bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain connectivity in major depressive disorder: a precision component of treatment modalities?
Authors: Tura Asude , Goya-Maldonado Roberto
Published: June 2023

Major depressive disorder (MDD) is a very prevalent mental disorder that imposes an enormous burden on individuals, society, and health care systems. Most patients benefit from commonly used treatment methods such as pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), and repetitive transcranial magnetic stimulation (rTMS). However, the clinical decision on which treatment method to use remains generally informed and the individual clinical response is difficult to predict. Most likely, a combination of neural variability and heterogeneity in MDD still impedes a full understanding of the disorder, as well as influences treatment success in many cases. With the help of neuroimaging methods like functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the brain can be understood as a modular set of functional and structural networks. In recent years, many studies have investigated baseline connectivity biomarkers of treatment response and the connectivity changes after successful treatment. Here, we systematically review the literature and summarize findings from longitudinal interventional studies investigating the functional and structural connectivity in MDD. By compiling and discussing these findings, we recommend the scientific and clinical community to deepen the systematization of findings to pave the way for future systems neuroscience roadmaps that include brain connectivity parameters as a possible precision component of the clinical evaluation and therapeutic decision.
CircRNAs in colorectal cancer: potential biomarkers and therapeutic targets
Authors: Zhang Yuying , Luo Jingyan , Yang Weikang , Ye Wen-Chu
Published: June 2023

Globally, colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer-related deaths. Circular RNAs (circRNAs) are single-stranded RNA with covalently closed-loop structures and are highly stable, conserved, and abundantly expressed in various organs and tissues. Recent research found abnormal circRNA expression in CRC patients’ blood/serum, cells, CRC tissues, and exosomes. Furthermore, mounting data demonstrated that circRNAs are crucial to the development of CRC. CircRNAs have been shown to exert biological functions by acting as microRNA sponges, RNA-binding protein sponges, regulators of gene splicing and transcription, and protein/peptide translators. These characteristics make circRNAs potential markers for CRC diagnosis and prognosis, potential therapeutic targets, and circRNA-based therapies. However, further studies are still necessary to improve the understanding of the roles and biological mechanisms of circRNAs in the development of CRC. In this review, up-to-date research on the role of circRNAs in CRC was examined, focusing on their potential application in CRC diagnosis and targeted therapy, which would advance the knowledge of the functions of circRNAs in the development and progression of CRC.
Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
Authors: Nguyen Thanh , Sridaran Dhivya , Chouhan Surbhi , Weimholt Cody , Wilson Audrey , Luo Jingqin , Li Tiandao , Koomen John , Fang Bin , Putluri Nagireddy , Sreekumar Arun , Feng Felix Y. , Mahajan Kiran , Mahajan Nupam P.
Published: June 2023

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.
Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A
Authors: Bergman Shana , Cater Rosemary J. , Plante Ambrose , Mancia Filippo , Khelashvili George
Published: June 2023

Major Facilitator Superfamily Domain containing 2 A (MFSD2A) is a transporter that is highly enriched at the blood-brain and blood-retinal barriers, where it mediates Na+-dependent uptake of ω−3 fatty acids in the form of lysolipids into the brain and eyes, respectively. Despite recent structural insights, it remains unclear how this process is initiated, and driven by Na+. Here, we perform Molecular Dynamics simulations which demonstrate that substrates enter outward facing MFSD2A from the outer leaflet of the membrane via lateral openings between transmembrane helices 5/8 and 2/11. The substrate headgroup enters first and engages in Na+ -bridged interactions with a conserved glutamic acid, while the tail is surrounded by hydrophobic residues. This binding mode is consistent with a “trap-and-flip” mechanism and triggers transition to an occluded conformation. Furthermore, using machine learning analysis, we identify key elements that enable these transitions. These results advance our molecular understanding of the MFSD2A transport cycle.
Inflationary theory of branching morphogenesis in the mouse salivary gland
Authors: Bordeu Ignacio , Chatzeli Lemonia , Simons Benjamin D.
Published: June 2023

The mechanisms that regulate the patterning of branched epithelia remain a subject of long-standing debate. Recently, it has been proposed that the statistical organization of multiple ductal tissues can be explained through a local self-organizing principle based on the branching-annihilating random walk (BARW) in which proliferating tips drive a process of ductal elongation and stochastic bifurcation that terminates when tips encounter maturing ducts. Here, applied to mouse salivary gland, we show the BARW model struggles to explain the large-scale organization of tissue. Instead, we propose that the gland develops as a tip-driven branching-delayed random walk (BDRW). In this framework, a generalization of the BARW, tips inhibited through steric interaction with proximate ducts may continue their branching program as constraints become alleviated through the persistent expansion of the surrounding tissue. This inflationary BDRW model presents a general paradigm for branching morphogenesis when the ductal epithelium grows cooperatively with the domain into which it expands.
Directed natural evolution generates a next-generation oncolytic virus with a high potency and safety profile
Authors: Guo Li , Hu Cheng , Liu Yang , Chen Xiaoyu , Song Deli , Shen Runling , Liu Zhanzhen , Jia Xudong , Zhang Qinfen , Gao Yuanzhu , Deng Zhezhi , Zuo Tao , Hu Jun , Zhu Wenbo , Cai Jing , Yan Guangmei , Liang Jiankai , Lin Yuan
Published: June 2023

Oncolytic viruses (OVs) represent a type of encouraging multi-mechanistic drug for the treatment of cancer. However, attenuation of virulence, which is generally required for the development of OVs based on pathogenic viral backbones, is frequently accompanied by a compromised killing effect on tumor cells. By exploiting the property of viruses to evolve and adapt in cancer cells, we perform directed natural evolution on refractory colorectal cancer cell HCT-116 and generate a next-generation oncolytic virus M1 (NGOVM) with an increase in the oncolytic effect of up to 9690-fold. The NGOVM has a broader antitumor spectrum and a more robust oncolytic effect in a range of solid tumors. Mechanistically, two critical mutations are identified in the E2 and nsP3 genes, which accelerate the entry of M1 virus by increasing its binding to the Mxra8 receptor and antagonize antiviral responses by inhibiting the activation of PKR and STAT1 in tumor cells, respectively. Importantly, the NGOVM is well tolerated in both rodents and nonhuman primates. This study implies that directed natural evolution is a generalizable approach for developing next-generation OVs with an expanded scope of application and high safety.
Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42
Authors: Ma Tao , Wang Lei , Chai Anping , Liu Chao , Cui Wenqiang , Yuan Shuguang , Wing Ngor Au Shannon , Sun Liang , Zhang Xiaokang , Zhang Zhenzhen , Lu Jianping , Gao Yuanzhu , Wang Peiyi , Li Zhifang , Liang Yujie , Vogel Horst , Wang Yu Tian , Wang Daping , Yan Kaige , Zhang Huawei
Published: June 2023

ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 Å resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42.
Predicting the storage time of green tea by myricetin based on surface-enhanced Raman spectroscopy
Authors: Xiao Mengxuan , Chen Yingqi , Zheng Fangling , An Qi , Xiao Mingji , Wang Huiqiang , Li Luqing , Dai Qianying
Published: June 2023

The quality of green tea changes rapidly due to the oxidation and degradation of polyphenols during storage. Herein, a simple and fast Surface-enhanced Raman spectroscopy (SERS) strategy was established to predict changes in green tea during storage. Raman spectra of green tea with different storage times (2020–2015) were acquired by SERS with silver nanoparticles. The PCA-SVM model was established based on SERS to quickly predict the storage time of green tea, and the accuracy of the prediction set was 97.22%. The Raman peak at 730 cm−1 caused by myricetin was identified as a characteristic peak, which increased with prolonged storage time and exhibited a linear positive correlation with myricetin concentration. Therefore, SERS provides a convenient method for identifying the concentration of myricetin in green tea, and myricetin can function as an indicator to predict the storage time of green tea.
A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project)
Authors: Leggatt Gary , Cheng Guo , Narain Sumit , Briseño-Roa Luis , Annereau Jean-Philippe ,   The Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Bevers R. , Bleda M. , Boardman-Pretty F. , Boustred C. R. , Brittain H. , Brown M. A. , Caulfield M. J. , Chan G. C. , Giess A. , Griffin J. N. , Hamblin A. , Henderson S. , Hubbard T. J. P. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Lakey A. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , McEntagart M. , Minneci F. , Mitchell J. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , O‘Donovan P. , Odhams C. A. , Patch C. , Perez-Gil D. , Pereira M. B. , Pullinger J. , Rahim T. , Rendon A. , Rogers T. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smith S. C. , Sosinsky A. , Stuckey A. , Tanguy M. , Tavares A. L. Taylor , Thomas E. R. A. , Thompson S. R. , Tucci A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. , Gast Christine , Gilbert Rodney D. , Ennis Sarah
Published: June 2023

Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior–Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.
Lifelong nnU-Net: a framework for standardized medical continual learning
Authors: González Camila , Ranem Amin , Pinto dos Santos Daniel , Othman Ahmed , Mukhopadhyay Anirban
Published: June 2023

As the enthusiasm surrounding Deep Learning grows, both medical practitioners and regulatory bodies are exploring ways to safely introduce image segmentation in clinical practice. One frontier to overcome when translating promising research into the clinical open world is the shift from static to continual learning. Continual learning, the practice of training models throughout their lifecycle, is seeing growing interest but is still in its infancy in healthcare. We present Lifelong nnU-Net, a standardized framework that places continual segmentation at the hands of researchers and clinicians. Built on top of the nnU-Net—widely regarded as the best-performing segmenter for multiple medical applications—and equipped with all necessary modules for training and testing models sequentially, we ensure broad applicability and lower the barrier to evaluating new methods in a continual fashion. Our benchmark results across three medical segmentation use cases and five continual learning methods give a comprehensive outlook on the current state of the field and signify a first reproducible benchmark.
MATLAB simulation based study on poliovirus sensing through one-dimensional photonic crystal with defect
Authors: Aly Arafa H. , Mohamed B. A. , Awasthi S. K. , Abdallah Suhad Ali Osman , Amin A. F.
Published: June 2023

The present work, theoretically examined the poliovirus sensor model composed of one-dimensional photonic crystal with defect. The transfer matrix method with the help of MATLAB software has been used to detect poliovirus present in the water sample. The main objective of the present work is to design an efficient sensor by identifying the minute variation in the refractive index of water sample due to change in the poliovirus concentration present in the sample. The alternate layers of aluminum nitride and gallium nitride has been taken to realize Bragg reflector having defect layer of air at center of the Bragg reflector. The effect of change in thickness of defect layer region, period number and incident angle corresponding to transverse electric wave has been examined to optimize the structure which correspond maximum performance of the proposed poliovirus sensing structure. The maximum performance of the structure has been obtained with optimum value of defect layer thickness 1200 nm, period number 10 and incident angle 40°. Under optimum condition maximum sensitivity of 1189.65517 nm/RIU has been obtained when the structure is loaded with waters sample of poliovirus concentration C = 0.005 g/ml whereas figure of merit, quality factor, signal to noise ratio, dynamic range, limit of detection and resolution values become 2618.28446 per RIU, 3102.06475, 2.27791, 2090.99500, 1.91E−05 and 0.24656 respectively.
Real time monitoring of COVID-19 intervention effectiveness through contact tracing data
Authors: Gibson Graham C. , Woody Spencer , James Emily , Weldon Minda , Fox Spencer J. , Meyers Lauren Ancel , Bhavnani Darlene
Published: June 2023

Communities worldwide have used vaccines and facemasks to mitigate the COVID-19 pandemic. When an individual opts to vaccinate or wear a mask, they may lower their own risk of becoming infected as well as the risk that they pose to others while infected. The first benefit–reducing susceptibility–has been established across multiple studies, while the second–reducing infectivity–is less well understood. Using a new statistical method, we estimate the efficacy of vaccines and facemasks at reducing both types of risks from contact tracing data collected in an urban setting. We find that vaccination reduced the risk of onward transmission by 40.7% [95% CI 25.8–53.2%] during the Delta wave and 31.0% [95% CI 19.4–40.9%] during the Omicron wave and that mask wearing reduced the risk of infection by 64.2% [95% CI 5.8–77.3%] during the Omicron wave. By harnessing commonly-collected contact tracing data, the approach can broadly provide timely and actionable estimates of intervention efficacy against a rapidly evolving pathogen.
Improve the performance of CT-based pneumonia classification via source data reweighting
Authors: Xie Pengtao , Zhao Xingchen , He Xuehai
Published: June 2023

Pneumonia is a life-threatening disease. Computer tomography (CT) imaging is broadly used for diagnosing pneumonia. To assist radiologists in accurately and efficiently detecting pneumonia from CT scans, many deep learning methods have been developed. These methods require large amounts of annotated CT scans, which are difficult to obtain due to privacy concerns and high annotation costs. To address this problem, we develop a three-level optimization based method which leverages CT data from a source domain to mitigate the lack of labeled CT scans in a target domain. Our method automatically identifies and downweights low-quality source CT data examples which are noisy or have large domain discrepancy with target data, by minimizing the validation loss of a target model trained on reweighted source data. On a target dataset with 2218 CT scans and a source dataset with 349 CT images, our method achieves an F1 score of 91.8% in detecting pneumonia and an F1 score of 92.4% in detecting other types of pneumonia, which are significantly better than those achieved by state-of-the-art baseline methods.
A randomized controlled trial for comparing efficacy and safety between intraarticular polynucleotide and hyaluronic acid for knee osteoarthritis treatment
Authors: Kim Tae Woo , Chang Moon Jong , Shin Chung Yeop , Chang Chong Bum , Kang Seung-Baik
Published: June 2023

Although the use of intra-articular polynucleotide (IA PN) injection as a viscosupplement for knee osteoarthritis (OA) treatment has been proposed, its efficacy and safety compared to high molecular weight hyaluronic acid (HMWHA) injection has not yet been established. The present double-blind, multicenter, randomized controlled trial aimed to investigate the efficacy and safety of IA PN injection compared to IA HMWHA injection. A total of 60 patients (15 men, 45 women, 64.5 ± 7.5 years) with knee OA (Kellgren–Lawrence grade 1–4) were randomly allocated to each group. All patients were given three IA injections of PN (n = 30) or HMWHA (n = 30) at intervals of 1 week. The primary endpoint was the change rate in weight-bearing pain (WBP) 16 weeks from the baseline. The secondary endpoint included multiple measurements: the change rate in WBP rate at 8 weeks; the change rate in pain level at rest and during walking at 8 and 16 weeks; the Korean-Western Ontario and McMaster University Osteoarthritis index; the Euro-Quality of Life-5 Dimension; Clinical Global Impression, Patient Global Impression at 8 and16 weeks, and total consumption of rescue medicine. The mean change rate in the WBP at 16 weeks from the baseline was − 54.0 ± 38.1% in the IA PN group and − 42.8 (± 35.8%) in the IA HMWHA group, and there was no significant difference between the two groups (p = 0.296). All secondary endpoints related with pain and functional outcome also showed no significant difference between the two groups. Pain at the injection site and swelling were reported as adverse events, and the incidence was similar between the two groups. IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be useful alternative to IA HMWHA for the treatment of knee OA.
The interaction of Schistosoma mansoni infection with diabetes mellitus and obesity in mice
Authors: Amer Alaa S. , Othman Ahmad A. , Dawood Lamees M. , El-Nouby Kholoud A. , Gobert Geoffrey N. , Abou Rayia Dina M.
Published: June 2023

Human schistosomiasis is one of the most prevalent parasitic diseases worldwide. Various host factors can affect the host–parasite interactions. Therefore, the aim of the present work was to determine the parasitological, histopathological, biochemical, and immunological status of Schistosoma mansoni-infected hosts with metabolic disorders to identify the underlying possible mechanisms of these comorbidities. The study animals were divided into four groups. Group I represented the control groups, namely, the normal control group, the S. mansoni-infected control group, and the noninfected type 1 diabetes (T1DM), type 2 diabetes (T2DM), and obesity groups. The mice of the other three groups underwent induction of T1DM (Group II), T2DM (Group III) and obesity (Group IV) before being infected with S. mansoni. All mice were subjected to body weight measurement, blood glucose and insulin assessment, parasitological evaluation of adult worm count, tissue egg count and intestinal oogram. Histopathological and immunohistochemical study using anti-glial fibrillary acidic protein (GFAP) in hepatic stellate cells (HSCs) and image analysis of Masson’s trichrome-stained liver sections using ImageJ (Fiji) software were carried out. Additionally, immunological analysis of tumour necrosis factor (TNF) beta, interleukin-5 (IL-5), IL-10, Forkhead box P3 (FOXP3) and pentraxin 3 (PTX3) levels besides biochemical study of total lipid profile were evaluated. The present study revealed a significant increase in the adult worm count and tissue egg output in the obesity group compared to the infected control group. The oogram of counted eggs showed prevalence of immature eggs in T1DM group, while T2DM and obese groups showed prevalence of mature eggs. The fibrosis area percentage showed significant increase in T2DM and obese groups while it was decreased in T1DM group in comparison to infected control group. Our data also showed significant increase in the levels of TNF-β, IL-5, PTX3 in T1DM, T2DM and obesity groups in comparison to infected control group, whilst the levels of FOXP3 and IL-10 were increased in the infected groups in comparison to their noninfected controls. Moreover, infected T1DM, T2DM and obesity groups showed higher blood glucose and lipid profile in comparison to the infected control group. However, these parameters were improved in comparison to their noninfected controls. In sum, induction of T2DM and obesity increased tissue egg counts, mature egg percentage, and fibrosis density, while schistosome infection induced changes in the lipid profile and blood glucose levels in infected diabetic and obese groups and impacted favorably insulin levels in obese mice. By better understanding the complexities of host–parasite interactions, efforts to reduce the burden of these debilitating diseases can be improved.
Re-irradiation combined with bevacizumab for recurrent glioblastoma beyond bevacizumab failure: survival outcomes and prognostic factors
Authors: You Weir-Chiang , Lee Hsu-Dung , Pan Hung-Chuan , Chen Hung-Chieh
Published: June 2023

The combination of re-irradiation and bevacizumab has emerged as a potential therapeutic strategy for patients experiencing their first glioblastoma multiforme (GBM) recurrence. This study aims to assess the effectiveness of the re-irradiation and bevacizumab combination in treating second-progression GBM patients who are resistant to bevacizumab monotherapy. This retrospective study enrolled 64 patients who developed a second progression after single-agent bevacizumab therapy. The patients were divided into two groups: 35 underwent best supportive care (none-ReRT group), and 29 received bevacizumab and re-irradiation (ReRT group). The study measured the overall survival time after bevacizumab failure (OST-BF) and re-irradiation (OST-RT). Statistical tests were used to compare categorical variables, evaluate the difference in recurrence patterns between the two groups, and identify optimal cutoff points for re-irradiation volume. The results of the Kaplan–Meier survival analysis indicated that the re-irradiation (ReRT) group experienced a significantly higher survival rate and longer median survival time than the non-ReRT group. The median OST-BF and OST-RT were 14.5 months and 8.8 months, respectively, for the ReRT group, while the OST-BF for the none-ReRT group was 3.9 months (p < 0.001). The multivariable analysis identified the re-irradiation target volume as a significant factor for OST-RT. Moreover, the re-irradiation target volume exhibited excellent discriminatory ability in the area under the curve (AUC) analysis, with an optimal cutoff point of greater than 27.58 ml. These findings suggest that incorporating re-irradiation with bevacizumab therapy may be a promising treatment strategy for patients with recurrent GBM resistant to bevacizumab monotherapy. The re-irradiation target volume may serve as a valuable selection factor in determining which patients with recurrent GBM are likely to benefit from the combined re-irradiation and bevacizumab treatment modality.
Tryptophan-like side chain holding aptamers inhibit respiratory syncytial virus infection of lung epithelial cells
Authors: Percze Krisztina , Tolnai Zoltán János , Eleveld Marc , Ou Li , Du Haijuan , Olia Adam S. , Kwong Peter D. , de Jonge Marien I. , Mészáros Tamás
Published: June 2023

Respiratory syncytial virus (RSV) is a leading cause of serious and even fatal acute lower respiratory tract infections in infants and in the elderly. Potent RSV neutralization has been achieved by antibodies that selectively bind the prefusion form of the viral fusion (F) protein. We hypothesised that similar potent neutralization could be achieved using F protein targeting aptamers. Aptamers have yet to reach their translational potential for therapeutics or diagnostics due to their short half-life and limited range of target-aptamer interactions; these shortcomings can, however, be ameliorated by application of amino acid-like side chain holding nucleotides. In this study, a stabilized version of the prefusion RSV F protein was targeted by aptamer selection using an oligonucleotide library holding a tryptophan-like side chain. This process resulted in aptamers that bound the F protein with high affinity and differentiated between its pre- and postfusion conformation. Identified aptamers inhibited viral infection of lung epithelial cells. Moreover, introduction of modified nucleotides extended aptamer half-lives. Our results suggest that targeting aptamers to the surface of viruses could yield effective drug candidates, which could keep pace with the continuously evolving pathogens.
A downscaling and bias correction method for climate model ensemble simulations of local-scale hourly precipitation
Authors: Yoshikane Takao , Yoshimura Kei
Published: June 2023

Ensemble simulations of climate models are used to assess the impact of climate change on precipitation, and require downscaling at the local scale. Statistical downscaling methods have been used to estimate daily and monthly precipitation from observed and simulated data. Downscaling of short-term precipitation data is necessary for more accurate prediction of extreme precipitation events and related disasters at the regional level. In this study, we developed and investigated the performance of a downscaling method for climate model simulations of hourly precipitation. Our method was designed to recognize time-varying precipitation systems that can be represented at the same resolution as the numerical model. Downscaling improved the estimation of the spatial distribution of hourly precipitation frequency, monthly average, and 99th percentile values. The climate change in precipitation amount and frequency were shown in almost all areas by using the 50 ensemble averages of estimated precipitation, although the natural variability was too large to compare with observations. The changes in precipitation were consistent with simulations. Therefore, our downscaling method improved the evaluation of the climatic characteristics of extreme precipitation events and more comprehensively represented the influence of local factors, such as topography, which have been difficult to evaluate using previous methods.
A simulation study on missing data imputation for dichotomous variables using statistical and machine learning methods
Authors: Ge Yingfeng , Li Zhiwei , Zhang Jinxin
Published: June 2023

The problem of missing data, particularly for dichotomous variables, is a common issue in medical research. However, few studies have focused on the imputation methods of dichotomous data and their performance, as well as the applicability of these imputation methods and the factors that may affect their performance. In the arrangement of application scenarios, different missing mechanisms, sample sizes, missing rates, the correlation between variables, value distributions, and the number of missing variables were considered. We used data simulation techniques to establish a variety of different compound scenarios for missing dichotomous variables and conducted real-data validation on two real-world medical datasets. We comprehensively compared the performance of eight imputation methods (mode, logistic regression (LogReg), multiple imputation (MI), decision tree (DT), random forest (RF), k-nearest neighbor (KNN), support vector machine (SVM), and artificial neural network (ANN)) in each scenario. Accuracy and mean absolute error (MAE) were applied to evaluating their performance. The results showed that missing mechanisms, value distributions and the correlation between variables were the main factors affecting the performance of imputation methods. Machine learning-based methods, especially SVM, ANN, and DT, achieved relatively high accuracy with stable performance and were of potential applicability. Researchers should explore the correlation between variables and their distribution pattern in advance and prioritize machine learning-based methods for practical applications when encountering dichotomous missing data.
Influence of aluminum and iron chlorides on the parameters of zigzag patterns on films dried from BSA solutions
Authors: Glibitskiy Dmitriy , Gorobchenko Olga , Nikolov Oleg , Cheipesh Tatyana , Dzhimieva Tatyana , Zaitseva Inna , Roshal Alexander , Semenov Mihail , Glibitskiy Gennadiy
Published: June 2023

The relationships between the structural and aggregational state of bovine serum albumin (BSA) and the specific length and total number of zigzag pattern segments of the film textures formed upon drying biopolymer solutions with aluminum and iron chlorides have been shown. To obtain films, saline solutions of BSA were dried in a glass cuvette under thermostatically controlled conditions. It is shown that the formation of zigzag structures is sensitive to the influence of aluminum chlorides Al3+ and iron chlorides Fe3+ and depend on the concentration of AlCl3 and FeCl3. This may be due to a change in the charge and size of BSA particles and due to a change in conformation or a violation of the structure of BSA. These factors, in turn, affect the hydration of the solution components and the structural state of free water in solution, which presumably also affects the formation of zigzag structures. It is established that the analysis of the specific length and the number of segments of zigzag patterns makes it possible to evaluate changes in the state of biopolymers in the initial solution during structural changes and aggregation.
Threshold magnetic field as a universal criterion for the selective transport of magnetized particles in microdroplets
Authors: Bono Shinji , Konishi Satoshi
Published: June 2023

Transportation of magnetized particles (MPs) against gravity is possible by applying a magnetic field to the particles. This transport phenomenon of MPs in microdroplets can be quantitatively assessed by determining the contribution of individual forces acting on the MPs. We studied the selective transportation of MPs in microdroplets. MPs in microdroplets were transported in the opposite direction to gravity when we applied an external magnetic field larger than a threshold value. We modulated the intensity of the external magnetic field and selectively manipulated the MPs. As a result, MPs were separated into different microdroplets based on their magnetic properties. Our quantitative investigation of transport dynamics shows that the threshold magnetic field depends only on the magnetic susceptibility and the density of MPs. This is a universal criterion for the selective transport of magnetized targets such as magnetized cells in microdroplets.
Multitemporal modeling and simulation of the complex dynamics in urban wetlands: the case of Bogota, Colombia
Authors: Cuellar Yenny , Perez Liliana
Published: June 2023

Urban wetlands are essential to the longstanding health and well-being of cities. Acknowledged as rich in biodiversity and highly productive ecosystems, they provide ecosystem services represented in aspects such as air purification, urban climate regulation, physical and mental health, recreation, and contemplation, among a wide variety of other goods and services on which the quality of life of the inhabitants of large cities such as Bogota depends largely. We used cellular automata to model and simulate urban wetland changes in Bogota, Colombia. The study applied the coupled Markov-Future Land Use Simulation (FLUS) model to simulate and analyze land use/land cover (LULC) change over 20 years. First, we used an orthomosaic (1998) and two WorldView-2 satellite images (2004 and 2010), to detect land cover changes. Then, using the artificial neural network FLUS module, we calculated the relationships between land classes and associated drivers and estimated the probability of occurrence of each land class. Finally, we applied Intensity Analysis to examine the observed and projected LULC change (1998–2034). Results indicate that gains in areas of crops and pastures are at the expense of wetlands. In addition, simulation outputs show that wetlands will likely represent less than 2% of the total study area in 2034, representing a 14% decrease in 24 years. The importance of this project lies in its potential contribution to the decision-making process within the city and as an instrument of natural resource management. Additionally, the results of this study could contribute to the United Nations Sustainable Development Goal 6, “Clean water and sanitation," and climate change mitigation.
Earth-vertical motion perception assessment using an elevator: a feasibility study
Authors: Schellenberg Simona , Straumann Dominik , Green David Andrew , Schuetz Philipp , Zehnder Yves , Swanenburg Jaap
Published: June 2023

A feasible, inexpensive, rapid, and easy-to-use method to measure vestibular vertical movement perception is needed to assess the sacculus-mediated low-frequency otolith function of dizzy patients. To evaluate the feasibility of reaction time assessment in response to vertical motion induced by an elevator in healthy young individuals. We recorded linear acceleration/deceleration reaction times (LA-RT/LD-RT) of 20 healthy (13 female) subjects (mean age: 22 years ± 1 SD) as a measure of vertical vestibular motion perception. LA-RT/LD-RT were defined as the time elapsed from the start of elevator acceleration or deceleration to the time at which subjects in a sitting position indicated perceiving a change in velocity by pushing a button with their thumb. The light reaction time was measured as a reference. All 20 subjects tolerated the assessment with repeated elevator rides and reported no adverse events. Over all experiments, one upward and four downward rides had to be excluded for technical reasons (2.5%). The fraction of premature button presses varied among the four conditions, possibly related to elevator vibration (upward rides: LA-RT-up 66%, LD-RT-up 0%; downward rides: LA-RT-down 12%, LD-RT-down 4%). Thus LD-RT-up yielded the most robust results. The reaction time to earth-vertical deceleration elicited by an elevator provides a consistent indicator of linear vestibular motion perception in healthy humans. The testing procedure is inexpensive and easy to use. Deceleration on upward rides yielded the most robust measurements.
The impact of seasonality on the annual air-sea carbon flux and its interannual variability
Authors: Rustogi Paridhi , Landschützer Peter , Brune Sebastian , Baehr Johanna
Published: June 2023

Interannual variability of the ocean carbon sink is often assessed using annual air–sea carbon fluxes, but the drivers of the variability may instead arise from seasonal processes that are neglected in the annual average. The seasonal cycle largely modulates air–sea carbon exchange, hence understanding seasonal mechanisms and their link to interannual variability is necessary to determine long-term changes in the ocean carbon sink. We contrast carbon fluxes from an Earth System Model large ensemble and an observation-based ensemble to assess the representation of annual and seasonal carbon fluxes in two distinct ocean regions—the North Atlantic basin and the Southern Ocean and investigate if seasonal variability can help diagnose interannual variability. Both ensembles show strong agreement in their annual mean fluxes. However, discrepancies between the two ensembles are one to two times greater for the seasonal fluxes than the annual fluxes in the North Atlantic basin and three to four times greater in the Southern Ocean. These seasonal discrepancies compensate in the annual mean, obscuring significant seasonal mismatches between the ensembles, particularly in the Southern Ocean. A solid understanding of seasonal variability can be leveraged to diagnose interannual variability of carbon fluxes where necessary observational constraints have been built, for example, in the North Atlantic basin, where boreal winter and spring drive the interannual variability. However, in a data-sparse region like the Southern Ocean, both ensembles disagree substantially in their representations of seasonal carbon fluxes and variability, and currently, seasonal variability is of limited use in diagnosing the interannual variability of carbon fluxes in the Southern Ocean.
Physics-informed neural networks for modeling physiological time series for cuffless blood pressure estimation
Authors: Sel Kaan , Mohammadi Amirmohammad , Pettigrew Roderic I. , Jafari Roozbeh
Published: June 2023

The bold vision of AI-driven pervasive physiological monitoring, through the proliferation of off-the-shelf wearables that began a decade ago, has created immense opportunities to extract actionable information for precision medicine. These AI algorithms model input-output relationships of a system that, in many cases, exhibits complex nature and personalization requirements. A particular example is cuffless blood pressure estimation using wearable bioimpedance. However, these algorithms need training over significant amount of ground truth data. In the context of biomedical applications, collecting ground truth data, particularly at the personalized level is challenging, burdensome, and in some cases infeasible. Our objective is to establish physics-informed neural network (PINN) models for physiological time series data that would use minimal ground truth information to extract complex cardiovascular information. We achieve this by building Taylor’s approximation for gradually changing known cardiovascular relationships between input and output (e.g., sensor measurements to blood pressure) and incorporating this approximation into our proposed neural network training. The effectiveness of the framework is demonstrated through a case study: continuous cuffless BP estimation from time series bioimpedance data. We show that by using PINNs over the state-of-the-art time series models tested on the same datasets, we retain high correlations (systolic: 0.90, diastolic: 0.89) and low error (systolic: 1.3 ± 7.6 mmHg, diastolic: 0.6 ± 6.4 mmHg) while reducing the amount of ground truth training data on average by a factor of 15. This could be helpful in developing future AI algorithms to help interpret pervasive physiologic data using minimal amount of training data.
Reorganization of the ancestral sex-determining regions during the evolution of trioecy in Pleodorina starrii
Authors: Takahashi Kohei , Suzuki Shigekatsu , Kawai-Toyooka Hiroko , Yamamoto Kayoko , Hamaji Takashi , Ootsuki Ryo , Yamaguchi Haruyo , Kawachi Masanobu , Higashiyama Tetsuya , Nozaki Hisayoshi
Published: June 2023

The coexistence of three sexual phenotypes (male, female and bisexual) in a single species, ‘trioecy’, is rarely found in diploid organisms such as flowering plants and invertebrates. However, trioecy in haploid organisms has only recently been reported in a green algal species, Pleodorina starrii. Here, we generated whole-genome data of the three sex phenotypes of P. starrii to reveal a reorganization of the ancestral sex-determining regions (SDRs) in the sex chromosomes: the male and bisexual phenotypes had the same “male SDR” with paralogous gene expansions of the male-determining gene MID, whereas the female phenotype had a “female SDR” with transposition of the female-specific gene FUS1 to autosomal regions. Although the male and bisexual sex phenotypes had the identical male SDR and harbored autosomal FUS1, MID and FUS1 expression during sexual reproduction differed between them. Thus, the coexistence of three sex phenotypes in P. starrii is possible.
Navoximod modulates local HSV-1 replication to reshape tumor immune microenvironment for enhanced immunotherapy via an injectable hydrogel
Authors: Zhuang Qiuyu , Zhao Binyu , Lin Zhiwen , Liang Yuzhi , Zhao Qingfu , Wang Yunhao , Liao Naishun , Tu Haibin , Zheng Youshi , Chen Hengkai , Zeng Yongyi , Zhang Da , Liu Xiaolong
Published: June 2023

Oncolytic virotherapy can lead to tumor lysis and systemic anti-tumor immunity, but the therapeutic potential in humans is limited due to the impaired virus replication and the insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). To solve the above problems, we identified that Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor Navoximod promoted herpes simplex virus type 1 (HSV-1) replication and HSV-1-mediated oncolysis in tumor cells, making it a promising combination modality with HSV-1-based virotherapy. Thus, we loaded HSV-1 and Navoximod together in an injectable and biocompatible hydrogel (V-Navo@gel) for hepatocellular carcinoma (HCC) virotherapy. The hydrogel formed a local delivery reservoir to maximize the viral replication and distribution at the tumor site with a single-dose injection. Notably, V-Navo@gel improved the disease-free survival time of HCC- bearing mice and protects the mice against tumor recurrence. What’s more, V-Navo@gel also showed an effective therapeutic efficacy in the rabbit orthotopic liver cancer model. Mechanistically, we further discovered that our combination strategy entirely reprogramed the TME through single-cell RNA sequencing. All these results collectively indicated that the combination of Navoximod with HSV-1 could boost the viral replication and reshape TME for tumor eradication through the hydrogel reservoir.
Group B Streptococcus Cas9 variants provide insight into programmable gene repression and CRISPR-Cas transcriptional effects
Authors: Gopalakrishna Kathyayini P. , Hillebrand Gideon H. , Bhavana Venkata H. , Elder Jordan L. , D’Mello Adonis , Tettelin Hervé , Hooven Thomas A.
Published: June 2023

Group B Streptococcus (GBS; S. agalactiae) causes chorioamnionitis, neonatal sepsis, and can also cause disease in healthy or immunocompromised adults. GBS possesses a type II-A CRISPR-Cas9 system, which defends against foreign DNA within the bacterial cell. Several recent publications have shown that GBS Cas9 influences genome-wide transcription through a mechanism uncoupled from its function as a specific, RNA-programmable endonuclease. We examine GBS Cas9 effects on genome-wide transcription through generation of several isogenic variants with specific functional defects. We compare whole-genome RNA-seq from Δcas9 GBS with a full-length Cas9 gene deletion; dcas9 defective in its ability to cleave DNA but still able to bind to frequently occurring protospacer adjacent motifs; and scas9 that retains its catalytic domains but is unable to bind protospacer adjacent motifs. Comparing scas9 GBS to the other variants, we identify nonspecific protospacer adjacent motif binding as a driver of genome-wide, Cas9 transcriptional effects in GBS. We also show that Cas9 transcriptional effects from nonspecific scanning tend to influence genes involved in bacterial defense and nucleotide or carbohydrate transport and metabolism. While genome-wide transcription effects are detectable by analysis of next-generation sequencing, they do not result in virulence changes in a mouse model of sepsis. We also demonstrate that catalytically inactive dCas9 expressed from the GBS chromosome can be used with a straightforward, plasmid-based, single guide RNA expression system to suppress transcription of specific GBS genes without potentially confounding off-target effects. We anticipate that this system will be useful for study of nonessential and essential gene roles in GBS physiology and pathogenesis.
Treadmill exercise modulates the medial prefrontal-amygdala neural circuit to improve the resilience against chronic restraint stress
Authors: Luo Zhihua , Chen Junlin , Dai Yelin , So Kwok-Fai , Zhang Li
Published: June 2023

Aerobic exercise effectively ameliorates mental disorders including anxiety and depression. Current findings mainly attribute its neural mechanism to the improvement of adult neurogenesis, while leaving the possible circuitry mechanism unclear. In the current study, we identify the overexcitation of the medial prefrontal cortex (mPFC) to basolateral amygdala (BLA) pathway under chronic restraint stress (CRS), and 14-day treadmill exercise selectively reverses such abnormalities. Using chemogenetic approaches, we find that the mPFC-BLA circuit is necessary for preventing anxiety-like behaviors in CRS mice. These results collectively suggest a neural circuitry mechanism by which exercise training improves the resilience against environmental stress.