bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive model for BNT162b2 vaccine response in cancer patients based on cytokines and growth factors
Authors: Konnova Angelina , De Winter Fien HR , Gupta Akshita , Verbruggen Lise , Hotterbeekx An , Berkell Matilda , Teuwen Laure-Anne , Vanhoutte Greetje , Peeters Bart , Raats Silke , Van der Massen Isolde , De Keersmaecker Sven , Debie Yana , Huizing Manon , Pannus Pieter , Neven Kristof Y , Ariën Kevin K , Martens Geert A. , Van Den Bulcke Marc , Roelant Ella , Desombere Isabelle , Anguille Sébastien , Berneman Zwi , Goossens Maria E , Goossens Herman , Malhotra-Kumar Surbhi , Taconelli Evelina , Vandamme Timon , Peeters Marc , van Dam Peter , Kumar-Singh Samir 
Published: September 2022

AbstractBackgroundPatients with cancer, especially haematological cancer, are at increased risk for breakthrough COVID-19 infection. However, so far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed.MethodsHere, we employed machine learning approaches to identify a biomarker signature based on blood cytokine and growth factors linked to vaccine response from 199 cancer patients receiving BNT162b2 vaccine.ResultsWe show that C-reactive protein (CRP; general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) can correctly classify patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments.ConclusionWhile we propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at continued risk of COVID-19, our data also importantly suggest that such a signature could reflect the inherent make-up of some cancer patients who are also refractive to immunotherapy.
The additive effect of genetic modifiers on ALS prognosis: a population-based study
Authors: Chiò Adriano , Moglia Cristina , Canosa Antonio , Manera Umberto , Grassano Maurizio , Vasta Rosario , Palumbo Francesca , Gallone Salvatore , Brunetti Maura , Barberis Marco , De Marchi Fabiola , Dalgard Clifton , Chia Ruth , Mora Gabriele , Iazzolino Barbara , Peotta Laura , Traynor Bryan , Corrado Lucia , D’Alfonso Sandra , Mazzini Letizia , Calvo Andrea 
Published: September 2022

AbstractObjectiveTo determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients.MethodsThe study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A (rs12608932), CAMTA1 (rs2412208), SLC112A (rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats and C9ORF72 GGGGCC intronic expansion.ResultsThe variants in C9orf72 (p=0.016), ATXN2 (p<0.001) and UNC13A (p<0.001) were significantly related to survival in univariate analysis, while the other considered variants did not influence ALS outcome. However, in the Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival. When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes.Conclusionswe demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials.Key messagesWhat is already known on this topicBesides the disease-causing genes, several other genes have been reported to act as modifiers of ALS phenotype, especially patients’ survival. However, the interactions of these genes at clinical level have never been explored.What this study addsWe demonstrated that gene polymorphisms and expansions acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental allele at common polymorphism or repeat expansion, highlighting the clinical impact of our findings.How this study might affect research, practice, or policThe identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity, will have deep effects on clinical trial design and interpretation and support the inclusion of these polymorphisms in ALS genetic panels.
Impact of cellular prion protein expression on disease progression and pathology in two mouse models of Alzheimer’s disease
Authors: Purro Silvia A. , Farmer Michael , Noble Elizabeth , Sarell Claire J. , Powell Megan , Yip Daniel Chun-Mun , Giggins Lauren , Zakka Leila , Thomas David X. , Farrow Mark A. , Nicoll Andrew J. , Walsh Dominic , Collinge John 
Published: September 2022

AbstractThe aggregation of amyloid-β (Aβ) monomers increases their neurotoxicity, and these oligomeric species are thought to be central to the pathogenesis of Alzheimer’s disease. Unsurprisingly for such a complex disease, current Alzheimer’s disease mouse models fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproducible in a different model. Cellular prion protein (PrPC) is now an established receptor for Aβ oligomers. However, different groups studying the Aβ-PrPC interaction in vivo using a variety of mouse models have obtained contradictory results. Here we performed a longitudinal study in two commonly used AD mouse models using a range of biochemical, histological and behavioural techniques and found similar contradictory results and a possible explanation for the discrepancy. We propose that these two mouse models produce Aβ oligomers with different conformations. Therefore, binding to PrPC and the subsequent activation of toxic signalling cascade will occur only when the Aβ oligomer species with appropriate conformation are present. Hence, it is crucial to select the appropriate model producing the appropriate species of Aβ oligomers to study specific aspects of β-amyloidosis and its downstream pathways. Further conformational characterisation of Aβ oligomers and their binding to PrPC is required to better understand Aβ neurotoxicity.
Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against Omicron
Authors: Chi Xiangyang , Xia Lingyun , Zhang Guanying , Chi Ximin , Huang Bangdong , Zhang Yuanyuan , Chen Zhengshan , Han Jin , Wu Liushu , Li Zeya , Sun Hancong , Huang Ping , Yu Changming , Chen Wei , Zhou Qiang 
Published: September 2022

AbstractThe pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the antibodies’ epitopes and genotypes. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of one class of antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments show that such antibodies can effectively inhibit the immune escape of Omicron. Cryo-EM results show that this class of antibodies utilizes a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. At the same time, it also provides guidance and insights for developing Omicron antibodies and vaccines.
“Primed to Perform:” Dynamic white matter graph communicability may drive metastable network representations of enhanced preparatory cognitive control
Authors: Buch Vivek P. , Bernabei John M. , Ng Grace , Richardson Andrew G. , Ramayya Ashwin , Brandon Cameron , Stiso Jennifer , Bassett Danielle S. , Lucas Timothy H. 
Published: September 2022

AbstractSpontaneous neural activity has become increasingly linked to behavioral and cognitive output. A specific cognitive control mode, proactive control, uses prior information to plan and prepare the brain to be particularly sensitive to incoming goal-directed stimuli. Little is known about specific proactive mechanisms implemented via preparatory patterns of spontaneous neural activity, that may enable dynamically enhanced cognitive performance. In this study, humans implanted with intracranial electrodes performed a simple cognitive task. For each subject, pre-trial spectral power and communicability-based features from both grey and white matter nodes were extracted to identify preparatory control states that were “primed to perform”. The anatomical structure and topology of these states across subjects demonstrated a critical role for white matter communicability in decoding and intrinsically controlling preparatory network activity. Our results provide novel insights for putative cognitive network control and may be studied to develop prosthetic approaches for individuals with cognitive deficits.
Quantifying Spatio-Temporal Overlap of Invasive Wild Pigs and Domestic Pig Farms as a Proxy for Potential Disease Transmission Risk
Authors: Aschim Ruth A. , Brook Ryan K. 
Published: September 2022

AbstractDirect and indirect interactions between livestock and free-ranging wildlife creates important risks to animal health and agricultural productivity. The interface between newly established and rapidly spreading invasive wild pigs and the 2,549 domestic pig farms on the Prairie Provinces of western Canada has created important but poorly understood disease transmission risks. We mapped the spatial overlap of wild and domestic pigs to identify the areas of highest risk and associated distribution of diseases of concern using databases of wild pig occurrences and domestic pig farm locations. We also examined spatial and temporal overlap at the individual farm scale using GPS collared invasive wild pigs. Across the provinces of Alberta, Saskatchewan, and Manitoba, spatial overlap of invasive wild pigs with all combined, large-scale domestic pig farms, small-scale domestic pig farms, and domestic wild boar farms was 21%, 21%, 21%, and 53%. Invasive wild pig locations were significantly closer to domestic pig farms and domestic wild boar farms compared to random points on the landscape. The number of wild pig occurrences was greatest within 20 km of domestic pig farms and decreased linearly as distance increased. The Canadian distribution of wild pigs had considerable spatial overlap with recent areas detected with bovine tuberculosis (6,002 km2) in livestock and wildlife and Chronic Wasting Disease (156,159 km2) in wildlife, including mule deer, white-tailed deer, elk, and moose. The single best predictor of invasive wild pig occurrences across the landscape was close proximity to current or recently past existing domestic wild boar farms. The distance of GPS- collared wild pigs was significant for sex, farm type, month, and season and in southeastern Saskatchewan, average distance to domestic pig farms was 5.3 km. The weighted sum of cover type proportions, wild pig distance to domestic pig and wild boar farms, farm type, and farm density identified the relative risk of wild pig presence associated to each domestic pig farm occupied watershed. Risk was highest for small-scale domestic pig farms and lowest for large- scale domestic pig farms. Our findings highlight important potential routes for disease transmission at the invasive wild pig-domestic pig interface and identify areas where biosecurity improvements are urgently needed. While complete eradication of invasive wild pigs in Canada is no longer achievable, improved passive and active monitoring and removal of wild pigs is critical, especially where risks to domestic pig herds is highest.
Heterogeneity of burst firing in mouse thalamic reticular nucleus neurons
Authors: Harding-Jackson Laura M. , Beatty Joseph A. , Cox Charles L. 
Published: September 2022

ABSTRACTThe thalamic reticular nucleus (TRN) sits at the interface of the thalamus and neocortex and provides the majority of inhibition to thalamic relay nuclei. Functionally, the activity of TRN neurons can impact sensory processing and may influence arousal states. TRN neurons discharge action potentials in two distinct output modes: tonic or burst firing. Burst output, a transient high frequency discharge of action potentials, is dependent on the activation of transient low-threshold voltage-dependent T-type calcium current (IT). In our current study, we identify a broad range of burst firing frequencies in TRN neurons, which depend on the activation of IT. The amplitude of the low-threshold calcium spike (LTS) underlying the burst positively correlated with burst frequency and number of action potentials per burst. Activation of small conductance calcium-activated potassium (SK) channels on TRN neurons can impact burst discharge. Attenuation of SK channels increased TRN neuron burst frequency through an increase in LTS duration, but not magnitude. The broad range of burst firing frequencies could provide distinct downstream inhibition within thalamic nuclei.
A non-ligand surrogate agonist antibody that enhances canonical Wnt signaling and bone regeneration
Authors: Lee Nam-Kyung , Bidlingmaier Scott , Su Yang , Seo Youngho , Liu Bin 
Published: September 2022

AbstractThe Wnt signaling pathway promotes tissue regeneration and is a promising therapeutic target for treatment of osteolytic bone diseases. Here we report the discovery of a novel type of canonical Wnt agonist antibody that does not operate as a ligand surrogate. The antibody increases Wnt/β-catenin signaling with or without exogenously provided Wnt ligands. It binds to a site on the P3 domain of LRP6 that is distinct from where the Wnt3a ligand and the DKK1 antagonist bind. The agonist effect persists in the presence of DKK1 and is further amplified by R-spondin even when Wnt ligands are not provided, suggesting a potential use for this antibody in ligand-low or insufficient settings. The antibody induces osteoblastic differentiation and mineralization in vitro and restores bone loss in vivo in a myeloma-derived intrafemoral mouse model, opening a potential path for therapeutic development in osteolytic diseases caused by cancer and aging.
Household transmission of SARS-CoV-2 during the Omicron wave in Shanghai, China:a case-ascertained study
Authors: Wei Zhongqiu , Ma Wenjie , Wang Zhonglin , Li Jingjing , Fu Xiaoming , Chang Hailing , Qiu Yue , Tian He , Ge Yanling , Zhu Yanfeng , Xia Aimei , Wu Qianhui , Liu Gongbao , Zhai Xiaowen , Zhang Xiaobo , Wang Yan , Zeng Mei 
Published: September 2022

AbstractBackgroundSince late 2021, the highly transmissible SARS-CoV-2 Omicron variant has driven a new surge of infections across the world. We used a case-ascertained study to determine the features of household transmission of SARS-CoV-2 Omicron variant in Shanghai, China.MethodsWe collected detailed information on 323 pediatric cases and their 951 household members in April 2022 during the Omicron outbreak. All household members received consecutively intensive RT-PCR testing for SARS-CoV-2 and routine symptom monitoring within 14 days after exposure to a confirmed case. We described the characteristics of study participants and estimated the transmission parameters. Both secondary infection attack rates (SARI) and secondary clinical attack rates (SARC) among adult household contacts were computed, through which the transmission heterogeneities in infectivity and susceptibility were characterized and the vaccine effectiveness were estimated.ResultsWe estimated the mean incubation period of SARS-CoV-2 Omicron variant to be 4.6 (median: 4.4, IQR: 3.1-6.0) days and the mean serial interval to be 3.9 (median:4.0, IQR: 1.4-6.5) days. The overall SARI and SARC among adult household contacts were 77.11% (95% confidence interval [CI]: 73.58%-80.63%) and 67.03% (63.09%-70.98%). We found higher household susceptibility in females, while infectivity was not significantly different in primary cases by age, sex, vaccination status and clinical severity. The estimated VEs of full vaccination was 14.8% (95% CI: 5.8%-22.9%) against Omicron infection and 21.5% (95% CI: 10.4%-31.2%) against symptomatic disease. The booster vaccination was 18.9% (95% CI: 9.0%-27.7%) and 24.3% (95% CI: 12.3%-34.7%) effective against infection and symptomatic disease, respectively.ConclusionsWe found high household transmission during the Omicron wave in Shanghai due to asymptomatic and pre-symptomatic transmission in the context of city-wide lockdown, indicating the importance of early detection and timely isolation of SARS-CoV-2 infections and quarantine of close contacts. Marginal effectiveness of inactivated vaccines against Omicron infection poses great challenge for prevention and control of the SARS-CoV-2 Omicron variant.
Alendronate Conjugate for Targeted Delivery to Bone-Forming Prostate Cancer
Authors: Damasco Jossana A. , Yu Guoyu , Kumar Ajay , Perez Joy , Lirag Rio Carlo M. , Whitley Elizabeth M. , Lin Sue-Hwa , Melancon Marites P. 
Published: September 2022

AbstractBone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability. Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, which targets bone. Characterization, such as infrared spectroscopy, confirmed the synthesis of the Cy5.5-ALN conjugate. The maximum absorbance of free Cy5.5, which was at 675 nm, did not change upon conjugation. Alendronate targeted the bone component hydroxyapatite in a dose-dependent manner up to 2.5 μM, with a maximum of 85% of Cy5.5-ALN bound to hydroxyapatite, while free Cy5.5 alone had 6% binding. In in vitro cell binding studies, Cy5.5-ALN bound specifically with mineralized bone matrix of differentiated MC3T3-E1 cells or 2H11 endothelial cells that were induced to become osteoblasts through endothelial-to-osteoblast transition, the underlying mechanism of prostate-cancer-induced bone formation. Neither Cy5.5-ALN nor free Cy5.5 bound to undifferentiated MC3T3-E1 or 2H11 cells. Bone-targeting efficiency studies in non-tumor-bearing mice revealed accumulation over time in the spine, jaw, knees, and paws injected with Cy5.5-ALN, and quantification showed higher accumulation in femurs than in muscle at up to 28 days, while the free Cy5.5 dye was observed circulating without preferential accumulation and decreased over time. There was a linear relationship with fluorescence when the injected concentration of Cy5.5-ALN was between 0.313 and 1.25 nmol/27 g of mouse, as quantified in mouse femurs both in vivo and ex vivo. Ex vivo evaluation of bone-targeting efficiency in nude mice was 3 times higher for bone-forming C4-2b-BMP4 tumors compared to non-bone-forming C4-2b tumors (p-value < 0.001). Fluorescence microscopy imaging of the tumors showed that Cy5.5-ALN co-localized with the bone matrix surrounding tumor-induced bone, but not with the viable tumor cells. Together, these results suggest that a drug-ALN conjugate is a promising approach for targeted delivery of drug to the tumor-induced bone area in the metastatic foci of prostate cancer.
PF-D-Trimer, a broadly protective SARS-CoV-2 subunit vaccine: immunogenicity and application
Authors: Zhang Zhihao , Zhou Jinhu , Ni Peng , Hu Bing , Deng Shuang , Xiao Qian , He Qian , Li Gai , Xia Yan , Liu Mei , Wang Cong , Fang Zhizheng , Xia Nan , Zhang Zhe-Rui , Zhang Bo , Cai Kun , Jolicoeur Normand , Xu Yan , Liu Binlei 
Published: September 2022

AbstractThe COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and still has a considerable impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, the primary responsible for the host immune response upon infection. Here we show the preclinical studies of a broad protective SARS-CoV-2 subunit vaccine developed from our Trimer Domain platform using the Delta spike protein, from antigen design to purification, vaccine evaluation and manufacturability. The prefusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. The immunogenicity studies demonstrated that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous virus challenge. The neutralizing antibodies induced by this vaccine display a cross-reactive capacity against the ancestral WA1 and Delta variants as well as different Omicron, including BA.5.2. The Trimer Domain platform was proven to be a key technology in the rapid production of the PF-D-Trimer vaccine and may be crucial to accelerate the development of updated versions of SARS-CoV-2 vaccines.