bluuebunny/crossref_metadata_2025 huggingface dataset:
The Roles of Winter Versus Summer Precipitation in Supplying Evapotranspiration Across US Ecoregions: A Cross‐Catchment End‐Member‐Splitting Analysis
Authors: Kesting Helen M. , Allen Scott T.
Published: June 2024

Understanding how changing seasonal precipitation will affect ecosystems and water resources can benefit from understanding how precipitation from different seasons contributes to runoff versus evapotranspiration (ET). We use stable‐isotope data from 23 National Ecological Observatory Network watersheds to quantify the fractions of winter and summer precipitation that supply ET, and the fractions of ET supplied by summer versus winter precipitation. Across 20 watersheds, 34%–101% of summer precipitation supplied ET, with 8%–105% of ET supplied by summer precipitation; these end‐member‐splitting solutions were poorly constrained in the other three watersheds. These precipitation partitioning fractions were significantly correlated with many topographic, climatic, and vegetation metrics. This first empirical study of seasonal precipitation partitioning fractions across diverse ecoregions demonstrates that they can be well‐constrained in many locations using existing public data sets, and that partitioning‐fraction variations are largely explained by climate variations.
CREB1 promotes expression of immune checkpoint HLA-E leading to immune escape in multiple myeloma
Authors: Ismael Aya , Robinette Allen J. , Huric Laila , Schuetz Jamie , Dona Kameron , Benson Don , Cocucci Emanuele , Cottini Francesca
Published: June 2024

Multiple myeloma (MM) cells effectively escape anti-tumoral immunity to survive in the tumor microenvironment (TME). Herein, we identify non-classical major histocompatibility complex (MHC) class I molecule HLA-E as a major contributing factor in immune escape. Clinically, HLA-E expression correlates with aggressive disease features such as t(4;14) and CD56 expression and is induced by IFN-gamma (IFN-γ) in the TME. We discovered that HLA-E is regulated by cAMP responsive element binding protein 1 (CREB1) transcription factor by direct promoter binding; genomic and pharmacological inhibition of CREB1 reduced HLA-E levels even in the presence of IFN-γ or IFN-γ activating agents, such as immunomodulatory drugs and panobinostat. HLA-E binds to natural killer group 2A (NKG2A), delivering an inhibitor signal to natural killer (NK) cells. Treatment with a CREB1 inhibitor was able to restore NK cell-mediated cytotoxicity against MM cell lines and patient samples. In conclusion, our results strongly demonstrate that CREB1 inhibition promotes anti-tumoral immunity in MM by limiting HLA-E expression and enhancing the activity of NK cells.
Stable diffusion gradients in microfluidic conduits bounded by fluid walls
Authors: Nebuloni Federico , Deroy Cyril , Cook Peter R. , Walsh Edmond J.
Published: June 2024

Assays mimicking in vitro the concentration gradients triggering biological responses like those involved in fighting infections and blood clotting are essential for biomedical research. Microfluidic assays prove especially attractive as they allow precise control of gradient shape allied to a reduction in scale. Conventional microfluidic devices are fabricated using solid plastics that prevent direct access to responding cells. Fluid-walled microfluidics allows the manufacture of circuits on standard Petri dishes in seconds, coupled to simple operating methods; cell-culture medium sitting in a standard dish is confined to circuits by fluid walls made of an immiscible fluorocarbon. We develop and experimentally validate an analytical model of diffusion between two or more aqueous streams flowing at different rates into a fluid-walled conduit with the cross-section of a circular segment. Unlike solid walls, fluid walls morph during flows as pressures fall, with wall shape changing down the conduit. The model is validated experimentally for Fourier numbers < 0.1 using fluorescein diffusing between laminar streams. It enables a priori prediction of concentration gradients throughout a conduit, so allowing rapid circuit design as well as providing bio-scientists with an accurate way of predicting local concentrations of bioactive molecules around responsive and non-responsive cells.
Optimized RNA interference therapeutics combined with interleukin-2 mRNA for treating hepatitis B virus infection
Authors: Zai Wenjing , Yang Min , Jiang Kuan , Guan Juan , Wang Huijing , Hu Kongying , Huang Chao , Chen Jieliang , Fu Wei , Zhan Changyou , Yuan Zhenghong
Published: June 2024

This study aimed to develop a pan-genotypic and multifunctional small interfering RNA (siRNA) against hepatitis B virus (HBV) with an efficient delivery system for treating chronic hepatitis B (CHB), and explore combined RNA interference (RNAi) and immune modulatory modalities for better viral control. Twenty synthetic siRNAs targeting consensus motifs distributed across the whole HBV genome were designed and evaluated. The lipid nanoparticle (LNP) formulation was optimized by adopting HO-PEG2000-DMG lipid and modifying the molar ratio of traditional polyethylene glycol (PEG) lipid in LNP prescriptions. The efficacy and safety of this formulation in delivering siHBV (tLNP/siHBV) along with the mouse IL-2 (mIL-2) mRNA (tLNP/siHBVIL2) were evaluated in the rAAV-HBV1.3 mouse model. A siRNA combination (terms “siHBV”) with a genotypic coverage of 98.55% was selected, chemically modified, and encapsulated within an optimized LNP (tLNP) of high efficacy and security to fabricate a therapeutic formulation for CHB. The results revealed that tLNP/siHBV significantly reduced the expression of viral antigens and DNA (up to 3log10 reduction; vs PBS) in dose- and time-dependent manners at single-dose or multi-dose frequencies, with satisfactory safety profiles. Further studies showed that tLNP/siHBVIL2 enables additive antigenic and immune control of the virus, via introducing potent HBsAg clearance through RNAi and triggering strong HBV-specific CD4+ and CD8+ T cell responses by expressed mIL-2 protein. By adopting tLNP as nucleic acid nanocarriers, the co-delivery of siHBV and mIL-2 mRNA enables synergistic antigenic and immune control of HBV, thus offering a promising translational therapeutic strategy for treating CHB.
Fifteen-year recall period on zirconia-based single crowns and fixed dental prostheses. A prospective observational study
Authors: Khijmatgar Shahnawaz , Tumedei Margherita , Tartaglia Guilia , Crescentini Michele , Isola Gaetano , Sidoti Ernesto , Sforza Chiarella , Del Fabbro Massimo , Tartaglia Gianluca Martino
Published: June 2024

Aim

The aim of this study was to evaluate the long-term clinical outcomes of zirconia-based prostheses used for tooth-supported or implant-supported single crowns and fixed dental prostheses (FPD).

Methods

The authors conducted a prospective analysis of 562 zirconia core restorations supported by endodontically treated teeth or titanium implant in 276 patients in a general dental private practice, with a follow-up period of 15 years. The study was stopped after patients achieved 15 yrs of follow-up. The study analyzed the failure and complication rates of single and multiple crowns, based on Kaplan Meier analysis.

Results

During follow-up period, there were 26 complications and 156 failures. The crown level analysis revealed a cumulative failure rate of 28.33% and complication rate of 8.47% for zirconia crowns after 15 years. The complication rate was found to be higher for titanium implant-supported than for natural teeth-supported crowns. The different types of crown-based failure include: veener fracture 5.01% (N = 29), metal zirconia led to 14.85% (N = 86) loss of retention, and 1.73% (N = 10) loss of crown due to extraction.

Conclusion

Based on these findings, zirconia core restorations appear to be a reliable long-term solution for crowns and fixed dental prostheses.

Clinical relevance

The study suggests that zirconia restorations can be successfully used for long-term prostheses on natural teeth or implants supported. The study results provide clinicians valuable information when selecting prosthetic restorations material.
Construction of a digital twin of chronic graft vs. host disease patients with standard of care
Authors: Li Gen , Chen Yi-Bin , Peachey Jonathan
Published: June 2024

There is an unmet medical need for new clinical trials to evaluate novel therapies in chronic graft-versus-host disease (cGvHD). Disease rarity, ethical issues regarding placebo arms, time, and cost impede clinical trial conduct. Digital twin (DT) technology enables virtual clinical trial arm construction using historical data, circumventing these obstacles. We evaluated the feasibility of constructing a DT trial arm using a large database of real-world clinical trial data and performed an efficacy assessment of a standard-of-care (SOC) drug to examine agreement with literature data. We constructed a flGvHD DT cohort (cGvHD patients at first-line treatment) (2042 patients; 32 cohorts) using the Trial Accelerator™ Digital Twin platform and derived an SOC arm from this cohort (flGvHD DT SOC cohort) (438 patients; eight cohorts); we analyzed the efficacy of SOC (prednisone) (overall response rate (ORR)) at six months. Our analysis results are in agreement with literature: flGvHD DT: disease onset time: 7.58 months post-allogeneic hematopoietic cell transplantation; most used graft source: peripheral blood stem cells; flGvHD DT SOC: ORR at six months for prednisone: 52.7%. It is feasible to construct a DT cohort using existing clinical trial data; a DT SOC arm can potentially replace a control arm in clinical trials.
An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications
Authors: De Florian Fania Rossella , Bellazzo Arianna , Collavin Licio
Published: June 2024

The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors.
Nodal degree centrality in the default mode-like network of the TgF344-AD Alzheimer’s disease rat model as a measure of early network alterations
Authors: Amiri Saba , van den Berg Monica , Nazem-Zadeh Mohammad-Reza , Verhoye Marleen , Amiri Mahmood , Keliris Georgios A.
Published: June 2024

This study investigates brain network alterations in the default mode-like network (DMLN) at early stages of disease progression in a rat model of Alzheimer’s disease (AD) with application in the development of early diagnostic biomarkers of AD in translational studies. Thirteen male TgF344-AD (TG) rats, and eleven male wild-types (WT) littermates underwent longitudinal resting-state fMRI at the age of 4 and 6 months (pre and early-plaque stages of AD). Alterations in connectivity within DMLN were characterized by calculating the nodal degree (ND), a graph theoretical measure of centrality. The ND values of the left CA2 subregion of the hippocampus was found to be significantly lower in the 4-month-old TG cohort compared to the age-matched WT littermates. Moreover, a lower ND value (hypo-connectivity) was observed in the right prelimbic cortex (prL) and basal forebrain in the 6-month-old TG cohort, compared to the same age WT cohort. Indeed, the ND pattern in the DMLN in both TG and WT cohorts showed significant differences across the two time points that represent pre-plaque and early plaque stages of disease progression. Our findings indicate that lower nodal degree (hypo-connectivity) in the left CA2 in the pre-plaque stage of AD and hypo-connectivity between the basal forebrain and the DMLN regions in the early-plaque stage demonstrated differences in comparison to healthy controls. These results suggest that a graph-theoretical measure such as the nodal degree, can characterize brain networks and improve our insights into the mechanisms underlying Alzheimer’s disease.
Transcriptome analysis of cynomolgus macaques throughout their lifespan reveals age-related immune patterns
Authors: Cho Hyeon-Mu , Choe Se-Hee , Lee Ja-Rang , Park Hye-Ri , Ko Min-Gyeong , Lee Yun-Jung , Lee Hwal-Yong , Park Sung Hyun , Park Sang-Je , Kim Young-Hyun , Huh Jae-Won
Published: June 2024

Despite the different perspectives by diverse research sectors spanning several decades, aging research remains uncharted territory for human beings. Therefore, we investigated the transcriptomic characteristics of eight male healthy cynomolgus macaques, and the annual sampling was designed with two individuals in four age groups. As a laboratory animal, the macaques were meticulously shielded from all environmental factors except aging. The results showed recent findings of certain immune response and the age-associated network of primate immunity. Three important aging patterns were identified and each gene clusters represented a different immune response. The increased expression pattern was predominantly associated with innate immune cells, such as Neutrophils and NK cells, causing chronic inflammation with aging whereas the other two decreased patterns were associated with adaptive immunity, especially “B cell activation” affecting antibody diversity of aging. Furthermore, the hub gene network of the patterns reflected transcriptomic age and correlated with human illness status, aiding in future human disease prediction. Our macaque transcriptome profiling results offer systematic insights into the age-related immunological features of primates.
Facemask acne attenuation through modulation of indirect microbiome interactions
Authors: Na Han-Hee , Kim Seil , Kim Jun‐Seob , Lee Soohyun , Kim Yeseul , Kim Su-Hyun , Lee Choong-Hwan , Kim Dohyeon , Yoon Sung Ho , Jeong Haeyoung , Kweon Daehyuk , Seo Hwi Won , Ryu Choong-Min
Published: June 2024

During the COVID-19 pandemic, facemasks played a pivotal role in preventing person-person droplet transmission of viral particles. However, prolonged facemask wearing causes skin irritations colloquially referred to as ‘maskne’ (mask + acne), which manifests as acne and contact dermatitis and is mostly caused by pathogenic skin microbes. Previous studies revealed that the putative causal microbes were anaerobic bacteria, but the pathogenesis of facemask-associated skin conditions remains poorly defined. We therefore characterized the role of the facemask-associated skin microbiota in the development of maskne using culture-dependent and -independent methodologies. Metagenomic analysis revealed that the majority of the facemask microbiota were anaerobic bacteria that originated from the skin rather than saliva. Previous work demonstrated direct interaction between pathogenic bacteria and antagonistic strains in the microbiome. We expanded this analysis to include indirect interaction between pathogenic bacteria and other indigenous bacteria classified as either ‘pathogen helper (PH)’ or ‘pathogen inhibitor (PIn)’ strains. In vitro screening of bacteria isolated from facemasks identified both strains that antagonized and promoted pathogen growth. These data were validated using a mouse skin infection model, where we observed attenuation of symptoms following pathogen infection. Moreover, the inhibitor of pathogen helper (IPH) strain, which did not directly attenuate pathogen growth in vitro and in vivo, functioned to suppress symptom development and pathogen growth indirectly through PH inhibitory antibacterial products such as phenyl lactic acid. Taken together, our study is the first to define a mechanism by which indirect microbiota interactions under facemasks can control symptoms of maskne by suppressing a skin pathogen.
Simultaneous application of oral and intravaginal probiotics for Helicobacter pylori and its antibiotic-therapy-induced vaginal dysbacteriosis
Authors: Wang Yufan , Zhang Zhenyu , Chen Qi , Chen Tingtao
Published: June 2024

Helicobacter pylori is a prevalent bacterial pathogen globally, implicated in various gastrointestinal disorders. Current recommended antibiotic therapies for H. pylori infection have been proven to be therapeutically insufficient, with low eradication rates and high recurrence rates. Emerging evidence suggests that antibiotic therapy for H. pylori can lead to gastrointestinal and subsequent vaginal dysbiosis, posing challenges for conventional antibiotic approaches. Thus, this article proposes a novel probiotic therapy involving simultaneous oral and intra-vaginal probiotic administration alongside antibiotics for H. pylori treatment, aiming to enhance eradication rates and mitigate dysbiosis. We begin by providing an overview of gastrointestinal and vaginal microbiota and their interconnectedness through the vagina-gut axis. We then review the efficacy of current antibiotic regimens for H. pylori and discuss how antibiotic treatment impacts the vaginal microenvironment. To explore the feasibility of this approach, we evaluate the effectiveness of oral and intra-vaginal probiotics in restoring normal microbiota in the gastrointestinal and vaginal tracts, respectively. Additionally, we analyze the direct mechanisms by which oral and intra-vaginal probiotics act on their respective tracts and discuss potential cross-tract mechanisms. Considering the potential synergistic therapeutic effects of probiotics in both the gastrointestinal and vaginal tracts, dual-channel probiotic therapy holds promise as a more effective approach for H. pylori eradication and dysbiosis mitigation, presenting a novel concept in the collaborative treatment of gastrointestinal and genital disorders.
Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial
Authors: Eijsvogel Pepijn , Misra Pinaki , Concha-Marambio Luis , Boyd Justin D. , Ding Shuang , Fedor Lauren , Hsieh Yueh-Ting , Sun Yu Shuang , Vroom Madeline M. , Farris Carly M. , Ma Yihua , de Kam Marieke L. , Radanovic Igor , Vissers Maurits F. J. M. , Mirski Dario , Shareghi Ghazal , Shahnawaz Mohammad , Singer Wolfgang , Kremer Philip , Groeneveld Geert Jan , Yu Hui Jing , Dodart Jean-Cosme
Published: June 2024

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson’s disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 μg and 300/300/300 μg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov:NCT04075318.
A new small-sized predatory pseudosuchian archosaur from the Middle-Late Triassic of Southern Brazil
Authors: Müller Rodrigo T.
Published: June 2024

Before the rise of dinosaurs and pterosaurs, pseudosuchians—reptiles from the crocodilian lineage—dominated the Triassic land ecosystems. This lineage diversified into several less inclusive clades, resulting in a wide ecomorphological diversity during the Middle and Late Triassic. Some giant pseudosuchians occupied the top of the trophic webs, while others developed extensive bony armor as a defense mechanism, which later evolved as a convergence in the avemetatarsalian lineage. On the other hand, there were groups like the Gracilisuchidae, which was composed of carnivorous forms with lightweight build and less than 1 m in length. The fossil record of gracilisuchids is geographically restricted to China and Argentina, with one ambiguous record from Brazil. In the present study, the first unambiguous gracilisuchid from Brazil is described. Parvosuchus aurelioi gen. et sp. nov. comes from the Dinodontosaurus Assemblage Zone of the Santa Maria Formation, which is associated with the Ladinian-Carnian boundary. Composed of a complete cranium, vertebrae, pelvic girdle and hindlimbs, the new species nests with Gracilisuchus stipanicicorum and Maehary bonapartei in a phylogenetic analysis. Its discovery fills a taxonomic gap in Brazilian pseudosuchian fauna and reveals the smallest known member of this clade from the Dinodontosaurus Assemblage Zone, highlighting the diversity of pseudosuchians during the moment that preceded the dawn of dinosaurs.
Hybrid transformer-CNN model for accurate prediction of peptide hemolytic potential
Authors: Almotairi Sultan , Badr Elsayed , Abdelbaky Ibrahim , Elhakeem Mohamed , Abdul Salam Mustafa
Published: June 2024

Hemolysis is a crucial factor in various biomedical and pharmaceutical contexts, driving our interest in developing advanced computational techniques for precise prediction. Our proposed approach takes advantage of the unique capabilities of convolutional neural networks (CNNs) and transformers to detect complex patterns inherent in the data. The integration of CNN and transformers' attention mechanisms allows for the extraction of relevant information, leading to accurate predictions of hemolytic potential. The proposed method was trained on three distinct data sets of peptide sequences known as recurrent neural network-hemolytic (RNN-Hem), Hlppredfuse, and Combined. Our computational results demonstrated the superior efficacy of our models compared to existing methods. The proposed approach demonstrated impressive Matthews correlation coefficients of 0.5962, 0.9111, and 0.7788 respectively, indicating its effectiveness in predicting hemolytic activity. With its potential to guide experimental efforts in peptide design and drug development, this method holds great promise for practical applications. Integrating CNNs and transformers proves to be a powerful tool in the fields of bioinformatics and therapeutic research, highlighting their potential to drive advancement in this area.
Oscillatory zoning of minerals as a fingerprint of impurity-mediated growth
Authors: Torii Hiroki , Miura Hitoshi
Published: June 2024

We propose a kinetic mathematical model of the oscillatory compositional zoning profile recorded in minerals based on the crystal growth suppression induced by impurities. Notably, the presence of a small amount of impurities significantly inhibits crystal growth, and a growth inhibition mechanism called the pinning effect is widely accepted. Here we show that a model that considers the pinning effect and adsorption/desorption kinetics of impurities on the crystal surface can reproduce the oscillatory compositional zoning. As impurities are common in nature, this model suggests the existence of a universal mechanism that can occur in the growth processes of various crystals.
Performance evaluation of a new sponge-based moving bed biofilm reactor for the removal of pharmaceutical pollutants from real wastewater
Authors: Chalipa Zohreh , Hosseinzadeh Majid , Nikoo Mohammad Reza
Published: June 2024

Pharmaceutical pollutants, a group of emerging contaminants, have attracted outstanding attention in recent years, and their removal from aquatic environments has been addressed. In the current study, a new sponge-based moving bed biofilm reactor (MBBR) was developed to remove chemical oxygen demand (COD) and the pharmaceutical compound Ibuprofen (IBU). A 30-L pilot scale MBBR was constructed, which was continuously fed from the effluent of the first clarifier of the Southern Tehran wastewater treatment plant. The controlled operational parameters were pH in the natural range, Dissolved Oxygen of 1.5–2 mg/L, average suspended mixed liquor suspended solids (MLSS), and mixed liquor volatile suspended solids (MLVSS) of 1.68 ± 0.1 g/L and 1.48 ± 0.1 g/L, respectively. The effect of hydraulic retention time (HRT) (5 h, 10 h, 15 h), filling ratio (10%, 20%, 30%), and initial IBU concentration (2 mg/L, 5 mg/L, 10 mg/L) on removal efficiencies was assessed. The findings of this study revealed a COD removal efficiency ranging from 48.9 to 96.7%, with the best removal efficiency observed at an HRT of 10 h, a filling ratio of 20%, and an initial IBU concentration of 2 mg/L. Simultaneously, the IBU removal rate ranged from 25 to 92.7%, with the highest removal efficiency observed under the same HRT and filling ratio, albeit with an initial IBU concentration of 5 mg/L. An extension of HRT from 5 to 10 h significantly improved both COD and IBU removal. However, further extension from 10 to 15 h slightly enhanced the removal efficiency of COD and IBU, and even in some cases, removal efficiency decreased. Based on the obtained results, 20% of the filling ratio was chosen as the optimum state. Increasing the initial concentration of IBU from 2 to 5 mg/L generally improved COD and IBU removal, whereas an increase from 5 to 10 mg/L caused a decline in COD and IBU removal. This study also optimized the reactor’s efficiency for COD and IBU removal by using response surface methodology (RSM) with independent variables of HRT, filling ratio, and initial IBU concentration. In this regard, the quadratic model was found to be significant. Utilizing the central composite design (CCD), the optimal operating parameters at an HRT of 10 h, a filling ratio of 21%, and an initial IBU concentration of 3 mg/L were pinpointed, achieving the highest COD and IBU removal efficiencies. The present study demonstrated that sponge-based MBBR stands out as a promising technology for COD and IBU removal.
Cox proportional hazards regression in small studies of predictive biomarkers
Authors: Jóźwiak K. , Nguyen V. H. , Sollfrank L. , Linn S. C. , Hauptmann M.
Published: June 2024

Predictive biomarkers are essential for personalized medicine since they select the best treatment for a specific patient. However, of all biomarkers that are evaluated, only few are eventually used in clinical practice. Many promising biomarkers may be erroneously abandoned because they are investigated in small studies using standard statistical techniques which can cause small sample bias or lack of power. The standard technique for failure time endpoints is Cox proportional hazards regression with a multiplicative interaction term between binary variables of biomarker and treatment. Properties of this model in small studies have not been evaluated so far, therefore we performed a simulation study to understand its small sample behavior. As a remedy, we applied a Firth correction to the score function of the Cox model and obtained confidence intervals (CI) using a profile likelihood (PL) approach. These methods are generally recommended for small studies of different design. Our results show that a Cox model estimates the biomarker-treatment interaction term and the treatment effect in one of the biomarker subgroups with bias, and overestimates their standard errors. Bias is however reduced and power is increased with Firth correction and PL CIs. Hence, the modified Cox model and PL CI should be used instead of a standard Cox model with Wald based CI in small studies of predictive biomarkers.
Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane
Authors: González-López Adrián , Larsson Daniel S. D. , Koripella Ravi Kiran , Cain Brett N. , Chavez Martin Garcia , Hergenrother Paul J. , Sanyal Suparna , Selmer Maria
Published: June 2024

The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 Å resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 Å resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.
Transcranial electrical stimulation modulates emotional experience and metabolites in the prefrontal cortex in a donation task
Authors: Mugnol-Ugarte Luiza , Bortolini Tiago , Yao Bo , Mikkelsen Mark , Carneiro Monteiro Marina , Andorinho de Freitas Ferreira Ana Carolina , Bramatti Ivanei , Melo Bruno , Hoefle Sebastian , Meireles Fernanda , Moll Jorge , Pobric Gorana
Published: June 2024

Understanding the neural, metabolic, and psychological mechanisms underlying human altruism and decision-making is a complex and important topic both for science and society. Here, we investigated whether transcranial Direct Current Stimulation (tDCS) applied to two prefrontal cortex regions, the ventromedial prefrontal cortex (vmPFC, anode) and the right dorsolateral prefrontal cortex (DLPFC, cathode) can induce changes in self-reported emotions and to modulate local metabolite concentrations. We employed in vivo quantitative MR Spectroscopy in healthy adult participants and quantified changes in GABA and Glx (glutamate + glutamine) before and after five sessions of tDCS delivered at 2 mA for 20 min (active group) and 1 min (sham group) while participants were engaged in a charitable donation task. In the active group, we observed increased levels of GABA in vmPFC. Glx levels decreased in both prefrontal regions and self-reported happiness increased significantly over time in the active group. Self-reported guiltiness in both active and sham groups tended to decrease. The results indicate that self-reported happiness can be modulated, possibly due to changes in Glx concentrations following repeated stimulation. Therefore, local changes may induce remote changes in the reward network through interactions with other metabolites, previously thought to be unreachable with noninvasive stimulation techniques.
Prognostic scoring system based on indicators reflecting the tumor glandular differentiation and microenvironment for patients with colorectal cancer
Authors: Kobayashi Toshinori , Ishida Mitsuaki , Miki Hisanori , Yamamoto Nobuyuki , Harino Takashi , Yagyu Takuki , Hori Soshi , Hatta Masahiko , Hashimoto Yuki , Kotsuka Masaya , Yamasaki Makoto , Inoue Kentaro , Hirose Yoshinobu , Sekimoto Mitsugu
Published: June 2024

Prognostic stratification is an urgent concern for patients with colorectal cancer (CRC). The desmoplastic reaction (DR) is speculated to mirror the tumor microenvironment. DR types are considered independent prognostic indicators in CRC, but have not been incorporated in previous prognostic nomograms. We aimed to assess the prognostic significance of a novel approach incorporating histopathological indicators reflecting tumor glandular differentiation and microenvironment. We evaluated 329 consecutive patients with CRC who underwent surgical resection at Kansai Medical University. Histological glandular differentiation was scored as 2 (0 point), 3 (1 point), or 4 (2 points). Tumor buddings (TBs) were classified as TB1 (0 point), TB2 (1 point), or TB3 (2 points). pT1 or 2 was considered as 0 point, pT3 or 4 + DR non-immature type as 1 point, and pT3 or 4 + DR immature type as 2 points. Lymph node metastasis was classified as pN0 (0 point), pN1 (1 point), or pN2 (2 points). The preoperative carcinoembryonic antigen levels were categorized as < 5.0 ng/mL (0 point) and ≧5.0 (1 point). Considering these factors, the following D&M (tumor differentiation and microenvironment) scoring system was applied: I (0–2 points), II (3–4 points), III (5–6 points), and IV (7–9 points). Kaplan–Meier curves showed significant differences in disease-specific survival and recurrence-free survival among the assigned scores, highlighting their enhanced utility compared with the American Joint Committee on Cancer 8th edition staging system. The D&M scoring system was valuable as the initial prognostic nomogram, including DR.
Sex-related DNA methylation is associated with inflammation and gene expression in the lungs of healthy individuals
Authors: Patel Devki , McElroy Joseph P. , Weng Daniel Y. , Sahar Kamel , Reisinger Sarah A. , Freudenheim Jo L. , Wewers Mark D. , Shields Peter G. , Song Min-Ae
Published: June 2024

Lung cancer exhibits sex-biased molecular characteristics and epidemiological trends, suggesting a need for sex-specific approaches to understanding its etiology and treatment. DNA methylation alterations play critical roles in lung carcinogenesis and may serve as valuable biomarkers for precision medicine strategies. We employed the Infinium MethylationEPIC array to identify autosomal sex-related differentially methylated CpG sites (DM-CpGs) in lung epithelium of healthy individuals (32 females and 37 males) while controlling for age, BMI, and tobacco use. We correlated DM-CpGs with gene expression in lung epithelium and immune responses in bronchoalveolar lavage. We validated these DM-CpGs in lung tumors and adjacent normal tissue from The Cancer Genome Atlas (TCGA). Among 522 identified DM-CpGs, 61% were hypermethylated in females, predominantly located in promoter regions. These DM genes were implicated in cell-to-cell signaling, cellular function, transport, and lipid metabolism. Correlation analysis revealed sex-specific patterns between DM-CpGs and gene expression. Additionally, several DM-CpGs were correlated significantly with cytokines (IL-1β, IL-4, IL-12p70, and IFN-γ), macrophage, and lymphocyte counts. Also, some DM-CpGs were observed in TCGA lung adenocarcinoma, squamous cell carcinoma, and adjacent normal tissues. Our findings highlight sex-specific DNA methylation patterns in healthy lung epithelium and their associations with lung gene expression and lung immune biomarkers. These findings underscore the potential role of lung sex-related CpGs as epigenetic predispositions influencing sex disparities in lung cancer risk and outcomes, warranting further investigation for personalized lung cancer management strategies.
Mitigation of drought stress in chili plants (Capsicum annuum L.) using mango fruit waste biochar, fulvic acid and cobalt
Authors: Hareem Misbah , Danish Subhan , Obaid Sami Al , Ansari Mohammad Javed , Datta Rahul
Published: June 2024

Drought stress can have negative impacts on crop productivity. It triggers the accumulation of reactive oxygen species, which causes oxidative stress. Limited water and nutrient uptake under drought stress also decreases plant growth. Using cobalt and fulvic acid with biochar in such scenarios can effectively promote plant growth. Cobalt (Co) is a component of various enzymes and co-enzymes. It can increase the concentration of flavonoids, total phenols, antioxidant enzymes (peroxidase, catalase, and polyphenol oxidase) and proline. Fulvic acid (FA), a constituent of soil organic matter, increases the accessibility of nutrients to plants. Biochar (BC) can enhance soil moisture retention, nutrient uptake, and plant productivity during drought stress. That’s why the current study explored the influence of Co, FA and BC on chili plants under drought stress. This study involved 8 treatments, i.e., control, 4 g/L fulvic acid (4FA), 20 mg/L cobalt sulfate (20CoSO4), 4FA + 20CoSO4, 0.50%MFWBC (0.50 MFWBC), 4FA + 0.50MFWBC, 20CoSO4 + 0.50MFWBC, 4FA + 20CoSO4 + 0.50MFWBC. Results showed that 4 g/L FA + 20CoSO4 with 0.50MFWBC caused an increase in chili plant height (23.29%), plant dry weight (28.85%), fruit length (20.17%), fruit girth (21.41%) and fruit yield (25.13%) compared to control. The effectiveness of 4 g/L FA + 20CoSO4 with 0.50MFWBC was also confirmed by a significant increase in total chlorophyll contents, as well as nitrogen (N), phosphorus (P), and potassium (K) in leaves over control. In conclusion4g/L, FA + 20CoSO4 with 0.50MFWBC can potentially improve the growth of chili cultivated in drought stress. It is suggested that 4 g/L FA + 20CoSO4 with 0.50MFWBC be used to alleviate drought stress in chili plants.
Regio- and diastereoselective synthesis of thioxothiazolidin-indolin-2-ones, oxoindolin-carbamodithioate hybrids, and their base-catalyzed conversion into dispirocyclopentanebisoxindoles
Authors: Aghamiri Bagher , Moghaddam F. Matloubi , Badpa Sara , Kavoosi Leila
Published: June 2024

In this publication, we reported a regio-, diastereoselective, and kinetically controlled reaction for synthesizing thioxothiazolidin-indolin-2-ones, oxoindolin-carbamodithioate hybrids, and their base-catalyzed conversion into dispirocyclopentanebisoxindoles. Obtaining only the kinetic thioxothiazolidin-indolin-2-one products together with their straightforward conversion to dispirocyclopentanebisoxindoles, excellent regio- and diastereoselectivity, easy reaction workup, and one-pot synthetic operation are considerable advantages of this work.
Recent daily life burdens associated with neovascular age-related macular degeneration involve difficulties in use of electronic devices
Authors: Ozawa Yoko , Yoshihara Keisuke , Mezghani Marwa , Pierzchała Paulina , Nikodem Mateusz , Barbier Sylvaine , Nomoto Mariko , Aitoku Yasuko
Published: June 2024

Neovascular age-related macular degeneration (nAMD) is a prevalent cause of permanent vision loss and blindness in the elderly worldwide, with a significant impact on patients’ daily lives. However, burdens related to nAMD from the patients’ perspective have not been well documented. Here we developed a new questionnaire after eliciting nAMD patients’ daily challenges followed by a pilot survey. Seven daily life burden domains were identified, and a quantitative survey was conducted using the questionnaire in the real-world clinic. Of the total 153 participants (mean age, 76.3 ± 8.3 years), 67 (43.8%) had bilateral nAMD, and 79 (52.7%) were classified into severe nAMD according to the best-corrected visual acuity with cut-off value of 0.52 in logMAR. Patients with bilateral and severe nAMD had significantly higher burden scores across all domains. Network models for the bilateral and severe disease subgroups identified the interactions between “activity of daily living” and “hand–eye coordination” and between “use of electronic devices” and “face recognition” domains, which were considered to be important burdens for the patients. These results can advance ophthalmologists’ understanding of the impact of nAMD on patients’ daily lives and the importance of active and continuing treatment for patients with nAMD.
Chemotherapy-induced high expression of IL23A enhances efficacy of anti-PD-1 therapy in TNBC by co-activating the PI3K-AKT signaling pathway of CTLs
Authors: Pan Fan , Liu Jiajing , Chen Ying , Zhu Binghan , Chen Weiwei , Yang Yuchen , Zhu Chunyan , Zhao Hua , Liu Xiaobei , Xu Yichen , Xu Xiaofan , Huo Liqun , Xie Li , Wang Rui , Gu Jun , Huang Guichun
Published: June 2024

Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
Deep-level defects induced by implantations of Si and Mg ions into undoped epitaxial GaN
Authors: Kamiński Paweł , Turos Andrzej , Kozłowski Roman , Stefańska-Skrobas Kamila , Żelazko Jarosław , Grzanka Ewa
Published: June 2024

The properties and concentrations of deep-level defects induced by implantations of Si and Mg ions into unintentionally doped (UID) epitaxial GaN have been revealed by using the Laplace-transform photoinduced transient spectroscopy (LPITS) and molecular dynamics (MD) calculations. The material lattice damage, produced by the Si ions implanted at room temperature in the single process at the energies of 200 and 340 keV, is compared with that produced by the Mg ions implanted in the similar process at the energies of 150, 210, and 270 keV. The LPITS results indicate that the same deep traps with the activation energies of 396, 512, 531, 587, 635, and 736 meV are present in the tail regions of the semi-insulating Si- and Mg-implanted films. It is argued that the predominant implantation-induced point defects in the tail region of the Si-implanted films are nitrogen vacancies, whose concentration is 7.7 × 1017 cm−3. In the Mg-implanted films, the predominant implantation-induced point defects are gallium interstitials, whose concentration is 1.2 × 1 018 cm−3.
Comparison of methods for estimating Young’s moduli of mortar specimens
Authors: Schmid Simon , Timothy Jithender J. , Woydich Elena , Kollofrath Jochen , Grosse Christian U.
Published: June 2024

Precisely estimating material parameters for cement-based materials is crucial for assessing the structural integrity of buildings. Both destructive (e.g., compression test) and non-destructive methods (e.g., ultrasound, computed tomography) are used to estimate Young’s modulus. Since ultrasound estimates the dynamic Young’s modulus, a formula is required to adapt it to the static modulus. For this formulas from the literature are compared. The investigated specimens are cylindrical mortar specimens with four different sand-to-cement mass fractions of 20%, 35%, 50%, and 65%. The ultrasound signals are analyzed in two distinct ways: manual onset picking and full-waveform inversion. Full-waveform inversion involves comparing the measured signal with a simulated one and iteratively adjusting the ultrasound velocities in a numerical model until the measured signal closely matches the simulated one. Using computed tomography measurements, Young’s moduli are semi-analytically determined based on sand distribution in cement images. The reconstructed volume is segmented into sand, cement, and pores. Young’s moduli, as determined by compression tests, were better represented by full-waveform inversions (best RMSE = 0.34 GPa) than by manual onset picking (best RMSE = 0.87 GPa). Moreover, material parameters from full-waveform inversion showed less deviation than those manually picked. The maximal standard deviation of a Young’s modulus determined with FWI was 0.36, while that determined with manual picking was 1.11. Young’s moduli from computed tomography scans match those from compression tests the closest, with an RMSE of 0.13 GPa.
Biochemistry of microwave controlled Heracleum sosnowskyi (Manden.) roots with an ecotoxicological aspect
Authors: Słowiński Krzysztof , Grygierzec Beata , Wajs-Bonikowska Anna , Baran Agnieszka , Tabor Sylwester , Waligórski Pitr , Rys Magdalena , Bocianowski Jan , Synowiec Agnieszka
Published: June 2024

Sosnowski hogweed is an invasive weed in eastern-middle Europe that is dangerous to human health and the environment. The efficacy of its control using chemical and mechanical methods is limited. Electromagnetic radiation (microwaves) could be an environmentally friendly alternative for controlling this species. This study aims to: (1) Determine the effect of varying microwave treatment (MWT) durations on the control of S. hogweed using a device emitting microwaves at 2.45 GHz, 32.8 kW/m2; (2) Evaluate the impact of MWT on soil by an ecotoxicological bioassays; (3) Analyze biochemical changes occurring in the roots during the process. A field study was performed to assess the efficacy of S. hogweed control using MWT in times from 2.5 to 15 min. The MWT-treated soil was collected immediately after treatment (AT) and tested using bioassays (Phytotoxkit, Ostracodtoxkit, and Microtox). Fourteen days AT, the MWT hogweed roots were dug out, air-dried, and analyzed for the content and composition of essential oil, sugars, and fatty acids. According to the ecotoxicological biotests, the MWT soils were classified as non-toxic or low-toxic. The regeneration of hogweed was observed only in non-treated plants (control). Hogweed MWT for 2.5–15 min did not regenerate up to 14 days AT. The average weight of roots in hogweed MWT for 15.0 min was ca. two times smaller than the control plants. Those roots contained significantly higher amounts of sugars and saturated fatty acids than the control. We did not find a correlation between S. hogweed root essential oil content and composition and MWT time. The main compounds of essential oil were p‑cymene and myristicin. No highly photosensitizing compounds were identified in the tested root oil. We conclude that MWT of S. hogweed could be an environmentally safe and prospective control method, but more studies are needed.