bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSPG4-dependent cytotoxicity for
C. difficile
TcdB is influenced by extracellular calcium and chondroitin sulfate
Authors: Doyle D. Annie , DeAngelis Paul L. , Ballard Jimmy D. 
Published: March 2024

ABSTRACT

TcdB is an intracellular bacterial toxin indispensable to
Clostridioides difficile
infections. The ability to use chondroitin sulfate proteoglycan 4 (CSPG4) as a primary cell surface receptor is evolutionarily conserved by the two major variants of TcdB. As CSPG4 does not typically undergo receptor-mediated endocytosis, we sought to identify environmental factors that stabilize interactions between TcdB and CSPG4 to promote cell binding and entry into the cytosol. Using a series of TcdB receptor-binding mutants and cell lines with various receptor expression profiles, we discovered that extracellular Ca
2+
promotes receptor-specific interactions with TcdB. Specifically, TcdB exhibits preferential binding to CSPG4 in the presence of Ca
2+
, with the absence of Ca
2+
resulting in CSPG4-independent cell surface interactions. Furthermore, Ca
2+
did not enhance TcdB binding to chondroitin sulfate (CS), the sole glycosaminoglycan of CSPG4. Instead, CS was found to impact the rate of cell entry by TcdB. Collectively, results from this study indicate that Ca
2+
enhances cell binding by TcdB and CS interactions contribute to subsequent steps in cell entry.

IMPORTANCE

Clostridioides difficile
is a leading cause of antibiotic-associated gastrointestinal illness, and many disease pathologies are caused by the toxin TcdB. TcdB engages multiple cell surface receptors, with receptor tropisms differing among the variants of the toxin. Chondroitin sulfate proteoglycan 4 (CSPG4) is a critical receptor for multiple forms of TcdB, and insights into TcdB–CSPG4 interactions are applicable to many disease-causing strains of
C. difficile
. CSPG4 is modified by chondroitin sulfate (CS) and contains laminin-G repeats stabilized by Ca
2+
, yet the relative contributions of CS and Ca
2+
to TcdB cytotoxicity have not been determined. This study demonstrates distinct roles in TcdB cell binding and cell entry for Ca
2+
and CS, respectively. These effects are specific to CSPG4 and contribute to the activities of a prominent isoform of TcdB that utilizes this receptor. These findings advance an understanding of factors contributing to TcdB’s mechanism of action and contribution to
C. difficile
disease.
Inhibition of inosine metabolism of the gut microbiota decreases testosterone secretion in the testis
Authors: Tang Lei , Yang Xizhong , Zhou Mengting , Feng Lingxin , Ji Cuijie , Liang Jie , Zhang Bei , Shen Ruowu , Wang Luoyang 
Published: March 2024

ABSTRACT

Growing evidence indicates that gut microbiota is involved in the regulation of the host’s sex hormone levels, such as through interfering with the sex hormone metabolism in the intestine. However, if gut microbiota or its metabolites directly influence the sex hormone biosynthesis in the gonad remains largely unknown. Our previous study showed that colistin, as a narrow-spectrum antibiotic, can significantly downregulate the serum testosterone levels and thus enhance the antitumor efficiency of anti-PD-L1 in male mice; however, the underlying mechanism for the regulation of the host’s testosterone levels remains uninvestigated. In the present study, we analyzed the impact of colistin on the immune microenvironment of the testis as well as the composition and metabolism of gut microbiota in male mice. Our results showed that colistin has an impact on the immune microenvironment of the testis and can downregulate serum testosterone levels in male mice through inhibition of
Akkermansia
, leading to destroyed inosine metabolism. Supplement with inosine can restore testosterone secretion probably by prompting the recovery of the intestinal mucus barrier and the serum lipopolysaccharides levels. All these findings reveal a new pathway for the regulation of the host’s sex hormone levels by gut microbiota.

IMPORTANCE
This study demonstrates that exposure to even narrow-spectrum antibiotics may affect the host’s testosterone levels by altering the gut microbiota and its metabolites. Our findings provide evidence that some specific gut bacteria have an impact on the sex hormone biosynthesis in the testis.
Diversity and distribution of biosynthetic gene clusters in agricultural soil microbiomes
Authors: Zhang Zhiguo , Zhang Lu , Zhang Lihan , Chu Haiyan , Zhou Jizhong , Ju Feng 
Published: March 2024

ABSTRACT

Bacterial secondary metabolites serve as an important source of molecules for drug discovery. They also play an important function in mediating the interactions of microbial producers with their living environment and surrounding organisms. However, little is known about the genetic novelty, distribution, and community-level impacts of soil bacterial biosynthetic potential on a large geographic scale. Here, we constructed the first catalog of 11,149 biosynthetic gene clusters (BGCs) from agricultural soils across China and unearthed hidden biosynthetic potential for new natural product discovery from the not-yet-cultivated soil bacteria. Notably, we revealed soil pH as the strongest environmental driver of BGC biogeography and predicted that soil acidification and global climate change could damage the biosynthetic potential of the soil microbiome. The co-occurrence network of bacterial genomes revealed two BGC-rich species, i.e.,
Nocardia niigatensis
from Actinobacteriota and
PSRF01
from Acidobacteriota, as the module hub and connector, respectively, indicating their keystone positions in the soil microbial communities. We also uncovered a dominant role of BGC-inferred biotic interactions over environmental drivers in structuring the soil microbiome. Overall, this study achieved novel insights into the BGC landscape in agricultural soils of China, substantially expanding our understanding of the diversity and novelty of bacterial secondary metabolism and the potential role of secondary metabolites in microbiota assembly.

IMPORTANCE
Bacterial secondary metabolites not only serve as the foundation for numerous therapeutics (e.g., antibiotics and anticancer drugs), but they also play critical ecological roles in mediating microbial interactions (e.g., competition and communication). However, our knowledge of bacterial secondary metabolism is limited to only a small fraction of cultured strains, thus restricting our comprehensive understanding of their diversity, novelty, and potential ecological roles in soil ecosystems. Here, we used culture-independent metagenomics to explore biosynthetic potentials in agricultural soils of China. Our analyses revealed a high degree of genetic diversity and novelty within biosynthetic gene clusters in agricultural soil environments, offering valuable insights for biochemists seeking to synthesize novel bioactive products. Furthermore, we uncovered the pivotal role of BGC-rich species in microbial communities and the significant relationship between BGC richness and microbial phylogenetic turnover. This information emphasizes the importance of biosynthetic potential in the assembly of microbial communities.
Body fluids should be identified before estimating the time since deposition (TsD) in microbiome-based stain analyses for forensics
Authors: Zhang Jun , Yu Daijing , Wang Tian , Gao Niu , Shi Linyu , Wang Yaya , Huo Yumei , Ji Zhimin , Li Junli , Zhang Xiaomeng , Zhang Liwei , Yan Jiangwei 
Published: March 2024

ABSTRACT

Identification and the time since deposition (TsD) estimation of body fluid stains from a crime scene could provide valuable information for solving the cases and are always difficult for forensics. Microbial characteristics were considered as a promising biomarker to address the issues. However, changes in the microbiota may damage the specific characteristics of body fluids. Correspondingly, incorrect body fluid identification may result in inaccurate TsD estimation. The mutual influence is not well understood and limited the codetection. In the current study, saliva, semen, vaginal secretion, and menstrual blood samples were exposed to indoor conditions and collected at eight time points (from fresh to 30 days). High-throughput sequencing based on the 16S rRNA gene was performed to characterize the microbial communities. The results showed that a longer TsD could decrease the discrimination of different body fluid stains. However, the accuracies of identification still reached a quite high value even without knowing the TsD. Correspondingly, the mean absolute error (MAE) of TsD estimation significantly increased without distinguishing the types of body fluids. The predictive TsD of menstrual blood reached a quite low MAE (1.54 ± 0.39 d). In comparison, those of saliva (6.57 ± 1.17 d), semen (6.48 ± 1.33 d), and vaginal secretion (5.35 ± 1.11 d) needed to be further improved. The great effect of individual differences on these stains limited the TsD estimation accuracy. Overall, microbial characteristics allow for codetection of body fluid identification and TsD estimation, and body fluids should be identified before estimating TsD in microbiome-based stain analyses.

IMPORTANCE
Emerged evidences suggest microbial characteristics could be considered a promising tool for identification and time since deposition (TsD) estimation of body fluid stains. However, the two issues should be studied together due to a potential mutual influence. The current study provides the first evidence to understand the mutual influence and determines an optimal process for codetection of identification and TsD estimation for unknown stains for forensics. In addition, we involved aged stains into our study for identification of body fluid stains, rather than only using fresh stains like previous studies. This increased the predictive accuracy. We have preliminary verified that individual differences in microbiotas limited the predictive accuracy of TsD estimation for saliva, semen, and vaginal secretion. Microbial characteristics could provide an accurate TsD estimation for menstrual blood. Our study benefits the comprehensive understanding of microbiome-based stain analyses as an essential addition to previous studies.
Tectonic dismemberment and plume-ridge interaction in the Sub-Antarctic South Atlantic Ocean Basin: Confirmation from in situ geochemical and Sr isotopic compositions of minerals
Authors: Chen Shuang-Shuang , Zhang Wenjing , Dingwell Donald B. , Gao Rui , Liu Jia-Qi 
Published: March 2024

Abstract
The Sub-Antarctic South Atlantic Ocean has been inferred to have undergone a complex tectonic history involving dismemberment and plume-ridge interaction. Here we report new in situ major (electron probe microanalysis, EPMA), trace element (laser ablation–inductively coupled plasma–mass spectrometry, LA-ICP-MS), and Sr isotopic (laser ablation–multicollector–inductively coupled plasma–mass spectrometry, LA-MC-ICP-MS) compositions for minerals (olivine, clinopyroxene, and plagioclase) from the Northeast Georgia Rise (NGR; Sites 698 and 699), Islas Orcadas Rise (IOR; Site 701), and Meteor Rise (MR; Site 703) volcanic samples in the Sub-Antarctic South Atlantic Ocean. Plagioclases and clinopyroxenes from Sites 698, 699, and 703 are characterized by similar incompatible element patterns and Sr isotopic characteristics, suggesting that they are likely to have originated from a cogenetic mantle source. The plagioclases and clinopyroxenes exhibit an oscillatory, reverse, and normal zoning texture, and display clear evidence of Sr isotopic disequilibrium, suggesting dynamic and open fractional-crystallization processes as well as extensive mixing of compositionally distinct magmas. Rims and groundmass of plagioclase exhibit much more highly radiogenic Sr isotopes than their cores, likely indicating the involvement of both continental lithospheric and recycled oceanic crust. The in situ geochemical and isotopic compositions of these minerals exhibit the features of both the oceanic-island basalt–type Tristan-Gough mantle plume track and the normal mid-oceanic-ridge basalt–type Mid-Atlantic spreading ridge (MAR) and Agulhas spreading ridge (AR) track. We speculate that the NGR, IOR, and MR were formed from the same mantle source with volcanic flow of the Tristan-Gough mantle plume. Subsequently, tectonic movement along the MAR and AR separated the originally combined MR-IOR-NGR, resulting in the incursion of depleted asthenospheric mantle and the contamination contributions of continental and recycled oceanic crust components.
Competing effects of crustal shortening, thermal inheritance, and surface processes explain subsidence anomalies in inverted rift basins
Authors: Oravecz Éva , Balázs Attila , Gerya Taras , May Dave A. , Fodor László 
Published: March 2024

Abstract
Structural inversion of rifted basins is generally associated with surface uplift and denudation of the sedimentary infill, reflecting the active contractional deformation in the crust. However, worldwide examples of inverted rifts show contrasting basin-scale subsidence and widespread sedimentation patterns during basin inversion. By conducting a series of three-dimensional coupled geodynamic and surface processes models, we investigated the dynamic controls on these subsidence anomalies during the successive stages of rifting and basin inversion, and we propose a new evolutionary model for this process. Our models show that the inherited thermo-rheological properties of the lithosphere influence the initial strain localization and subsequent migration of crustal deformation during inversion. The sense of the vertical movements (i.e., uplift or subsidence), however, is not directly linked to the underlying crustal stress patterns; rather, it reflects the balance among contraction-induced tectonic uplift, postrift thermal subsidence of the inherited lithosphere, and sediment redistribution. Based on the interplay among the competing differential vertical movements with different amplitudes and wavelengths, inversion of rifted basins may lead to the growth of intraplate orogens, or the contraction-driven localized uplift may be hindered by the thermal sag effects of the inherited shallow lithosphere-asthenosphere boundary, resulting in basin-scale subsidence. In such basins, dating the first erosional surfaces and other unconformities may not provide accurate timing for the onset of inversion.
rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors
Authors: Lee Minji , Im Sun-Kyoung , Baek Seungtae , Ji Mankyu , Kim Miyoung , Lee Eun Ju , Ji Seung Taek , Ferrando-Martinez Sara , Wolfarth Alexandra , Lee Jun-Young , Kim Daeun , Choi Donghoon 
Published: March 2024

BackgroundRecombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rβ)highCD8+T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+cells within the tumor and the tumor-draining lymph nodes (tdLN).MethodsMC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry.ResultsOur data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+T cells, and a decreased frequency of CD39highTIM-3+Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+early progenitor population of exhausted CD8+T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+TPEXrapidly into CD101+terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEXin the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors.ConclusionsrhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
Intrinsic compressibility of laterites and lateritic soils
Authors: Zhao Mingzhi , Gu Junjie , El Naggar M. Hesham , Liu Hongyang , Liu Gang , Wang Tengfei 
Published: March 2024

Laterites and lateritic soils, prevalent in tropical and subtropical climates, have growing applications in earthwork construction. They usually present unique compression properties compared to conventional clays. Therefore, a thorough understanding of their intrinsic compressibility is crucial. This paper reports on modified oedometer tests conducted on reconstituted samples of four distinct laterites and lateritic soils with varying initial water contents. In addition, scanning electron microscopy (SEM) was utilized to identify the microstructural features to reveal the mechanisms of intrinsic compression. The results demonstrate that intrinsic compression curves of reconstituted laterites and lateritic soils align with Burland’s normalization framework. However, they exhibit a higher void ratio at an effective vertical stress of 100 kPa ( e* 100) and a lower compression index ( C* c) compared to traditional clays; therefore, existing formulas for calculating e* 100 and C* c are inapplicable to laterites and lateritic soils. The SEM analysis revealed that sesquioxide interacts with soil minerals, resulting in a porous structure and robust inter-unit cementation. This unique microstructure contributes to the observed intrinsic constants of compressibility, e* 100 and C* c. Based on the experimental observations, new empirical equations are introduced to evaluate e* 100 and C* c in laterites and lateritic soils. The experimental results elucidate the role of sesquioxide in inherent compressibility and improve our understanding of compressibility characteristics that are unique to laterites and lateritic soils.
Non-singular gravitational collapse through modified Heisenberg algebra
Authors: Barca Gabriele , Montani Giovanni 
Published: March 2024

AbstractWe study the effects of cut-off physics, in the form of a modified algebra inspired by Polymer Quantum Mechanics and by the Generalized Uncertainty Principle representation, on the collapse of a spherical dust cloud. We analyze both the Newtonian formulation, originally developed by Hunter, and the general relativistic formulation, that is the Oppenheimer–Snyder model; in both frameworks we find that the collapse is stabilized to an asymptotically static state above the horizon, and the singularity is removed. In the Newtonian case, by requiring the Newtonian approximation to be valid, we find lower bounds of the order of unity (in Planck units) for the deformation parameter of the modified algebra. We then study the behaviour of small perturbations on the non-singular collapsing backgrounds, and find that for certain range of the parameters (the polytropic index for the Newtonian case and the sound velocity in the relativistic setting) the collapse is stable to perturbations of all scales, and the non-singular super-Schwarzschild configurations have physical meaning.
Novel naphthalimide bridged zinc porphyrin/BODIPY nanomaterials with D-A structure for photodynamic therapy
Authors: Cui Min , Zhu Sijie , Xiong Mengmeng , Zuo Huijie , Li Xiang , Wang Kai , Jiang Jun 
Published: March 2024

As a non-invasive cancer therapy method, photodynamic therapy (PDT) shows tremendous promise in clinical cancer treatment. Light-activated singlet oxygen production of photosensitizers (PSs) is the prerequisite for cancer PDT, and the use of organic photosensitizers is always limited by visible light-based activation, hydrophilicity, biocompatibility, selectivity and quantum yield of singlet oxygen. Currently, both zinc porphyrin- and BODIPY-based structures have been widely used in the development of PDT PSs. Here, we developed a novel naphthalimide bridged zinc porphyrin/BODIPY molecule (Por-BDP-1) with two poly(ethylene glycol) (PEG) chains, in which D-A structure was constructed between the naphthalimide group and porphyrin group. After self-assembly into nanoparticles, Por-BDP-1 NPs (Diameter: 122.4 nm) could quench fluorescence in 600–700 nm, bind with calf thymus-DNA, and produce singlet oxygen during light-irradiation (laser: 680 nm, 1.0 W/cm[Formula: see text]. In addition, Por-BDP-1 NPs effectively killed HeLa cells with a IC[Formula: see text] value = 44.8 μg/mL and showed a lower dark toxicity under the same conditions. All our results demonstrated that our naphthalimide bridged zinc porphyrin/BODIPY nano-photosensitizer is a promising nanoagent for PDT in the clinic.
Data from Inhibition of ADP Ribosylation Prevents and Cures <i>Helicobacter</i>-Induced Gastric Preneoplasia
Authors: Toller Isabella M. , Altmeyer Matthias , Kohler Esther , Hottiger Michael O. , Müller Anne 
Published: March 2024

<div>Abstract<p>Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium <i>Helicobacter pylori</i>. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of <i>Helicobacter</i>-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing <i>Helicobacter</i>-specific T-cell priming and T<sub>H</sub>1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell–driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-γ production of mesenteric lymph node T cells <i>ex vivo</i>. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-γ, interleukin 2, and the interleukin 2 receptor α chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and T<sub>H</sub>1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of <i>Helicobacter</i>-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell–driven chronic inflammatory conditions and autoimmune pathologies. Cancer Res; 70(14); 5912–22. ©2010 AACR.</p></div>