bluuebunny/crossref_metadata_2025 huggingface dataset:
Architecture, Opportunity, and Conflict in Eighteenth-Century Sicily
Authors: Nixon Martin
Published: November 2023

The catastrophic Sicilian earthquake of 1693 led to the rebuilding of over sixty towns in the island's south-west. The rebuilding extended into the eighteenth century and gave opportunities for the reassertion and the transformation of power relations. Although eight of the towns are now protected by UNESCO, the remarkable architecture resulting from this rebuilding is little known outside Sicily.

This is the first book-length study in English of this interesting area of early modern architecture. Rather than seek to address all of the towns, five case studies discuss key aspects of the rebuilding by approaching the architecture from different scales, from that of a whole town to parts of a town, or single buildings, or parts of buildings and their decoration. Each case study also investigates a different theoretical assumption in architecture, including ideas of the Baroque, rational planning, and the relegation of decoration in architectural discourse.
Overview of transparency and inspectability mechanisms to achieve accountability of artificial intelligence systems
Authors: Hauer Marc P. , Krafft Tobias D. , Zweig Katharina
Published: November 2023

Several governmental organizations all over the world aim for algorithmic accountability of artificial intelligence systems. However, there are few specific proposals on how exactly to achieve it. This article provides an extensive overview of possible transparency and inspectability mechanisms that contribute to accountability for the technical components of an algorithmic decision-making system. Following the different phases of a generic software development process, we identify and discuss several such mechanisms. For each of them, we give an estimate of the cost with respect to time and money that might be associated with that measure.
Towards an Antiwar Transnational Populism? An Analysis of the Construction of ‘the Russian People’ in Volodymyr Zelensky's Wartime Speeches
Authors: Kim Seongcheol
Published: November 2023

This article examines how the identity of the citizens or ‘the people’ of Russia is constructed in the wartime speeches of Ukrainian president Volodymyr Zelensky. Drawing on a discursive approach to populism using post-foundational discourse analysis (PDA), the article first identifies in Zelensky's eve-of-invasion address an antiwar transnational populist construction of a common antiwar interest of ‘ordinary people’ in Russia and Ukraine against the Russian government's overtures towards war. After the full-scale invasion, this construction initially carried over into Zelensky's appeals to ordinary Russians as being under threat from and capable of resisting their own government, before his messaging shifted towards ascribing collective responsibility for the invasion to Russian citizens, following the revelation of the Bucha war crimes. Ultimately, antiwar transnational populism remained a short-lived and contextually bounded phenomenon, limited to an initial phase until early April and briefly resurfacing in Zelensky's appeal to ‘indigenous peoples’ of the Caucasus and Siberia in late September 2022.
Determination of suitable reference genes for RT-qPCR normalisation in Bombyx mori (Lepidoptera: Bombycidae) infected by the parasitoid Exorista sorbillans (Diptera, Tachinidae)
Authors: Liu Xinyi , Gu Haoyi , Xu Qian , Jiang Zhe , Li Bing , Wei Jing
Published: November 2023

The silkworm Bombyx mori (Lepidoptera: Bombycidae) is a lepidopteran model insect of great economic importance. The parasitoid Exorista sorbillans (Diptera, Tachinidae) is the major pest of B. mori and also a promising candidate for biological control. However, the molecular interactions between hosts and dipteran parasitoids have only partially been studied. Gene expression analysis by reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) is indispensable to characterise their interactions. Accurate normalisation of RT-qPCR-based gene expression requires the use of reference genes that are constantly expressed irrespective of experimental conditions. In this study, the expression stability of 13 traditionally used reference genes was estimated by five statistical algorithms (ΔCt, geNorm, Normfinder, BestKeeper, and RefFinder) to determine the best reference genes for gene expression studies in different tissues of B. mori under E. sorbillans parasitism. Specifically, TATA-box-binding protein was the best reference gene in epidermis and testis, while elongation factor 1α was the most stable gene in prothoracic gland and midgut. Elongation factor 1γ, ribosomal protein L3, actin A1, ribosomal protein L40, glyceraldehyde-3-phosphate dehydrogenase and eukaryotic translation initiation factor 4A were the most suitable genes in head, silk gland, fat body, haemolymph, Malpighian tubule and ovary, respectively. Our study offers a set of suitable reference genes for gene expression normalisation in B. mori under the parasitic stress of E. sorbillans, which will benefit the in-depth exploration of host-dipteran parasitoid interactions, and also provide insights for further improvements of B. mori resistance against parasitoids and biocontrol efficacy of dipteran parasitoids.
Searching for spots: a comprehensive survey for the Arabian leopard Panthera pardus nimr in Saudi Arabia
Authors: Dunford Carolyn E. , Faure J. Philip B. , Ross Michael D. , Spalton J. Andrew , Drouilly Marine , Pryce-Fitchen Kai J.P. , De Bruin Ross , Botha Alexander E. , Alshehri Abdullah , Le Roex Nikki , Balme Guy , Almalki Ahmed , Gallacher Emma , Alhlafi Mesfer , Alaamri Saleh , Mills David R. , Mann Gareth
Published: November 2023

The Arabian leopard Panthera pardus nimr is categorized as Critically Endangered, with < 200 individuals estimated to remain in the wild. Historically the species ranged over an extensive area of western Saudi Arabia but, with no confirmed sightings since 2014, investigating potential continued presence and distribution is of critical conservation importance. We present the results of a comprehensive survey designed to detect any remaining Arabian leopard populations in Saudi Arabia. We conducted 14 surveys, deploying 586 camera-trap stations at 13 sites, totalling 82,075 trap-nights. Questionnaire surveys were conducted with 843 members of local communities across the Arabian leopard's historical range to assess the presence of leopards, other predators and prey species. Predator scats were collected ad hoc by field teams and we used mitochondrial DNA analysis to identify the originating species. We obtained 62,948 independent photographs of animals and people, but none were of Arabian leopards. Other carnivores appeared widespread and domestic animals were numerous, but wild prey were comparatively scarce. Three questionnaire respondents reported sightings of leopards within the previous year, but targeted camera-trap surveys in these areas did not yield evidence of leopards. Of the 143 scats sent for analysis, no DNA was conclusively identified as that of the leopard. From this extensive study, we conclude there are probably no surviving, sustainable populations of Arabian leopards in Saudi Arabia. Individual leopards might be present but were not confirmed. Any future Arabian leopard conservation in Saudi Arabia will probably require reintroduction of captive-bred leopards.
Use of Simulation in Full-Scale Exercises for Response to Disasters and Mass-Casualty Incidents: A Scoping Review
Authors: Pek Jen Heng , Quah Li Juan Joy , Valente Martina , Ragazzoni Luca , Della Corte Francesco
Published: November 2023

Disasters or mass-casualty incidents are uncommon events. The use of simulation is an ideal training modality in full-scale exercises as it immerses the participants in a replication of the actual environment where they can respond to simulated casualties in accordance with existing protocols.

The objective of this scoping review is to answer the research question: “How effective is simulation, as assessed in full-scale exercises, for response to disasters and mass-casualty incidents world-wide?” Studies on full-scale exercises, as defined in World Health Organization (WHO) simulation exercise toolbox, that were published in peer-reviewed journals using the English language from 2001 through 2021 were included. Twenty studies were included from searching PubMed, Embase, and Web of Science. Simulated casualties were the most common simulation modality. Using Kirkpatrick’s levels of evaluation to synthesize the data, simulation was reported to be generally effective and mostly demonstrated at the levels of learning of individuals and/or systems, as well as reaction of individuals. Evaluations at levels of behavior and results were limited due to the uncommon nature of disasters and mass-casualty incidents. However, evaluation outcomes across the full-scale exercises were varied, leading to the inability to consolidate effectiveness of simulation into a single measure. It is recommended for best evidence-based practices for simulation to be adhered to in full-scale exercises so that the trainings could translate into better outcomes for casualties during an actual disaster or mass-casualty incident. In addition, the reporting of simulation use in full-scale exercises should be standardized using a framework, and the evaluation process should be rigorous so that effectiveness could be determined and compared across full-scale exercises.
Introduction to the Symposium: China and the Campus
Authors: Newland Sara A.
Published: November 2023

The US-China relationship has worsened dramatically in recent years. After decades of pro-engagement policies toward China, a bipartisan consensus began to emerge around 2016 that engagement had neither accomplished US policy goals (such as encouraging China to liberalize politically) nor served US citizens well.1At the same time, political changes within China have pointed to a declining appetite for engagement with the United States and sidelined the domestic constituencies who remained interested in cooperation and exchange. Further restrictions have shrunk the already limited space for media, civil society groups, and academic exchange in China. Pandemic-related border closures eliminated in-person exchanges almost completely for nearly three years. And some are concerned that China’s 2021 Personal Information Protection Law could be used to prosecute foreign researchers who conduct research in China (Lewis 2023).
Race, Corruption, and Southern Republicanism
Authors: Heersink Boris , Jenkins Jeffery A.
Published: November 2023

While Republicans enjoyed unified control of the national government during the 1920s, scandals involving executive patronage and GOP state bosses in the South dogged the national party throughout the decade. The Republican Party in the South had been a set of “rotten boroughs” for decades, used by national politicians—especially presidents—for the sole purpose of controlling delegates at the Republican National Convention. This patronage-for-delegates arrangement was generally understood among political elites, but the murder-suicide involving a U.S. postmaster in Georgia in April 1928 brought the Southern GOP’s patronage practices to national light. This forced Republican leaders in an election year to call for a Senate investigation. Chaired by Sen. Smith W. Brookhart (R-IA), the committee investigation lasted for eighteen months, covered portions of two Republican presidential administrations, and showed how state GOP leaders in Georgia, Mississippi, South Carolina, and Texas engaged in office selling. The fallout would be a thorn in the side of President Herbert Hoover, who tried to clean up the corrupt GOP organizations in the South—and build an electorally-viable Republican Party in the ex-Confederate states—but largely failed.
A systematic review of chemical weed management in peanut (Arachis hypogaea) in the United States: challenges and opportunities
Authors: Daramola Olumide S. , Iboyi Joseph E. , MacDonald Gregory E. , Kanissery Ramdas G. , Tillman Barry L. , Singh Hardeep , Devkota Pratap
Published: November 2023

Herbicides are the primary tool for controlling weeds in peanut (Arachis hypogaeaL.) and are crucial to sustainable peanut production in the United States. The literature on chemical weed management in peanut in the past 53 yr (1970 to 2022) in the United States was systematically reviewed to highlight the strengths and weaknesses of different herbicides and identify current research gaps in chemical weed management. Residual weed control in peanut is achieved mainly with dimethenamid-P, ethalfluralin, pendimethalin, andS-metolachlor. More recently, the use of the protoporphyrinogen oxidase inhibitor flumioxazin and acetolactate synthase inhibitors, such as diclosulam, for residual weed control in peanut has increased considerably. Postemergence broadleaf weed control in peanut is achieved mainly with acifluorfen, bentazon, diclosulam, imazapic, lactofen, paraquat, and 2,4-DB, while the graminicides clethodim and sethoxydim are the major postemergence grass weed control herbicides in peanut. Although several herbicides are available for weed control in peanut, no single herbicide can provide season-long weed control due to limited application timing, lack of extended residual activity, variability in weed control spectrum, and rotational restrictions. Therefore, effective weed management in peanut often requires herbicide mixtures and/or sequential application of preplant-incorporated, preemergence, and/or postemergence herbicides. However, the available literature showed a substantive range in herbicide efficacy due to variations in environmental conditions and flushes of weed germination across years and locations. Despite the relatively high efficacy of herbicides, the selection of herbicide-resistant weeds is another area of increasing concern. Future research should focus on developing new strategies for preventing or delaying the development of resistance and improving herbicide efficacy within the context of climate change and emerging constraints such as water shortages, rising temperatures, and increasing CO2concentration.
Rapid Saline Permafrost Thaw Below a Shallow Thermokarst Lake in Arctic Alaska
Authors: Jones Benjamin M. , Kanevskiy Mikhail Z. , Parsekian Andrew D. , Bergstedt Helena , Ward Jones Melissa K. , Rangel Rodrigo C. , Hinkel Kenneth M. , Shur Yuri
Published: November 2023

Permafrost warming and degradation is well documented across the Arctic. However, observation‐ and model‐based studies typically consider thaw to occur at 0°C, neglecting the widespread occurrence of saline permafrost in coastal plain regions. In this study, we document rapid saline permafrost thaw below a shallow arctic lake. Over the 15‐year period, the lakebed subsided by 0.6 m as ice‐rich, saline permafrost thawed. Repeat transient electromagnetic measurements show that near‐surface bulk sediment electrical conductivity increased by 198% between 2016 and 2022. Analysis of wintertime Synthetic Aperture Radar satellite imagery indicates a transition from a bedfast to a floating ice lake with brackish water due to saline permafrost thaw. The regime shift likely contributed to the 65% increase in thermokarst lake lateral expansion rates. Our results indicate that thawing saline permafrost may be contributing to an increase in landscape change rates in the Arctic faster than anticipated.
Heterogeneous Crustal Structure of the Hikurangi Plateau Revealed by SHIRE Seismic Data: Origin and Implications for Plate Boundary Tectonics
Authors: Bassett Dan , Fujie Gou , Kodaira Shuichi , Arai Ryuta , Yamamoto Yojiro , Henrys Stuart , Barker Dan , Gase Andrew , van Avendonk Harm , Bangs Nathan , Seebeck Hannu , Tozer Brook , Jacobs Katie , Luckie Thomas , Okaya David , Mochizuki Kimi
Published: November 2023

Marine multichannel and wide‐angle seismic data constrain the distribution of seamounts, sediment cover sequence and crustal structure along a 460 km margin‐parallel transect of the Hikurangi Plateau. Seismic reflection data reveals five seamount up‐to 4.5 km high and 35–75 km wide, with heterogeneous internal velocity structure. Sediment cover decreases south‐to‐north from ∼4.5 km to ∼1–2 km. The Hikurangi Plateau crust (VP 5.5–7.5 km/s) is 11 ± 1 km thick in the south, but thins by 3–4 km further north (∼7–8 km). Gravity models constructed along two seismic lines show the reduction in crustal thickness persists further east, coinciding with a bathymetric scarp. Gravity data suggest the transition in crustal thickness may reflect spatial variability in deformation and lithospheric extension associated with plateau breakup. Variability in the thickness of subducting crust may contribute to differences in megathrust geometry, upper‐plate stress state and high‐rates of contraction and uplift along the southern Hikurangi margin.
Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy
Authors: Weth Freya R. , Hoggarth Georgia B. , Weth Anya F. , Paterson Erin , White Madeleine P. J. , Tan Swee T. , Peng Lifeng , Gray Clint
Published: November 2023

High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing “old” drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or “smart” malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy.
Estimating the proportion of nonsense variants undergoing the newly described phenomenon of manufactured splice rescue
Authors: Haque Bushra , Cheerie David , Birkadze Saba , Xu Alice Linyan , Nalpathamkalam Thomas , Thiruvahindrapuram Bhooma , Walker Susan , Costain Gregory
Published: November 2023

A recent report described a nonsense variant simultaneously creating a donor splice site, resulting in a truncated but functional protein. To explore the generalizability of this unique mechanism, we annotated >115,000 nonsense variants using SpliceAI. Between 0.61% (donor gain delta score >0.8, for high precision) and 2.57% (>0.2, for high sensitivity) of nonsense variants were predicted to create new donor splice sites at or upstream of the stop codon. These variants were less likely than other nonsense variants in the same genes to be classified as pathogenic/likely pathogenic in ClinVar (p < 0.001). Up to 1 in 175 nonsense variants were predicted to result in small in-frame deletions and loss-of-function evasion through this “manufactured splice rescue” mechanism. We urge caution when interpreting nonsense variants where manufactured splice rescue is a strong possibility and correlation with phenotype is challenging, as will often be the case with secondary findings and newborn genomic screening programs.
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

Somatic 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

Electroreduction 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

Eusocial 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

Atezolizumab (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

Phonon 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

The 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

Polar 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

The 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

Cellular 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

Pediatric 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

Cerebral 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

An 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

Immunization 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

The 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.
Ex-vivo CS1-OKT3 dual specific bivalent antibody-armed effector T cells mediate cellular immunity against multiple myeloma
Authors: Awuah Dennis , Li Lin , Williams Lindsay , Urak Ryan , Kujawski Maciej , Forman Stephen J. , Shively John E. , Wang Xiuli
Published: November 2023

Bispecific T cell engaging antibodies (bsAbs) have emerged as novel and powerful therapeutic agents for redirecting T cells towards antigen-specific tumor killing. The cell surface glycoprotein and SLAM family member, CS1, exhibits stable and high-level expression on malignant plasma cells including multiple myeloma, which is indicative of an ideal target for bsAb therapy. Here, we developed a CS1 bsAb (CS1-dbBiTE) using Click chemistry to conjugate intact anti-CS1 antibody (Elotuzumab) and anti-huOKT3 antibody at their respective hinge regions. Using a cellular therapy approach, human T cells were armed ex-vivo with CS1-dbBiTE prior to examining effector activity. Our data indicates that arming T cells with CS1-dbBiTE induced T cell activation and expansion and subsequent cytotoxic activity against CS1-bearing MM tumors, demonstrated by significant CD107a expression as well as inflammatory cytokine secretion. As expected, CS1-dbBiTE armed T cells showed significantly reduced effector activity in the absence of CS1 expression. Similarly, in MM mouse xenograft studies, armed T cells exhibited effective anti-tumor efficacy highlighted by reduced tumor burden in MM.1S tumor-bearing mice compared to controls. On the basis of these findings, the rationale for CS1 targeting by human T cells armed with CS1-dbBiTE presents a potentially effective therapeutic approach for targeting MM.
Response surface optimization of process parameters for preparation of cellulose nanocrystal stabilized nanosulphur suspension
Authors: Mahawar Manoj Kumar , Bharimalla Ashok Kumar , Arputharaj A. , Palkar Jagdish , Dhakane-Lad Jyoti , Jalgaonkar Kirti , Vigneshwaran N.
Published: November 2023

This study employed response surface methodology (RSM) to optimize various parameters involved in the synthesis of nanosulphur (NS) stabilized by cellulose nanocrystals (CNCs). The elemental sulphur (ES) mixed with CNCs was processed in a high-pressure homogenizer to make a stable formulation of CNC-stabilized NS (CNC-NS). RSM was adopted to formulate the experiments using Box-Behnken design (BBD) by considering three independent variables i.e., ES (5, 10, 15 g), CNCs (25, 50, 75 ml), and the number of passes (NP) in the high-pressure homogenizer (1, 2, 3). For the prepared suspensions (CNC-NS), the range of the responses viz. settling time (0.84–20.60 min), particle size (500.41–1432.62 nm), viscosity (29.20–420.60 cP), and surface tension (60.35–73.61 N/m) were observed. The numerical optimization technique was followed by keeping the independent and dependent factors in the range yielded in the optimized solution viz. 46 ml (CNCs), 8 g (ES), and 2 (NP). It was interpreted from the findings that the stability of the suspension had a positive correlation with the amount of CNC while the increasing proportion of ES resulted in reduced stability. The quadratic model was fitted adequately to all the responses as justified with the higher coefficient of determination (R2 ≥ 0.88). The characterization performed by X-ray diffraction (XRD), zeta potential, Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR) revealed better-stabilizing properties of the optimized CNCs–ES suspension. The study confirmed that CNCs have the potential to be utilized as a stabilizing agent in synthesizing stable nanosulphur formulation by high-pressure homogenization.
Active production and passive observation of hand movements shift visual hand location
Authors: Langenberg Maryvonne , Bayer Manuel , Zimmermann Eckart
Published: November 2023

Which factors influence the perception of our hand location is a matter of current debate. Here, we test if sensorimotor processing contributes to the perception of hand location. We developed a novel visuomotor adaptation procedure to measure whether actively performing hand movements or passively observing them, influences visual perception of hand location. Participants had to point with a handheld controller to a briefly presented visual target. When they reached the remembered position of the target, the controller presented a tactile buzz. In adaptation trials, the tactile buzz was presented when the hand had not yet reached the target. Over the course of trials, participants adapted to the manipulation and pointed to a location between the visual target and the tactile buzz. We measured the perceived location of the hand by flashing a virtual pair of left and right hands before and after adaptation. Participants had to judge which hand they perceived closer to their body on the fronto-parallel plane. After adaptation, they judged the right hand, that corresponded to the hand used during adaptation, to be located further away from the body. We conclude that sensorimotor prediction of the consequences of hand movements shape sensory processing of hand location.