, UCLP, and CPO groups with an influence on the palate, maxilla, and mandible and a direct impact on facial appearance. This effect was more severe in the BCLP group. Measurements in the CL group were similar to those in the control group. Cleft characteristics and cleft type seem to be the main determining factors of long-term craniofacial growth alterations in these patients. Prospective research is needed to clearly delineate the effects of different treatments on the craniofacial appearance of adult cleft patients.
New optimum solutions of nonlinear fractional acoustic wave equations via optimal homotopy asymptotic method-2 (OHAM-2)
Authors: Zada Laiq , Nawaz Rashid , Jamshed Wasim , Ibrahim Rabha W. , Tag El Din El Sayed M. , Raizah Zehba , Amjad Ayesha
Published: November 2022

The second iteration of the optimal homotopy asymptotic technique (OHAM-2) has been protracted to fractional order partial differential equations in this work for the first time (FPDEs). Without any transformation, the suggested approach can be used to solve fractional-order nonlinear Zakharov–Kuznetsov equations. The Caputo notion of the fractional-order derivative, whose values fall within the closed interval [0, 1], has been taken into consideration. The method's appeal is that it provides an approximate solution after just one iteration. The suggested method's numerical findings have been contrasted with those of the variational iteration method, residual power series method, and perturbation iteration method. Through tables and graphs, the proposed method's effectiveness and dependability are demonstrated.
Transcriptomic profiling analysis to identify genes associated with PA biosynthesis and insolubilization in the late stage of fruit development in C-PCNA persimmon
Authors: Wang Yiru , Zhang Qi , Pu Tingting , Suo Yujing , Han Weijuan , Diao Songfeng , Li Huawei , Sun Peng , Fu Jianmin
Published: November 2022

PA-enhanced content causes astringency in persimmon fruit. PCNA persimmons can lose their astringency naturally and they become edible when still on the tree, which allows for conserves of physical and financial resources. C-PCNA persimmon originates in China. Its deastringency trait primarily depends on decreased PA biosynthesis and PA insolubilization at the late stage of fruit development. Although some genes and transcription factors that may be involved in the deastringency of C-PCNA persimmon have been reported, the expression patterns of these genes during the key deastringency stage are reported less. To investigate the variation in PA contents and the expression patterns of deastringency-related genes during typical C-PCNA persimmon ‘Xiaoguo-tianshi’ fruit development and ripening, PA content and transcriptional profiling were carried out at five late stages from 70 to 160 DAF. The combinational analysis phenotype, PA content, and DEG enrichment revealed that 120–140 DAF and 140–160 DAF were the critical phases for PA biosynthesis reduction and PA insolubilization, respectively. The expression of PA biosynthesis-associated genes indicated that the downregulation of the ANR gene at 140–160 DAF may be associated with PA biosynthesis and is decreased by inhibiting its precursor cis-flavan-3-ols. We also found that a decrease in acetaldehyde metabolism-associated ALDH genes and an increase in ADH and PDC genes might result in C-PCNA persimmon PA insolubilization. In addition, a few MYB-bHLH-WD40 (MBW) homologous transcription factors in persimmon might play important roles in persimmon PA accumulation. Furthermore, combined coexpression network analysis and phylogenetic analysis of MBW suggested that three putative transcription factors WD40 (evm.TU.contig1.155), MYB (evm.TU.contig8910.486) and bHLH (evm.TU.contig1398.203), might connect and co-regulate both PA biosynthesis and its insolubilization in C-PCNA persimmon. The present study elucidated transcriptional insights into PA biosynthesis and insolubilization during the late development stages based on the C-PCNA D. kaki genome (unpublished). Thus, we focused on PA content variation and the expression patterns of genes involved in PA biosynthesis and insolubilization. Our work has provided additional evidence on previous knowledge and a basis for further exploration of the natural deastringency of C-PCNA persimmon.
Involvement of the calcitonin gene-related peptide system in the modulation of inflamed uterus contractile function in pigs
Authors: Jana Barbara , Całka Jarosław , Sikora Małgorzata , Palus Katarzyna
Published: November 2022

This study analyzed severe acute endometritis action on myometrial density and distribution of protein gene product (PGP)9.5- and calcitonin gene-related peptide (CGRP)-like immunoreactive nerve fibers and calcitonin receptor-like receptor (CLR) expression, and on CGRP receptor (CGRPR) participation in uterine contractility in pigs. E. coli suspension (E. coli group) or saline (SAL group) were injected into the uteri, or only laparotomy was performed (CON group). In the E. coli group myometrium, a lack of significant changes in PGP9.5 and CGRP innervation patterns and increased CLR protein level were revealed. In all groups, compared to the pretreatment period, human αCGRP increased amplitude in the myometrium, while reducing it in endometrium/myometrium. In the E. coli group endometrium/myometrium, human αCGRP lowered amplitude vs other groups. Human αCGRP reduced frequency in CON and SAL groups and enhanced it in the E. coli group endometrium/myometrium. The frequency in E. coli group increased vs other groups. CGRPR antagonist, human αCGRP8–37, reversed (CON, SAL groups) and eliminated (E. coli group) the rise in human αCGRP-induced myometrial amplitude. In endometrium/myometrium, human αCGRP8–37 abolished (CON group) and reversed (SAL group) a decrease in frequency, and reduced the rise in frequency (E. coli group) caused by human αCGRP. Collectively, in the myometrium, endometritis did not change PGP9.5 and CGRP innervation patterns and enhanced CLR protein level. CGRPR also mediated in CGRP action on inflamed uterus contractility.
Associations of decayed teeth and localized periodontitis with mental stress in young adults: CHIEF oral health study
Authors: Tsai Kun-Zhe , Tsai Sung-Chiao , Lin Ko-Huan , Chang Yun-Chen , Lin Yen-Po , Lin Gen-Min
Published: November 2022

The associations of mental stress with decayed teeth in children and periodontitis in old-aged adults have been described. However, the associations for young adults were not clear. This study aimed to examine the associations of decayed teeth and localized periodontitis with mental stress in young adults. This study included 334 military recruiters, aged 19–45 years in Taiwan. Mental stress was assessed by the brief symptom rating scale-5 (BSRS-5), including five domains: anxiety, depression, hostility, interpersonal sensitivity and insomnia (maximum score of 20). Those with symptomatic mental stress were defined as having BSRS-5 > 5 (n = 34). Multiple linear and logistic regression models were used to determine the associations of decayed tooth numbers and periodontitis with BSRS-5, with adjustments for age, sex, education level, physical activity, body weight category and smoking status. The BSRS-5 was positively correlated with decayed tooth numbers [β: 0.26 (95% confidence interval: 0.01–0.52)]. Those who had more than two decayed teeth [odds ratio: 3.59 (1.52–8.46)] had a higher risk of symptomatic mental stress. In contrast, the correlation between BSRS-5 and localized severer periodontitis was null. Our study recommended that decayed teeth instead of localized periodontitis, was a risk factor for mental stress in young adults.