bluuebunny/crossref_metadata_2025_split huggingface dataset:
Looking ahead: ethical and social challenges of somatic gene therapy for sickle cell disease in Africa
Authors: Munung Nchangwi Syntia , Nnodu Obiageli E. , Moru Patrick Ohiani , Kalu Akpaka A. , Impouma Benido , Treadwell Marsha J. , Wonkam Ambroise 
Published: November 2023

AbstractSomatic gene therapy will be one of the most exciting practices of genetic medicine in Africa and is primed to offer a “new life” for persons living with sickle cell disease (SCD). Recently, successful gene therapy trials for SCD in the USA have sparked a ray of hope within the SCD community in Africa. However, the high cost, estimated to exceed 1.5 million USD, continues to be a major concern for many stakeholders. While affordability is a key global health equity consideration, it is equally important to reflect on other ethical, legal and social issues (ELSIs) that may impact the responsible implementation of gene therapy for SCD in Africa. These include informed consent comprehension, risk of therapeutic misestimation and optimistic bias; priorities for SCD therapy trials; dearth of ethical and regulatory oversight for gene therapy in many African countries; identifying a favourable risk-benefit ratio; criteria for the selection of trial participants; decisional conflict in consent; standards of care; bounded justice; and genetic tourism. Given these ELSIs, we suggest that researchers, pharma, funders, global health agencies, ethics committees, science councils and SCD patient support/advocacy groups should work together to co-develop: (1) patient-centric governance for gene therapy in Africa, (2) public engagement and education materials, and (3) decision making toolkits for trial participants. It is also critical to establish harmonised ethical and regulatory frameworks for gene therapy in Africa, and for global health agencies to accelerate access to basic care for SCD in Africa, while simultaneously strengthening capacity for gene therapy.
Direct OC-CHO coupling towards highly C2+ products selective electroreduction over stable Cu0/Cu2+ interface
Authors: Zhang Xin Yu , Lou Zhen Xin , Chen Jiacheng , Liu Yuanwei , Wu Xuefeng , Zhao Jia Yue , Yuan Hai Yang , Zhu Minghui , Dai Sheng , Wang Hai Feng , Sun Chenghua , Liu Peng Fei , Yang Hua Gui 
Published: November 2023

AbstractElectroreduction of CO2 to valuable multicarbon (C2+) products is a highly attractive way to utilize and divert emitted CO2. However, a major fraction of C2+ selectivity is confined to less than 90% by the difficulty of coupling C-C bonds efficiently. Herein, we identify the stable Cu0/Cu2+ interfaces derived from copper phosphate-based (CuPO) electrocatalysts, which can facilitate C2+ production with a low-energy pathway of OC-CHO coupling verified by in situ spectra studies and theoretical calculations. The CuPO precatalyst shows a high Faradaic efficiency (FE) of 69.7% towards C2H4 in an H-cell, and exhibits a significant FEC2+ of 90.9% under industrially relevant current density (j = −350 mA cm−2) in a flow cell configuration. The stable Cu0/Cu2+ interface breaks new ground for the structural design of electrocatalysts and the construction of synergistic active sites to improve the activity and selectivity of valuable C2+ products.
Identification of peptides from honeybee gut symbionts as potential antimicrobial agents against Melissococcus plutonius
Authors: Lang Haoyu , Liu Yuwen , Duan Huijuan , Zhang Wenhao , Hu Xiaosong , Zheng Hao 
Published: November 2023

AbstractEusocial pollinators are crucial elements in global agriculture. The honeybees and bumblebees are associated with a simple yet host-restricted gut community, which protect the hosts against pathogen infections. Recent genome mining has led to the discovery of biosynthesis pathways of bioactive natural products mediating microbe-microbe interactions from the gut microbiota. Here, we investigate the diversity of biosynthetic gene clusters in the bee gut microbiota by analyzing 477 genomes from cultivated bacteria and metagenome-assembled genomes. We identify 744 biosynthetic gene clusters (BGCs) covering multiple chemical classes. While gene clusters for the post-translationally modified peptides are widely distributed in the bee guts, the distribution of the BGC classes varies significantly in different bee species among geographic locations, which is attributed to the strain-level variation of bee gut members in the chemical repertoire. Interestingly, we find that Gilliamella strains possessing a thiopeptide-like BGC show potent activity against the pathogenic Melissococcus plutonius. The spectrometry-guided genome mining reveals a RiPP-encoding BGC from Gilliamella with a 10 amino acid-long core peptide exhibiting antibacterial potentials. This study illustrates the widespread small-molecule-encoding BGCs in the bee gut symbionts and provides insights into the bacteria-derived natural products as potential antimicrobial agents against pathogenic infections.
Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells
Authors: Li Siqi , Li Kun , Wang Kang , Yu Haoyuan , Wang Xiangyang , Shi Mengchen , Liang Zhixing , Yang Zhou , Hu Yongwei , Li Yang , Liu Wei , Li Hua , Cheng Shuqun , Ye Linsen , Yang Yang 
Published: November 2023

AbstractAtezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8+ T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8+ T cells (CD8+ Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8+ Tpex, the progenitor exhausted CD8+ T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation.
Thermal and electrostatic tuning of surface phonon-polaritons in LaAlO3/SrTiO3 heterostructures
Authors: Zhou Yixi , Waelchli Adrien , Boselli Margherita , Crassee Iris , Bercher Adrien , Luo Weiwei , Duan Jiahua , van Mechelen J.L.M. , van der Marel Dirk , Teyssier Jérémie , Rischau Carl Willem , Korosec Lukas , Gariglio Stefano , Triscone Jean-Marc , Kuzmenko Alexey B. 
Published: November 2023

AbstractPhonon polaritons are promising for infrared applications due to a strong light-matter coupling and subwavelength energy confinement they offer. Yet, the spectral narrowness of the phonon bands and difficulty to tune the phonon polariton properties hinder further progress in this field. SrTiO3 – a prototype perovskite oxide - has recently attracted attention due to two prominent far-infrared phonon polaritons bands, albeit without any tuning reported so far. Here we show, using cryogenic infrared near-field microscopy, that long-propagating surface phonon polaritons are present both in bare SrTiO3 and in LaAlO3/SrTiO3 heterostructures hosting a two-dimensional electron gas. The presence of the two-dimensional electron gas increases dramatically the thermal variation of the upper limit of the surface phonon polariton band due to temperature dependent polaronic screening of the surface charge carriers. Furthermore, we demonstrate a tunability of the upper surface phonon polariton frequency in LaAlO3/SrTiO3 via electrostatic gating. Our results suggest that oxide interfaces are a new platform bridging unconventional electronics and long-wavelength nanophotonics.
Nanoparticles exhibiting virus-mimic surface topology for enhanced oral delivery
Authors: Sang Zhentao , Xu Lu , Ding Renyu , Wang Minjun , Yang Xiaoran , Li Xitan , Zhou Bingxin , Gou Kaijun , Han Yang , Liu Tingting , Chen Xuchun , Cheng Ying , Yang Huazhe , Li Heran 
Published: November 2023

AbstractThe oral delivery of nano-drug delivery systems (Nano-DDS) remains a challenge. Taking inspirations from viruses, here we construct core–shell mesoporous silica nanoparticles (NPs, ~80 nm) with virus-like nanospikes (VSN) to simulate viral morphology, and further modified VSN with L-alanine (CVSN) to enable chiral recognition for functional bionics. By comparing with the solid silica NPs, mesoporous silica NPs and VSN, we demonstrate the delivery advantages of CVSN on overcoming intestinal sequential barriers in both animals and human via multiple biological processes. Subsequently, we encapsulate indomethacin (IMC) into the nanopores of NPs to mimic gene package, wherein the payloads are isolated from bio-environments and exist in an amorphous form to increase their stability and solubility, while the chiral nanospikes multi-sited anchor and chiral recognize on the intestinal mucosa to enhance the penetrability and ultimately improve the oral adsorption of IMC. Encouragingly, we also prove the versatility of CVSN as oral Nano-DDS.
Phonon-enhanced nonlinearities in hexagonal boron nitride
Authors: Ginsberg Jared S. , Jadidi M. Mehdi , Zhang Jin , Chen Cecilia Y. , Tancogne-Dejean Nicolas , Chae Sang Hoon , Patwardhan Gauri N. , Xian Lede , Watanabe Kenji , Taniguchi Takashi , Hone James , Rubio Angel , Gaeta Alexander L. 
Published: November 2023

AbstractPolar crystals can be driven into collective oscillations by optical fields tuned to precise resonance frequencies. As the amplitude of the excited phonon modes increases, novel processes scaling non-linearly with the applied fields begin to contribute to the dynamics of the atomic system. Here we show two such optical nonlinearities that are induced and enhanced by the strong phonon resonance in the van der Waals crystal hexagonal boron nitride (hBN). We predict and observe large sub-picosecond duration signals due to four-wave mixing (FWM) during resonant excitation. The resulting FWM signal allows for time-resolved observation of the crystal motion. In addition, we observe enhancements of third-harmonic generation with resonant pumping at the hBN transverse optical phonon. Phonon-induced nonlinear enhancements are also predicted to yield large increases in high-harmonic efficiencies beyond the third.
The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome
Authors: Al-Aubodah Tho-Alfakar , Aoudjit Lamine , Pascale Giuseppe , Perinpanayagam Maneka A. , Langlais David , Bitzan Martin , Samuel Susan M. , Piccirillo Ciriaco A. , Takano Tomoko 
Published: November 2023

AbstractThe efficacy of the B cell-targeting drug rituximab (RTX) in childhood idiopathic nephrotic syndrome (INS) suggests that B cells may be implicated in disease pathogenesis. However, B cell characterization in children with INS remains limited. Here, using single-cell RNA sequencing, we demonstrate that a B cell transcriptional program poised for effector functions represents the major immune perturbation in blood samples from children with active INS. This transcriptional profile was associated with an extrafollicular B cell response marked by the expansion of atypical B cells (atBCs), marginal zone-like B cells, and antibody-secreting cells (ASCs). Flow cytometry of blood from 13 children with active INS and 24 healthy donors confirmed the presence of an extrafollicular B cell response denoted by the expansion of proliferating RTX-sensitive extrafollicular (CXCR5–) CD21low T-bet+ CD11c+ atBCs and short-lived T-bet+ ASCs in INS. Together, our study provides evidence for an extrafollicular origin for humoral immunity in active INS.
Improved in situ characterization of protein complex dynamics at scale with thermal proximity co-aggregation
Authors: Sun Siyuan , Zheng Zhenxiang , Wang Jun , Li Fengming , He An , Lai Kunjia , Zhang Shuang , Lu Jia-Hong , Tian Ruijun , Tan Chris Soon Heng 
Published: November 2023

AbstractCellular activities are carried out vastly by protein complexes but large repertoire of protein complexes remains functionally uncharacterized which necessitate new strategies to delineate their roles in various cellular processes and diseases. Thermal proximity co-aggregation (TPCA) is readily deployable to characterize protein complex dynamics in situ and at scale. We develop a version termed Slim-TPCA that uses fewer temperatures increasing throughputs by over 3X, with new scoring metrics and statistical evaluation that result in minimal compromise in coverage and detect more relevant complexes. Less samples are needed, batch effects are minimized while statistical evaluation cost is reduced by two orders of magnitude. We applied Slim-TPCA to profile K562 cells under different duration of glucose deprivation. More protein complexes are found dissociated, in accordance with the expected downregulation of most cellular activities, that include 55S ribosome and respiratory complexes in mitochondria revealing the utility of TPCA to study protein complexes in organelles. Protein complexes in protein transport and degradation are found increasingly assembled unveiling their involvement in metabolic reprogramming during glucose deprivation. In summary, Slim-TPCA is an efficient strategy for characterization of protein complexes at scale across cellular conditions, and is available as Python package at https://pypi.org/project/Slim-TPCA/.
Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures
Authors: Schoof Melanie , Godbole Shweta , Albert Thomas K. , Dottermusch Matthias , Walter Carolin , Ballast Annika , Qin Nan , Olivera Marlena Baca , Göbel Carolin , Neyazi Sina , Holdhof Dörthe , Kresbach Catena , Peter Levke-Sophie , Epplen Gefion Dorothea , Thaden Vanessa , Spohn Michael , Blattner-Johnson Mirjam , Modemann Franziska , Mynarek Martin , Rutkowski Stefan , Sill Martin , Varghese Julian , Afflerbach Ann-Kristin , Eckhardt Alicia , Münter Daniel , Verma Archana , Struve Nina , Jones David T. W. , Remke Marc , Neumann Julia E. , Kerl Kornelius , Schüller Ulrich 
Published: November 2023

AbstractPediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.
3D bioprinted multilayered cerebrovascular conduits to study cancer extravasation mechanism related with vascular geometry
Authors: Park Wonbin , Lee Jae-Seong , Gao Ge , Kim Byoung Soo , Cho Dong-Woo 
Published: November 2023

AbstractCerebral vessels are composed of highly complex structures that facilitate blood perfusion necessary for meeting the high energy demands of the brain. Their geometrical complexities alter the biophysical behavior of circulating tumor cells in the brain, thereby influencing brain metastasis. However, recapitulation of the native cerebrovascular microenvironment that shows continuities between vascular geometry and metastatic cancer development has not been accomplished. Here, we apply an in-bath 3D triaxial bioprinting technique and a brain-specific hybrid bioink containing an ionically crosslinkable hydrogel to generate a mature three-layered cerebrovascular conduit with varying curvatures to investigate the physical and molecular mechanisms of cancer extravasation in vitro. We show that more tumor cells adhere at larger vascular curvature regions, suggesting that prolongation of tumor residence time under low velocity and wall shear stress accelerates the molecular signatures of metastatic potential, including endothelial barrier disruption, epithelial–mesenchymal transition, inflammatory response, and tumorigenesis. These findings provide insights into the underlying mechanisms driving brain metastases and facilitate future advances in pharmaceutical and medical research.
Conjugation of HIV-1 envelope to hepatitis B surface antigen alters vaccine responses in rhesus macaques
Authors: Nettere Danielle , Unnithan Shakthi , Rodgers Nicole , Nohara Junsuke , Cray Paul , Berry Madison , Jones Caroline , Armand Lawrence , Li Shuk Hang , Berendam Stella J. , Fouda Genevieve G. , Cain Derek W. , Spence Taylor N. , Granek Joshua A. , Davenport Clemontina A. , Edwards Robert J. , Wiehe Kevin , Van Rompay Koen K. A. , Moody M. Anthony , Permar Sallie R. , Pollara Justin 
Published: November 2023

AbstractAn effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env–HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg–Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.
The effect of dosage on the protective efficacy of whole-sporozoite formulations for immunization against malaria
Authors: Moita Diana , Rôla Catarina , Nunes-Cabaço Helena , Nogueira Gonçalo , Maia Teresa G. , Othman Ahmad Syibli , Franke-Fayard Blandine , Janse Chris J. , Mendes António M. , Prudêncio Miguel 
Published: November 2023

AbstractImmunization with Plasmodium sporozoites, either attenuated or administered under the cover of an antimalarial drug, can induce strong protection against malaria in pre-clinical murine models, as well as in human trials. Previous studies have suggested that whole-sporozoite (WSpz) formulations based on parasites with longer liver stage development induce higher protection, but a comparative analysis of four different WSpz formulations has not been reported. We employed a rodent model of malaria to analyze the effect of immunization dosage on the protective efficacy of WSpz formulations consisting of (i) early liver arresting genetically attenuated parasites (EA-GAP) or (ii) radiation-attenuated sporozoites (RAS), (iii) late arresting GAP (LA-GAP), and (iv) sporozoites administered under chemoprophylaxis, that are eliminated upon release into the bloodstream (CPS). Our results show that, unlike all other WSpz formulations, EA-GAP fails to confer complete protection against an infectious challenge at any immunization dosage employed, suggesting that a minimum threshold of liver development is required to elicit fully effective immune responses. Moreover, while immunization with RAS, LA-GAP and CPS WSpz yields comparable, dosage-dependent protection, protection by EA-GAP WSpz peaks at an intermediate dosage and markedly decreases thereafter. In-depth immunological analyses suggest that effector CD8+ T cells elicited by EA-GAP WSpz immunization have limited developmental plasticity, with a potential negative impact on the functional versatility of memory cells and, thus, on protective immunity. Our findings point towards dismissing EA-GAP from prioritization for WSpz malaria vaccination and enhance our understanding of the complexity of the protection elicited by these WSpz vaccine candidates, guiding their future optimization.
The Milky Way revealed to be a neutrino desert by the IceCube Galactic plane observation
Authors: Fang Ke , Gallagher John S. , Halzen Francis 
Published: November 2023

AbstractThe Galactic diffuse emission (GDE) is formed when cosmic rays leave the sources where they were accelerated, diffusively propagate in the Galactic magnetic field and interact with the interstellar medium and interstellar radiation field. GDE in γ-rays (GDE-γ) has been observed up to subpetaelectronvolt energies, although its origin may be explained by either cosmic-ray nuclei or electrons. Here we show that the γ-rays accompanying the high-energy neutrinos recently observed by the IceCube Observatory from the Galactic plane have a flux that is consistent with the GDE-γ observed by the Fermi-LAT and Tibet ASγ experiments around 1 TeV and 0.5 PeV, respectively. The consistency suggests that the diffuse γ-ray emission above ~1 TeV could be dominated by hadronuclear interactions, although a partial leptonic contribution cannot be excluded. Moreover, by comparing the fluxes of the Galactic and extragalactic diffuse emission backgrounds, we find that the neutrino luminosity of the Milky Way is one-to-two orders of magnitude lower than the average of distant galaxies. This finding implies that our Galaxy has not hosted the type of neutrino emitters that dominates the isotropic neutrino background at least in the past few tens of kiloyears.