bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical/technical risk analysis of a new multi-directional nebulizer (MDN) and its clinical implementation for the safe administration of Pressurized Intraperitoneal Aerosol Chemotherapy (MDN-PIPAC)
Authors: Kockelmann Fabian , Göhler Daniel , Barbey Sarah , Gena Amayu Wakoya , Alsaad Hayder , Voelker Conrad , Zieren Jürgen , Ouaissi Mehdi , Giger-Pabst Urs 
Published: December 2023

ABSTRACTBackground/AimTo test the chemoresistance of a multi-directional nebulizer (MDN) and to establish and implement a perioperative clinical safety concept for its clinical use to deliver pressurised intraperitoneal aerosol chemotherapy (MDN-PIPAC).Study designEx-vivo nebulization of cytostatic drugs with the MDN device to assess chemoresistance/toxicological risks. Establishment of a perioperative safety concept for the clinical administration of MDN-PIPAC by ex- and in-vivo porcine simulation studies. Unicentric case series of 30 MDN-PIPACs in 21 patients with peritoneal surface malignancies (PSM). Endpoints were intraoperative adverse events and perioperative complications (Clavien-Dindo).ResultsToxicological studies/risk assessment confirm the safety of administering PIPAC with the MDN. The horizontal nozzles must protrude at least 7 mm beyond the most distal end of the trocar tip and lateral tilting should be prevented by fixation of the device in a single-arm holder. A total of 21 patients (male/female ratio: 2:1) with a mean age of 62 (range: 38-86) years underwent 30 consecutive MDN-PIPACs for peritoneal surface malignancies of different origin. ECOG 0 and 1 were seen in five and 16 patients, respectively. Thirteen, seven, and one patient underwent one, two, and three MDN-PIPACs, respectively. Two patients received only one cycle of MDN-PIPAC because they were considered candidates for cytoreductive surgery and heated intraperitoneal chemotherapy. There were no intraoperative technical/medical problems observed. Four patients suffered from postoperative grade I complications.ConclusionsCompounds leached during chemotherapy nebulization with the MDN are toxicologically safe. MDN-PIPAC administrations are safe and the postoperative course is comparable to that of the conventional PIPAC nebulizer.MINI ABSTRACTToxicological analyses confirm that doxorubicin, cisplatin, and oxaliplatin nebulized with the MDN do not release leachables that pose a toxicological risk to patients. Through technical risk analysis and PIPAC simulations, a safety concept for the administration of MDN-PIPAC was established. No technical/medical intraoperative adverse events were observed. The perioperative course was comparable to that of the conventional axial single-direction nebulizer (SDN) PIPAC.
Microsatellites reveal high polymorphism and high potential for use in antimalarial efficacy studies in areas with different transmission intensities in mainland Tanzania
Authors: Ishengoma Deus S. , Mandara Celine I. , Madebe Rashid A. , Warsame Marian , Ngasala Billy , Kabanywanyi Abdunoor M. , Mahende Muhidin K. , Kamugisha Erasmus , Kavishe Reginald A. , Muro Florida , Mandike Renata , Mkude Sigsbert , Chacky Frank , Njau Ritha , Martin Troy , Mohamed Ally , Bailey Jeffrey A. , Fola Abebe A. 
Published: December 2023

AbstractBackgroundTanzania is currently implementing therapeutic efficacy studies (TES) in areas of varying malaria transmission intensities as per the World Health Organization’s (WHO) recommendations. In TES, distinguishing reinfection from recrudescence is critical for the determination of antimalarial efficacy. Recently, the WHO recommended genotyping polymorphic coding genes (msp1, msp2, andglurp) and highly polymorphic neutral microsatellites inPlasmodium falciparumto adjust the efficacy of antimalarials in TES. This study assessed the polymorphisms of six neutral microsatellite markers and their potential use in TES, which are routinely performed in Tanzania.MethodsP. falciparumsamples were obtained from four TES sentinel sites, Kibaha (Pwani), Mkuzi (Tanga), Mlimba (Morogoro), and Ujiji (Kigoma), between April and September 2016. Parasite genomic DNA was extracted from dried blood spots on filter papers using commercial kits. Genotyping was performed using six microsatellites (Poly-α, PfPK2, TA1, C3M69, C2M34 and 2490) by the capillary method, and the data were analyzed to determine the extent of polymorphisms and genetic diversity at the four sites.ResultsOverall, 83 (88.3%) of the 94 samples were successfully genotyped (with positive results for ≥50.0% of the markers), and >50.0% (range = 47.6-59.1%) were polyclonal, with the mean multiplicity of infection ranging from 1.68 to 1.88 among the four sites. There was high genetic diversity but limited variability among the four sites based on mean allelic richness (RS = 7.48, range= 7.27- 8.03, for an adjusted minimum sample size of 18 per site) and mean expected heterozygosity (He= 0.83, range= 0.80-0.85). Cluster analysis of haplotypes using STRUCTURE, principal component analysis, and pairwise genetic differentiation (FST) did not detect any population structure, and isolates clustered independently of geographic origin. Of the six markers, Poly-α was the most polymorphic, followed by C2M34, TA1 and C3M69, while 2490 was the least polymorphic.ConclusionMicrosatellite genotyping revealed high polyclonality and genetic diversity but without any significant population structure. Poly-α, C2M34 and TA1 were the top polymorphic markers and could be adopted for use in TES in Tanzania.
Long-term impact of pre-natal exposure to the Ukraine famine of 1932-1933 on adult type 2 diabetes mellitus
Authors: Lumey L.H. , Li Chihua , Khalangot Mykola , Levchuk Nataliia , Wolowyna Oleh 
Published: December 2023

AbstractImportanceThe long-term impacts of early-life famine exposure on Type 2 Diabetes Mellitus (T2DM) have been widely documented across countries, but it remains less clear what is the critical time window and if there is a dose-response between famine intensity and risk of T2DM.ObjectiveTo establish the relation between prenatal famine exposure and adult Type 2 diabetes mellitus (T2DM).DesignA national cross-sectional study.SettingThe man-made Ukrainian Holodomor famine of 1932-1933.ParticipantsA total number of 128,225 T2DM cases diagnosed at age 40 or over from the national diabetes register 2000-2008 in Ukraine. The population at risk includes 10,186,016 Soviet Ukraine births (excepting one oblast/province) between 1930-1938 classified by month and year and oblast of birth.ExposureBirths born in January-June 1934 from oblasts that experienced extreme, severe, or significant famine in 1932-1933. Famine intensity was measured based on the excess mortality during the famine.Main Outcomes and MeasuresT2DM diagnosis was based on WHO (1999) criteria.ResultsWe observed in univariate analysis a 1.8-fold increase in T2DM (OR 1.80; 95% CI 1.74-1.85) among individuals born in the first half-year of 1934 in regions with extreme, severe, or significant famine. We observed no increase among individuals born in regions with no famine. In multivariate analysis across regions and adjusting for season of birth we observed a larger than 2-fold increase (OR 2.21; 95% CI 2.00-2.45). There was a dose-response by famine intensity, with ORs increasing from 1.94 to 2.39 across regions. The pattern was similar in men and women.Conclusions and RelevanceBirths in the first half-year of 1934 were conceived at the height of the Ukraine famine in 1933. This relation for T2DM outcomes points to early gestation as a critical time window relating maternal nutrition in pregnancy to offspring health in later life. Further studies of biological mechanisms should focus on this time window for which changes in DNA methylation and later body size have also been observed.Key PointsQuestionWhat is the critical time window for early-life famine exposure on Type 2 Diabetes Mellitus (T2DM)? Is there any dose-response relationship between early-life famine exposure and T2DM?FindingsWe found an increased risk of T2DM (Odds Ratio 2.21; 95% CI 2.00-2.45) among individuals born during the first half-year of 1934. A clear dose-response relationship was observed using excess mortality as a measure of famine intensity.MeaningEarly gestation is a critical time window relating maternal undernutrition in pregnancy to offspring health in later life.
Spatially resolved molecular and cellular atlas of the mouse brain
Authors: Han Lei , Liu Zhen , Jing Zehua , Liu Yuxuan , Chang Huizhong , Lei Junjie , Peng Yujie , Wang Kexin , Xu Yuanfang , Liu Wei , Wu Zihan , Li Qian , Shi Xiaoxue , Zheng Mingyuan , Wang He , Deng Juan , Zhong Yanqing , Pan Hailin , Lin Junkai , Zhang Ruiyi , Chen Yu , Wu Jinhua , Xu Mingrui , Ren Biyu , Cheng Mengnan , Yu Qian , Song Xinxiang , Lu Yanbing , Tang Yuanchun , Yuan Nini , Sun Suhong , An Yingjie , Ding Wenqun , Sun Xing , Wei Yanrong , Zhang Shuzhen , Dou Yannong , Zhao Yun , Han Luyao , Zhu Qianhua , Xu Junfeng , Wang Shiwen , Chen Hanbo , Wang Dan , Bai Yinqi , Liang Yikai , Liu Yuan , Chen Mengni , Xie Chun , Bo Binshi , Li Mei , Zhang Xinyan , Ting Wang , Chen Zhenhua , Fang Jiao , Li Shuting , Jiang Yujia , Tan Xing , Zuo Guolong , Xie Yue , Li Huanhuan , Tao Quyuan , Li Yan , Liu Jianfeng , Liu Yuyang , Hao Mingkun , Wang Jingjing , Wen Huiying , Liu Jiabing , Yan Yizhen , Zhang Hui , Sheng Yifan , Han Min , Yu Shui , Liao Xiaoyan , Jiang Xuyin , Wang Guangling , Liu Huanlin , Wang Congcong , Feng Ning , Liu Xin , Ma Kailong , Xu Xiangjie , Han Tianyue , Cao Huateng , Zheng Huiwen , Chen Yadong , Lu Haorong , Yu Zixian , Zhang Jinsong , Wang Bo , Wang Zhifeng , Xie Qing , Pan Shanshan , Liu Chuanyu , Xu Chan , Cui Luman , Li Yuxiang , Liu Shiping , Liao Sha , Chen Ao , Wu Qing-Feng , Wang Jian , Liu Zhiyong , Sun Yidi , Mulder Jan , Yang Huanming , Wang Xiaofei , Li Chao , Yao Jianhua , Xu Xun , Liu Longqi , Shen Zhiming , Wei Wu , Sun Yan-Gang 
Published: December 2023

AbstractA comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.
Characterization of cortical neurodevelopmentin vitrousing gene expression and morphology profiles from single cells
Authors: Sundaresh Adithi , Meistermann Dimitri , Lampela Riina , Yang Zhiyu , Woldegebriel Rosa , Ganna Andrea , Puigdevall Pau , Kilpinen Helena 
Published: December 2023

AbstractDifferentiation of induced pluripotent stem cells (iPSC) towards different neuronal lineages has enabled diverse cellular models of human neurodevelopment and related disorders. However,in vitrodifferentiation is a variable process that frequently leads to heterogeneous cell populations that may confound disease-relevant phenotypes. To characterize the baseline and diversity of cortical neurodevelopmentin vitro, we differentiated iPSC lines from multiple healthy donors to cortical neurons and profiled the transcriptomes of 60,000 single cells across three timepoints spanning 70 days. We compared the cell types observedin vitroto those seenin vivoand in organoid cultures to assess how well iPSC-derived cells recapitulate neurodevelopmentin vivo. We found that over 60% of the cells resembled those seen in the fetal brain with high confidence, while 28% represented metabolically abnormal cell states and broader neuronal classes observed in organoids. Further, we used high-content imaging to quantify morphological phenotypes of the differentiating neurons across the same time points using Cell Painting. By modeling the relationship between image-based features and gene expression, we compared cell type- and donor-specific effects across the two modalities at single cell resolution. We found that while morphological features capture broader neuronal classes than scRNA-seq, they enhance our ability to quantify the biological processes that drive neuronal differentiation over time, such as mitochondrial function and cell cycle. Finally, we show that iPSC-derived cortical neurons are a relevant model for a range of brain-related complex traits. Taken together, we provide a comprehensive molecular atlas of human cortical neuron developmentin vitrothat introduces a relevant framework for disease modeling.
ξ-π: a nonparametric model for neural power spectra decomposition
Authors: Hu Shiang , Zhang Zhihao , Zhang Xiaochu , Wu Xiaopei , Valdes-Sosa Pedro A. 
Published: December 2023

AbstractThe power spectra estimated from the brain recordings are the mixed representation of aperiodic transient activity and periodic oscillations, i.e., aperiodic component (AC) and periodic component (PC). Quantitative neurophysiology requires precise decomposition preceding parameterizing each component. However, the shape, statistical distribution, scale, and mixing mechanism of AC and PCs are unclear, challenging the effectiveness of current popular parametric models such as FOOOF, IRASA, BOSC, etc. Here,ξ-πwas proposed to decompose the neural spectra by embedding the nonparametric spectra estimation with penalized Whittle likelihood and the shape language modeling into the expectation maximization frame-work.ξ-πwas validated on the synthesized spectra with loss statistics and on the sleep EEG and the large sample iEEG with evaluation metrics and neurophysiological evidence. Compared to FOOOF, both the simulation presenting shape irregularities and the batch simulation with multiple isolated peaks indicated thatξ-πimproved the fit of AC and PCs with less loss and higher F1-score in recognizing the centering frequencies and the number of peaks; the sleep EEG revealed thatξ-πproduced more distinguishable AC exponents and improved the sleep state classification accuracy; the iEEG showed thatξ-πapproached the clinical findings in peak discovery. Overall,ξ-πoffered good performance in the spectra decomposition, which allows flexible parameterization using descriptive statistics or kernel functions.ξ-πmay be a promising tool for brain signal decoding in fields such as cognitive neuroscience, brain-computer interface, neurofeedback, and brain diseases.
Satellite glial GPR37L1 regulates maresin and potassium channel signaling for pain control
Authors: Bang Sangsu , Jiang Changyu , Xu Jing , Chandra Sharat , McGinnis Aidan , Luo Xin , He Qianru , Li Yize , Wang Zilong , Ao Xiang , Parisien Marc , Fernandes de Araujo Lorenna Oliveira , Esfahan Sahel Jahangiri , Zhang Qin , Tonello Raquel , Berta Temugin , Diatchenko Luda , Ji Ru-Rong 
Published: December 2023

AbstractG protein coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR and its function remains largely unknown. Here we report that GPR37L1 transcript is highly expressed compared to all known GPCRs in mouse and human dorsal root ganglia (DRGs) and selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following diabetes and chemotherapy by streptozotocin and paclitaxel resulted in downregulations of surface GPR37L1 in mouse and human DRGs. Transgenic mice withGpr37l1deficiency exhibited impaired resolution of neuropathic pain symptom (mechanical allodynia), whereas overexpression ofGpr37l1in mouse DRGs can reverse neuropathic pain. Notably, GPR37L1 is co-expressed and coupled with potassium channels in SGCs. We found striking species differences in potassium channel expression in SGCs, with predominant expression of KCNJ10 and KCNJ3 in mouse and human SGCs, respectively. GPR37L1 regulates the surface expression and function of KCNJ10 and KCNJ3. We identified the pro-resolving lipid mediator maresin 1 (MaR1) as a GPR37L1 ligand. MaR1 increases KCNJ10/KCNJ3-mediated potassium influx in SGCs via GPR37L1. MaR1 protected chemotherapy-induced suppression of KCNJ13/KCNJ10 expression and function in SGCs. Finally, genetic analysis revealed that theGPR37L1-E296Kvariant is associated with increased chronic pain risk by destabilizing the protein. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.
Spontaneous Intersibling Polymorphism in the Development of Dopaminergic Neuroendocrine Cells in Sea Urchin Larvae: Impacts on the Expansion of Marine Benthic Species
Authors: Obukhova Alexandra L. , Khabarova Marina Yu. , Semenova Marina N. , Starunov Viktor V. , Voronezhskaya Elena E. , Ivashkin Evgeny G. 
Published: December 2023

AbstractPlasticity of the nervous system enables the formation of the most adaptive neural circuits and the corresponding behavior of animals. The mechanism by which plasticity arises during development and its involvement in animal adaptation is one of the astonishing questions. Sea urchin larvae are known for their evolutionary and ecological diversity as well as their developmental forms and behavioral patterns. This research addresses the intricate neuroendocrine adaptations that govern larval development of sea urchins, focusing on the coordination between dopaminergic (DA) and serotonergic (5-HT) neurons. The study reveals a heterochronic polymorphism in the appearance of post oral DA neurons and confirms the stable differentiation pattern of apical 5-HT neurons in the larvae of Mesocentrotus nudus and Paracentrotus lividus. We demonstrate that an increased number of DA cells and DA application correlate with downward swimming of the larvae. In contrast, 5-HT cells and serotonin application unsure larval upward swimming. As a result, the 5-HT/DA ratio underlay stage-dependent vertical distribution of the larvae within the water column. In larvae of the same age, the precise balance of 5-HT and DA cells underlie the basis for the different potentials of individuals for upward and downward swimming. This coordination in humoral regulation underlies shifts in larval behavior within a single generation. Based on our findings on DA-cells polymorphism, we have proposed a model illustrating how the balance between the serotonin and dopamine systems, shaped by heterochrony in DA cell appearance, impacts larval behavior, reduces competition between siblings and ensures optimal population expansion. The study explores the evolutionary and ecological implications of these neuroendocrine adaptations in marine species.
EfNST: A composite scaling network of EfficientNet for improving spatial domain identification performance
Authors: Zhao Yanan , Long Chunshen , Yin Na , Si Zhihao , Shang Wenjing , Feng Zhenxing , Zuo Yongchun 
Published: December 2023

ABSTRACTSpatial Transcriptomics (ST) leverages Gene Expression Profiling while preserving Spatial Location and Histological Images, enabling it to provide new insights into tissue structure, tumor microenvironment, and biological development. The identification of spatial domains serves as not only the foundation for ST research but also a crucial step in various downstream analyses. However, accurately identifying spatial domains using computational methods remains a tremendous challenge due to the poor computational performance of many existing algorithms. Here, we propose EfNST, a deep learning algorithm based on a composite scaling network of the EfficientNet Network, designed specifically for the analysis of 10X Visium spatial transcriptomics data. We applied EfNST to three different datasets: human Dorsolateral Prefrontal Cortex, human breast cancer and mouse brain anterior. EfNST outperforms five advanced competing algorithms, achieving the best Adjusted Rand Index (ARI) scores of 0.554, 0.607, and 0.466, respectively. Notably, EfNST demonstrated high accuracy in identifying fine tissue structure and discovering corresponding marker genes with an improved running speed. In conclusion, EfNST offers a novel approach for inferring spatial organization of cells from discrete datapoints, facilitating the exploration of new insights in this field.
Homologous recombination contributes to the repair of acetaldehyde-induced DNA damages
Authors: Yamazaki Kosuke , Takayasu Kazuto , Ngo Trinh Thi To , Onuki Ayaka , Kawaji Hideya , Oshima Shunji , Kanda Tomomasa , Masai Hisao , Sasanuma Hiroyuki 
Published: December 2023

AbstractAcetaldehyde, a chemical that can cause DNA damage and contribute to cancer, is prevalently present in our environment, e.g., in alcohol, tobacco, and food. Although aldehyde potentially promotes crosslinking reaction among biological substances including DNA, RNA, and proteins, it remains unclear what types of DNA damage are caused by acetaldehyde and how they are repaired. In this study, we examined acetaldehyde sensitivity of DNA damage-deficient cells established from human TK6 cell line. Among the mutants, mismatch repair mutants did not show a hypersensitivity to acetaldehyde, while cells deficient in base and nucleotide excision repair pathways increased its sensitivity. We found a delayed repair and hypersensitivity in homologous recombination (HR)-deficient cells but not in non-homologous end joining-deficient cells after acetaldehyde treatment. By analyzing the formation of acetaldehyde-induced RAD51 foci, which represent HR intermediates, HR-deficient cells, but not NHEJ, exhibits delayed repair of acetaldehyde-induced DNA damages, compared withwild-type. These results suggest that acetaldehyde causes complex DNA damages that requires various types of repair pathways. Interestingly, mutants deficient in TDP1 and TDP2, which are involved in the removal of protein adducts from DNA ends, exhibited hypersensitivity to acetaldehyde. the acetaldehyde sensitivity of theTDP1-/-/RAD54-/-double mutant was similar to that of each single mutant. This epistatic relationship between TDP1 and RAD54 suggests that that the removal of protein-DNA adducts generated by acetaldehyde needs to be removed for efficient repair by HR. Our study would help understand the molecular mechanism of genotoxic and mutagenic effects of acetaldehyde.
Structural basis for inhibition of βFXIIa by garadacimab
Authors: Drulyte Ieva , Ghai Rajesh , Ow Saw Yen , Kapp Eugene A. , Quek Adam J. , Panousis Con , Wilson Michael J. , Nash Andrew D. , Pelzing Matthias 
Published: December 2023

AbstractFXIIa is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of Hereditary Angioedema (HAE). Here, we describe a high-resolution cryo-EM structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This atypical structural mechanism is likely the primary contributor in the inhibition of activated FXII proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXII. Structural analysis with other bonafide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a conserved mechanism of βFXIIa inhibition, a novel finding of this study. In summary, garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. This work reaffirms the benefits of cryo-EM as a primary tool to study antigen-antibody complexes in near native state, particularly where other methods have fallen short.