bluuebunny/crossref_metadata_2025 huggingface dataset:
Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders
Authors: He Jason L. , Oeltzschner Georg , Mikkelsen Mark , Deronda Alyssa , Harris Ashley D. , Crocetti Deana , Wodka Ericka L. , Mostofsky Stewart H. , Edden Richard A. E. , Puts Nicolaas A. J.
Published: July 2021

Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.
EGR2-mediated regulation of m6A reader IGF2BP proteins drive RCC tumorigenesis and metastasis via enhancing S1PR3 mRNA stabilization
Authors: Ying Yufan , Ma Xueyou , Fang Jiajie , Chen Shiming , Wang Weiyu , Li Jiangfeng , Xie Haiyun , Wu Jian , Xie Bo , Liu Ben , Wang Xiao , Zheng Xiangyi , Xie Liping
Published: July 2021

Emerging discoveries of dynamic and reversible N6-methyladenosine (m6A) modification on RNA in mammals have revealed the key roles of the modification in human tumorigenesis. As known m6A readers, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are upregulated in most cancers and mediates the enhancement of m6A-modified mRNAs stability. However, the mechanisms of IGF2BPs in renal cell cancer (RCC) still remain unclear. Bioinformatic analysis and RT-qPCR were performed to evaluate the expression of IGF2BPs and m6A writer Wilms tumor 1-associating protein (WTAP) in RCC samples and its correlation with patient prognosis. In vitro, in vivo biological assays were performed to investigate the functions of IGF2BPs and WTAP in RCC. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) combined with bioinformatics analysis and following western blot assay, dual-luciferase reporter assays were performed to validate the regulatory relationships between transcription factor (TF) early growth response 2 (EGR2) and potential target genes IGF2BPs. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation-qPCR (MERIP-qPCR), RIP-qPCR, m6A dot blot, and dual-luciferase reporter assays combined with bioinformatics analysis were employed to screen and validate the direct targets of IGF2BPs and WTAP. Here, we showed that early growth response 2 (EGR2) transcription factor could increase IGF2BPs expression in RCC. IGF2BPs in turn regulated sphingosine-1-phosphate receptor 3 (S1PR3) expression in an m6A-dependent manner by enhancing the stability of S1PR3 mRNA. They also promoted kidney tumorigenesis via PI3K/AKT pathway. Furthermore, IGF2BPs and WTAP upregulation predicted poor overall survival in RCC. Our studies showed that the EGR2/IGF2BPs regulatory axis and m6A-dependent regulation of S1PR3-driven RCC tumorigenesis, which enrich the m6A-modulated regulatory network in renal cell cancer. Together, our findings provide new evidence for the role of N6-methyladenosine modification in RCC.
Patient reported psychosocial functioning following successful ptosis surgery
Authors: Richards H. S. , Jenkinson E. , White P. , Harrad R. A.
Published: July 2021

Background

Ptosis may result in increased anxiety, appearance-related distress and social avoidance, and impacts visual function. Previous work demonstrates the benefits of ptosis surgery for health-related quality of life, but there is a paucity of research comparing such outcomes before and after surgery. The aim of this study was to determine potential patient benefits in health-related quality of life, social dysfunction and anxiety following successful ptosis surgery using validated measures.

Methods

Adult ptosis correction surgery patients completed validated measures of appearance-related social anxiety and avoidance, anxiety and depression, and fear of negative evaluation pre-surgery. Following successful surgery, these measures were repeated post-discharge in addition to another health-related quality of life measure.

Results

Of 61 patients recruited, follow-up measures were sent to 33 and completed by 23. Paired samples t-tests demonstrated positive significant changes in appearance-related social distress pre-op m = 30.94, post-op m = 23.67 (t(17) = 3.46, 95% CI 2.84–11.72, p = 0.003), anxiety pre-op m = 7.6, post-op m = 4.9 (t(19) = 4.27, 95% CI 1.38–4.02, p < 0.001) and fear of negative evaluation pre-op m = 34.79, post-op m = 31.26 (t(18) = 2.47, 95% CI 0.52–6.53, p = 0.024). There was no significant difference in depression scores pre-op m = 3.6; post-op m = 3.2 (t(19) = 0.672, 65% CL −0.85 to 1.65, p = 0.510). In total, 85% of patients reported positive benefit to well-being following surgery.

Conclusion

Increasingly, evidence suggests ptosis surgery may benefit patient’s well-being, appearance-related social anxiety and avoidance, as well as improving visual function. These psychosocial benefits should be considered alongside functional benefits in the provision of ptosis surgery.
Pseudomonas aeruginosa PA14 produces R-bodies, extendable protein polymers with roles in host colonization and virulence
Authors: Wang Bryan , Lin Yu-Cheng , Vasquez-Rifo Alejandro , Jo Jeanyoung , Price-Whelan Alexa , McDonald Shujuan Tao , Brown Lewis M. , Sieben Christian , Dietrich Lars E. P.
Published: July 2021

R-bodies are long, extendable protein polymers formed in the cytoplasm of some bacteria; they are best known for their role in killing of paramecia by bacterial endosymbionts. Pseudomonas aeruginosa PA14, an opportunistic pathogen of diverse hosts, contains genes (referred to as the reb cluster) with potential to confer production of R-bodies and that have been implicated in virulence. Here, we show that products of the PA14 reb cluster associate with R-bodies and control stochastic expression of R-body structural genes. PA14 expresses reb genes during colonization of plant and nematode hosts, and R-body production is required for full virulence in nematodes. Analyses of nematode ribosome content and immune response indicate that P. aeruginosa R-bodies act via a mechanism involving ribosome cleavage and translational inhibition. Our observations provide insight into the biology of R-body production and its consequences during P. aeruginosa infection.
SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts
Authors: Sun Jun , Shin Dong Yeon , Eiseman Mark , Yallowitz Alisha R. , Li Na , Lalani Sarfaraz , Li Zan , Cung Michelle , Bok Seoyeon , Debnath Shawon , Marquez Sofia Jenia , White Tommy E. , Khan Abdul G. , Lorenz Ivo C. , Shim Jae-Hyuck , Lee Francis S. , Xu Ren , Greenblatt Matthew B.
Published: July 2021

Hedgehog signaling is essential for bone formation, including functioning as a means for the growth plate to drive skeletal mineralization. However, the mechanisms regulating hedgehog signaling specifically in bone-forming osteoblasts are largely unknown. Here, we identified SLIT and NTRK-like protein-5(Slitrk5), a transmembrane protein with few identified functions, as a negative regulator of hedgehog signaling in osteoblasts. Slitrk5 is selectively expressed in osteoblasts and loss of Slitrk5 enhanced osteoblast differentiation in vitro and in vivo. Loss of SLITRK5 in vitro leads to increased hedgehog signaling and overexpression of SLITRK5 in osteoblasts inhibits the induction of targets downstream of hedgehog signaling. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.
The origin of the boundary strengthening in polycrystal-inspired architected materials
Authors: Liu Chen , Lertthanasarn Jedsada , Pham Minh-Son
Published: July 2021

Crystal-inspired approach is found to be highly successful in designing extraordinarily damage-tolerant architected materials. i.e. meta-crystals, necessitating in-depth fundamental studies to reveal the underlying mechanisms responsible for the strengthening in meta-crystals. Such understanding will enable greater confidence to control not only strength, but also spatial local deformation. In this study, the mechanisms underlying shear band activities were investigated and discussed to provide a solid basis for predicting and controlling the local deformation behaviour in meta-crystals. The boundary strengthening in polycrystal-like meta-crystals was found to relate to the interaction between shear bands and polygrain-like boundaries. More importantly, the boundary type and coherency were found to be influential as they govern the transmission of shear bands across meta-grains boundaries. The obtained insights in this study provide crucial knowledge in developing high strength architected materials with great capacity in controlling and programming the mechanical strength and damage path.
An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer
Authors: Das Rajdeep , Sjöström Martin , Shrestha Raunak , Yogodzinski Christopher , Egusa Emily A. , Chesner Lisa N. , Chen William S. , Chou Jonathan , Dang Donna K. , Swinderman Jason T. , Ge Alex , Hua Junjie T. , Kabir Shaheen , Quigley David A. , Small Eric J. , Ashworth Alan , Feng Felix Y. , Gilbert Luke A.
Published: July 2021

Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.
Large-area patterning of full-color quantum dot arrays beyond 1000 pixels per inch by selective electrophoretic deposition
Authors: Zhao Jinyang , Chen Lixuan , Li Dongze , Shi Zhiqing , Liu Pai , Yao Zhenlei , Yang Hongcheng , Zou Taoyu , Zhao Bin , Zhang Xin , Zhou Hang , Yang Yixing , Cao Weiran , Yan Xiaolin , Zhang Shengdong , Sun Xiao Wei
Published: July 2021

Colloidal quantum dot (QD) emitters show great promise in the development of next-generation displays. Although various solution-processed techniques have been developed for nanomaterials, high-resolution and uniform patterning technology amicable to manufacturing is still missing. Here, we present large-area, high-resolution, full-color QD patterning utilizing a selective electrophoretic deposition (SEPD) technique. This technique utilizes photolithography combined with SEPD to achieve uniform and fast fabrication, low-cost QD patterning in large-area beyond 1,000 pixels-per-inch. The QD patterns only deposited on selective electrodes with precisely controlled thickness in a large range, which could cater for various optoelectronic devices. The adjustable surface morphology, packing density and refractive index of QD films enable higher efficiency compared to conventional solution-processed methods. We further demonstrate the versatility of our approach to integrate various QDs into large-area arrays of full-color emitting pixels and QLEDs with good performance. The results suggest a manufacture-viable technology for commercialization of QD-based displays.
Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection
Authors: De Biasi Sara , Tartaro Domenico Lo , Gibellini Lara , Paolini Annamaria , Quong Andrew , Petes Carlene , Awong Geneve , Douglas Samuel , Lin Dongxia , Nieto Jordan , Galassi Francesco Maria , Borella Rebecca , Fidanza Lucia , Mattioli Marco , Leone Chiara , Neri Isabella , Meschiari Marianna , Cicchetti Luca , Iannone Anna , Trenti Tommaso , Sarti Mario , Girardis Massimo , Guaraldi Giovanni , Mussini Cristina , Facchinetti Fabio , Cossarizza Andrea
Published: July 2021

SARS-CoV-2 infection can affect all human beings, including pregnant women. Thus, understanding the immunological changes induced by the virus during pregnancy is nowadays of pivotal importance. Here, using peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection, we investigate cell proliferation and cytokine production, measure plasma levels of 62 cytokines, and perform a 38-parameter mass cytometry analysis. Our results show an increase in low density neutrophils but no lymphopenia or gross alterations of white blood cells, which display normal levels of differentiation, activation or exhaustion markers and show well preserved functionality. Meanwhile, the plasma levels of anti-inflammatory cytokines such as interleukin (IL)-1RA, IL-10 and IL-19 are increased, those of IL-17, PD-L1 and D-dimer are decreased, but IL-6 and other inflammatory molecules remain unchanged. Our profiling of antiviral immune responses may thus help develop therapeutic strategies to avoid virus-induced damages during pregnancy.
Spin–spin interactions in defects in solids from mixed all-electron and pseudopotential first-principles calculations
Authors: Ghosh Krishnendu , Ma He , Onizhuk Mykyta , Gavini Vikram , Galli Giulia
Published: July 2021

Understanding the quantum dynamics of spin defects and their coherence properties requires an accurate modeling of spin-spin interaction in solids and molecules, for example by using spin Hamiltonians with parameters obtained from first principles calculations. We present a real-space approach based on density functional theory for the calculation of spin-Hamiltonian parameters, where only selected atoms are treated at the all-electron level, while the rest of the system is described with the pseudopotential approximation. Our approach permits calculations for systems containing more than 1000 atoms, as demonstrated for defects in diamond and silicon carbide. We show that only a small number of atoms surrounding the defect needs to be treated at the all-electron level, in order to obtain an overall all-electron accuracy for hyperfine and zero-field splitting tensors. We also present results for coherence times, computed with the cluster correlation expansion method, highlighting the importance of accurate spin-Hamiltonian parameters for quantitative predictions of spin dynamics.
Modelling charge transport and electro-optical characteristics of quantum dot light-emitting diodes
Authors: Jung Sung-Min , Lee Tae Hoon , Bang Sang Yun , Han Soo Deok , Shin Dong-Wook , Lee Sanghyo , Choi Hyung Woo , Suh Yo-Han , Fan Xiang-Bing , Jo Jeong-Wan , Zhan Shijie , Yang Jiajie , Samarakoon Chatura , Kim Yoonwoo , Occhipinti Luigi G. , Amaratunga Gehan , Kim Jong Min
Published: July 2021

Abstracts

Quantum dot light-emitting diodes (QD-LEDs) are considered as competitive candidate for next-generation displays or lightings. Recent advances in the synthesis of core/shell quantum dots (QDs) and tailoring procedures for achieving their high quantum yield have facilitated the emergence of high-performance QD-LEDs. Meanwhile, the charge-carrier dynamics in QD-LED devices, which constitutes the remaining core research area for further improvement of QD-LEDs, is, however, poorly understood yet. Here, we propose a charge transport model in which the charge-carrier dynamics in QD-LEDs are comprehensively described by computer simulations. The charge-carrier injection is modelled by the carrier-capturing process, while the effect of electric fields at their interfaces is considered. The simulated electro-optical characteristics of QD-LEDs, such as the luminance, current density and external quantum efficiency (EQE) curves with varying voltages, show excellent agreement with experiments. Therefore, our computational method proposed here provides a useful means for designing and optimising high-performance QD-LED devices.
Assessment of genetic changes and neurovirulence of shed Sabin and novel type 2 oral polio vaccine viruses
Authors: Wahid Rahnuma , Mercer Laina , Macadam Andrew , Carlyle Sarah , Stephens Laura , Martin Javier , Chumakov Konstantin , Laassri Majid , Petrovskaya Svetlana , Smits Saskia L. , Stittelaar Koert J. , Gast Chris , Weldon William C. , Konopka-Anstadt Jennifer L. , Steven Oberste M. , Van Damme Pierre , De Coster Ilse , Rüttimann Ricardo , Bandyopadhyay Ananda , Konz John
Published: July 2021

Sabin-strain oral polio vaccines (OPV) can, in rare instances, cause disease in recipients and susceptible contacts or evolve to become circulating vaccine-derived strains with the potential to cause outbreaks. Two novel type 2 OPV (nOPV2) candidates were designed to stabilize the genome against the rapid reversion that is observed following vaccination with Sabin OPV type 2 (mOPV2). Next-generation sequencing and a modified transgenic mouse neurovirulence test were applied to shed nOPV2 viruses from phase 1 and 2 studies and shed mOPV2 from a phase 4 study. The shed mOPV2 rapidly reverted in the primary attenuation site (domain V) and increased in virulence. In contrast, the shed nOPV2 viruses showed no evidence of reversion in domain V and limited or no increase in neurovirulence in mice. Based on these results and prior published data on safety, immunogenicity, and shedding, the nOPV2 viruses are promising alternatives to mOPV2 for outbreak responses.
The beneficial effects of menopausal hormone therapy on renal survival in postmenopausal Korean women from a nationwide health survey
Authors: Ahn Shin Young , Choi Yoon Jin , Kim Jieun , Ko Gang Jee , Kwon Young Joo , Han Kyungdo
Published: July 2021

Several studies have demonstrated the nephroprotective effects of estrogen on renal damage. In light of the inconsistent results of previous findings, this study aims to evaluate the in-depth role of menopausal hormone therapy (MHT) on the development of end stage renal disease (ESRD). 3,109,506 Korean adult women who had undergone a medical examination in 2009 (index year) were initially identified for inclusion in this study. We excluded subjects had not experienced menopause naturally, had data missing for at least one variable, and were diagnosed with ESRD within 1 year from the index year. MHT data was obtained from self-reporting questionnaires and the primary outcome was the development of ESRD from the index year until December 31, 2018. A final total of 1,460,311 subjects were included in this study. The participants were divided into four groups according to the duration of MHT; no history of MHT, MHT < 2 years, 2 ≤ MHT < 5 years, MHT ≥ 5 years. During the 9-year study period, a total of 4905 participants developed ESRD. The participants who had a history of MHT use were found to have a 30% reduced risk of developing ESRD. Results from the subgroup analyses were similar to that of the primary study. The findings in this study demonstrate the beneficial effects of MHT on the development of ESRD in postmenopausal women. Based on results, our study may offer suggestions for further studies to investigate the therapeutic options on kidney disease.
Larval cryopreservation as new management tool for threatened clam fisheries
Authors: Heres P. , Troncoso J. , Paredes E.
Published: July 2021

Cryopreservation is the only reliable method for long-term storage of biological material that guarantees genetic stability. This technique can be extremely useful for the conservation of endangered species and restock natural populations for declining species. Many factors have negatively affected the populations of high economical value shellfish in Spain and, as a result, many are declining or threatened nowadays. This study was focused on early-life stages of Venerupis corrugata, Ruditapes decussatus and Ruditapes philippinarum to develop successful protocols to enhance the conservation effort and sustainable shellfishery resources. Firstly, common cryoprotecting agents (CPAs) were tested to select the suitable permeable CPA attending to toxicity. Cryopreservation success using different combinations of CPA solutions, increasing equilibrium times and larval stages was evaluated attending to survival and shell growth at 2 days post-thawing. Older clam development stages were more tolerant to CPA toxicity, being ethylene-glycol (EG) and Propylene-glycol (PG) the least toxic CPAs. CPA solution containing EG yielded the highest post-thawing survival rate and the increase of equilibration time was not beneficial for clam larvae. Cryopreservation of trochophores yielded around 50% survivorship, whereas over 80% of cryopreserved D-larvae were able to recover after thawing.
Maternal biological age assessed in early pregnancy is associated with gestational age at birth
Authors: Lancaster Eva E. , Lapato Dana M. , Jackson-Cook Colleen , Strauss Jerome F. , Roberson-Nay Roxann , York Timothy P.
Published: July 2021

Maternal age is an established predictor of preterm birth independent of other recognized risk factors. The use of chronological age makes the assumption that individuals age at a similar rate. Therefore, it does not capture interindividual differences that may exist due to genetic background and environmental exposures. As a result, there is a need to identify biomarkers that more closely index the rate of cellular aging. One potential candidate is biological age (BA) estimated by the DNA methylome. This study investigated whether maternal BA, estimated in either early and/or late pregnancy, predicts gestational age at birth. BA was estimated from a genome-wide DNA methylation platform using the Horvath algorithm. Linear regression methods assessed the relationship between BA and pregnancy outcomes, including gestational age at birth and prenatal perceived stress, in a primary and replication cohort. Prenatal BA estimates from early pregnancy explained variance in gestational age at birth above and beyond the influence of other recognized preterm birth risk factors. Sensitivity analyses indicated that this signal was driven primarily by self-identified African American participants. This predictive relationship was sensitive to small variations in the BA estimation algorithm. Benefits and limitations of using BA in translational research and clinical applications for preterm birth are considered.
Combined bioinformatics technology to explore pivot genes and related clinical prognosis in the development of gastric cancer
Authors: Xu Jiasheng , Wang Xinlu , Ke Qiwen , Liao Kaili , Wan Yanhua , Zhang Kaihua , Zhang Guanyu , Wang Xiaozhong
Published: July 2021

To screen the key genes in the development of gastric cancer and their influence on prognosis. The GEO database was used to screen gastric cancer-related gene chips as a training set, and the R packages limma tool was used to analyze the differential genes expressed in gastric cancer tissues compared to normal tissues, and then the selected genes were verified in the validation set. The String database was used to calculate their Protein–protein interaction (PPI) network, using Cytoscape software's Centiscape and other plug-ins to analyze key genes in the PPI network. The DAVID database was used to enrich and annotate gene functions of differential genes and PPI key module genes, and further explore correlation between expression level and clinical stage and prognosis. Based on clinical data and patient samples, differential expression of key node genes was verified by immunohistochemistry. The 63 characteristic differential genes screened had good discrimination between gastric cancer and normal tissues, and are mainly involved in regulating extracellular matrix receptor interactions and the PI3k-AKT signaling pathway. Key nodes in the PPI network regulate tumor proliferation and metastasis. Analysis of the expression levels of key node genes found that relative to normal tissues, the expression of ITGB1 and COL1A2 was significantly increased in gastric cancer tissues, and patients with late clinical stages of tumors had higher expression of ITGB1 and COL1A2 in tumor tissues, and their survival time was longer (P < 0.05). This study found that ITGB1 and COL1A2 are key genes in the development of gastric cancer and can be used as prognostic markers and potential new targets for gastric cancer.
Pseudoboehmite as a drug delivery system for acyclovir
Authors: Peres Renato Meneghetti , Sousa Jéssica Maiara Leme , de Oliveira Mariana Oliva , Rossi Maura Vincenza , de Oliveira Rene Ramos , de Lima Nelson Batista , Bernussi Ayrton , Warzywoda Juliusz , Sarmento Bruno , Munhoz Antonio Hortencio
Published: July 2021

Herpes simplex virus is among the most prevalent sexually transmitted infections. Acyclovir is a potent, selective inhibitor of herpes viruses and it is indicated for the treatment and management of recurrent cold sores on the lips and face, genital herpes, among other diseases. The problem of the oral bioavailability of acyclovir is limited because of the low permeability across the gastrointestinal membrane. The use of nanoparticles of pseudoboehmite as a drug delivery system in vitro assays is a promising approach to further the permeability of acyclovir release. Here we report the synthesis of high purity pseudoboehmite from aluminium nitrate and ammonium hydroxide containing nanoparticles, using the sol–gel method, as a drug delivery system to improve the systemic bioavailability of acyclovir. The presence of pseudoboehmite nanoparticles were verified by infrared spectroscopy, transmission electron microscopy, and X-ray diffraction techniques. In vivo tests were performed with Wistar rats to compare the release of acyclovir, with and without the addition of pseudoboehmite. The administration of acyclovir with the addition of pseudoboehmite increased the drug content by 4.6 times in the plasma of Wistar rats after 4 h administration. We determined that the toxicity of pseudoboehmite is low up to 10 mg/mL, in gel and the dried pseudoboehmite nanoparticles.
Procedural outcomes in patients with dual versus single antiplatelet therapy prior to transcatheter aortic valve replacement
Authors: Seoudy Hatim , Thomann Maren , Frank Johanne , Lutz Matthias , Puehler Thomas , Lutter Georg , Müller Oliver J. , Frey Norbert , Saad Mohammed , Frank Derk
Published: July 2021

The impact of uninterrupted dual antiplatelet therapy (DAPT) on bleeding events among patients undergoing transcatheter aortic valve replacement (TAVR) has not been well studied. We conducted an analysis of 529 patients who underwent transfemoral TAVR in our centre and were receiving either DAPT or single antiplatelet therapy (SAPT) prior to the procedure. Accordingly, patients were grouped into a DAPT or SAPT group. Following current guidelines, patients in the SAPT group were switched to DAPT for 90 days after the procedure. The primary endpoint of our analysis was the incidence of bleeding events at 30 days according to the VARC-2 classification system. Any VARC-2 bleeding complications were found in 153 patients (28.9%), while major/life-threatening or disabling bleeding events occurred in 60 patients (11.3%). Our study revealed no significant difference between the DAPT vs. SAPT group regarding periprocedural bleeding complications. Based on multivariable analyses, major bleeding (HR 4.59, 95% CI 1.64–12.83, p = 0.004) and life-threatening/disabling bleeding (HR 8.66, 95% CI 3.31–22.65, p < 0.001) events were significantly associated with mortality at 90 days after TAVR. Both pre-existing DAPT and SAPT showed a comparable safety profile regarding periprocedural bleeding complications and mortality at 90 days. Thus, DAPT can be safely continued in patients undergoing transfemoral TAVR.
A bioimpedance-based monitor for real-time detection and identification of secondary brain injury
Authors: Everitt Alicia , Root Brandon , Calnan Daniel , Manwaring Preston , Bauer David , Halter Ryan
Published: July 2021

Secondary brain injury impacts patient prognosis and can lead to long-term morbidity and mortality in cases of trauma. Continuous monitoring of secondary injury in acute clinical settings is primarily limited to intracranial pressure (ICP); however, ICP is unable to identify essential underlying etiologies of injury needed to guide treatment (e.g. immediate surgical intervention vs medical management). Here we show that a novel intracranial bioimpedance monitor (BIM) can detect onset of secondary injury, differentiate focal (e.g. hemorrhage) from global (e.g. edema) events, identify underlying etiology and provide localization of an intracranial mass effect. We found in an in vivo porcine model that the BIM detected changes in intracranial volume down to 0.38 mL, differentiated high impedance (e.g. ischemic) from low impedance (e.g. hemorrhagic) injuries (p < 0.001), separated focal from global events (p < 0.001) and provided coarse ‘imaging’ through localization of the mass effect. This work presents for the first time the full design, development, characterization and successful implementation of an intracranial bioimpedance monitor. This BIM technology could be further translated to clinical pathologies including but not limited to traumatic brain injury, intracerebral hemorrhage, stroke, hydrocephalus and post-surgical monitoring.
Cooperative roles of introns 1 and 2 of tobacco resistance gene N in enhanced N transcript expression and antiviral defense responses
Authors: Ikeda Chihiro , Taku Kazuo , Miyazaki Tsumugi , Shirai Rikako , Nelson Richard S. , Nyunoya Hiroshi , Matsushita Yasuhiko , Sasaki Nobumitsu
Published: July 2021

The tobacco virus resistance geneNcontains four introns. Transient expression of transcripts from anNtransgene containing these introns and driven by the native promoter in the presence of the elicitor of tobacco mosaic virus resulted in its increased expression. The requirement of the native promoter, the elicitor, or the individual introns for enhanced expression ofNhas not been fully studied. Here, we determined that 35S promoter-drivenNtranscript expression could be enhanced in the presence of the four introns regardless of the co-expression of the virus elicitor in tobacco. Function analyses using a series ofNtransgenes with different combination of introns revealed that the presence of intron 1 more so than intron 2 allowed higher accumulation of premature and matureNtranscripts; however, both introns were important for not only enhanced gene expression but also for induction of cell death in tobacco and induced local resistance to spread of virus inNicotiana benthamiana. Our findings indicate that introns 1 and 2 cooperatively contribute toNexpression and virus resistance.
Rapid statistical discrimination of fluorescence images of T cell receptors on immobilizing surfaces with different coating conditions
Authors: Saed Badeia , Munaweera Rangika , Anderson Jesse , O’Neill William D. , Hu Ying S.
Published: July 2021

The spatial organization of T cell receptors (TCRs) correlates with membrane-associated signal amplification, dispersion, and regulation during T cell activation. Despite its potential clinical importance, quantitative analysis of the spatial arrangement of TCRs from standard fluorescence images remains difficult. Here, we report Statistical Classification Analyses of Membrane Protein Images or SCAMPI as a technique capable of analyzing the spatial arrangement of TCRs on the plasma membrane of T cells. We leveraged medical image analysis techniques that utilize pixel-based values. We transformed grayscale pixel values from fluorescence images of TCRs into estimated model parameters of partial differential equations. The estimated model parameters enabled an accurate classification using linear discrimination techniques, including Fisher Linear Discriminant (FLD) and Logistic Regression (LR). In a proof-of-principle study, we modeled and discriminated images of fluorescently tagged TCRs from Jurkat T cells on uncoated cover glass surfaces (Null) or coated cover glass surfaces with either positively charged poly-L-lysine (PLL) or TCR cross-linking anti-CD3 antibodies (OKT3). Using 80 training images and 20 test images per class, our statistical technique achieved 85% discrimination accuracy for both OKT3 versus PLL and OKT3 versus Null conditions. The run time of image data download, model construction, and image discrimination was 21.89 s on a laptop computer, comprised of 20.43 s for image data download, 1.30 s on the FLD-SCAMPI analysis, and 0.16 s on the LR-SCAMPI analysis. SCAMPI represents an alternative approach to morphology-based qualifications for discriminating complex patterns of membrane proteins conditioned on a small sample size and fast runtime. The technique paves pathways to characterize various physiological and pathological conditions using the spatial organization of TCRs from patient T cells.
Interactions of platelets with circulating tumor cells contribute to cancer metastasis
Authors: Anvari Sina , Osei Ernest , Maftoon Nima
Published: July 2021

Recent studies have suggested that platelets have a crucial role in enhancing the survival of circulating tumor cells in the bloodstream and aggravating cancer metastasis. The main function of platelets is to bind to the sites of the damaged vessels to stop bleeding. However, in cancer patients, activated platelets adhere to circulating tumor cells and exacerbate metastatic spreading. Several hypotheses have been proposed about the platelet–cancer cell interactions, but the underlying mechanisms of these interactions are not completely understood yet. In this work, we quantitatively investigated the interactions between circulating tumor cells, red blood cells, platelets, plasma flow and microvessel walls via computational modelling at the cellular scale. Our highly detailed computational model allowed us to understand and quantitatively explain the role of platelets in deformation, adhesion and survival of tumor cells in their active arrest to the endothelium.
CRISPR/Cas9-based genetic screen of SCNT-reprogramming resistant genes identifies critical genes for male germ cell development in mice
Authors: Akter Most Sumona , Hada Masashi , Shikata Daiki , Watanabe Gen , Ogura Atsuo , Matoba Shogo
Published: July 2021

Male germ cells undergo complex developmental processes eventually producing spermatozoa through spermatogenesis, although the molecular mechanisms remain largely elusive. We have previously identified somatic cell nuclear transfer-reprogramming resistant genes (SRRGs) that are highly enriched for genes essential for spermatogenesis, although many of them remain uncharacterized in knockout (KO) mice. Here, we performed a CRISPR-based genetic screen using C57BL/6N mice for five uncharacterized SRRGs (Cox8c, Cox7b2, Tuba3a/3b, Faiml, and Gm773), together with meiosis essential gene Majin as a control. RT-qPCR analysis of mouse adult tissues revealed that the five selected SRRGs were exclusively expressed in testis. Analysis of single-cell RNA-seq datasets of adult testis revealed stage-specific expression (pre-, mid-, or post-meiotic expression) in testicular germ cells. Examination of testis morphology, histology, and sperm functions in CRISPR-injected KO adult males revealed that Cox7b2, Gm773, and Tuba3a/3b are required for the production of normal spermatozoa. Specifically, Cox7b2 KO mice produced poorly motile infertile spermatozoa, Gm773 KO mice produced motile spermatozoa with limited zona penetration abilities, and Tuba3a/3b KO mice completely lost germ cells at the early postnatal stages. Our genetic screen focusing on SRRGs efficiently identified critical genes for male germ cell development in mice, which also provides insights into human reproductive medicine.
Osseodensification enables bone healing chambers with improved low-density bone site primary stability: an in vivo study
Authors: Mello-Machado Rafael Coutinho , Sartoretto Suelen Cristina , Granjeiro Jose Mauro , Calasans-Maia José de Albuquerque , de Uzeda Marcelo Jose Pinheiro Guedes , Mourão Carlos Fernando de Almeida Barros , Ghiraldini Bruna , Bezerra Fabio Jose Barbosa , Senna Plinio Mendes , Calasans-Maia Mônica Diuana
Published: July 2021

Primary implant stability is a prerequisite for successful implant osseointegration. The osseodensification technique (OD) is a non-subtractive drilling technique that preserves the bone tissue, increases osteotomy wall density, and improves the primary stability. This study aimed to investigate the hypothesis that OD, through a wider osteotomy, produces healing chambers (HCs) at the implant-bone interface without impacting low-density bone primary stability. Twenty implants (3.5 × 10 mm) with a nanohydroxyapatite (nHA) surface were inserted in the ilium of ten sheep. Implant beds were prepared as follows: (i) 2.7-mm-wide using subtractive conventional drilling (SCD) technique (n = 10); (ii) 3.8-mm-wide using an OD bur system (n = 10). The sheep were randomized to two groups, with samples collected at either 14-(n = 5) or 28-days (n = 5) post-surgery and processed for histological and histomorphometric evaluation of bone-implant contact (BIC) and bone area fraction occupancy (BAFO). No significant group differences were found with respect to final insertion torque and implant stability quotient (p > 0.050). BIC values were higher for SCD after 14 and 28 days (p < 0.050); however, BAFO values were similar (p > 0.050). It was possible to conclude that the OD technique allowed a wider implant bed preparation without prejudice on primary stability and bone remodeling.
Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries
Authors: Hsu Hung-Ju , Tung Chao-Ping , Yu Chung-Ming , Chen Chi-Yung , Chen Hong-Sen , Huang Yu-Chuan , Tsai Pei-Hsun , Lin Su-I , Peng Hung-Pin , Chiu Yi-Kai , Tsou Yueh-Liang , Kuo Wei-Ying , Jian Jhih-Wei , Hung Fei-Hung , Hsieh Chiao-Yun , Hsiao Michael , Chuang Simon Shih-Hsien , Shen Chia-Ning , Wang Yong Alison , Yang An-Suei
Published: July 2021

Mesothelin (MSLN) is an attractive candidate of targeted therapy for several cancers, and hence there are increasing needs to develop MSLN-targeting strategies for cancer therapeutics. Antibody–drug conjugates (ADCs) targeting MSLN have been demonstrated to be a viable strategy in treating MSLN-positive cancers. However, developing antibodies as targeting modules in ADCs for toxic payload delivery to the tumor site but not to normal tissues is not a straightforward task with many potential hurdles. In this work, we established a high throughput engineering platform to develop and optimize anti-MSLN ADCs by characterizing more than 300 scFv CDR-variants and more than 50 IgG CDR-variants of a parent anti-MSLN antibody as candidates for ADCs. The results indicate that only a small portion of the complementarity determining region (CDR) residues are indispensable in the MSLN-specific targeting. Also, the enhancement of the hydrophilicity of the rest of the CDR residues could drastically increase the overall solubility of the optimized anti-MSLN antibodies, and thus substantially improve the efficacies of the ADCs in treating human gastric and pancreatic tumor xenograft models in mice. We demonstrated that the in vivo treatments with the optimized ADCs resulted in almost complete eradication of the xenograft tumors at the treatment endpoints, without detectable off-target toxicity because of the ADCs’ high specificity targeting the cell surface tumor-associated MSLN. The technological platform can be applied to optimize the antibody sequences for more effective targeting modules of ADCs, even when the candidate antibodies are not necessarily feasible for the ADC development due to the antibodies’ inferior solubility or affinity/specificity to the target antigen.
Diagnostic and prognostic significance of serum angiopoietin-1 and -2 concentrations in patients with pulmonary hypertension
Authors: Enomoto Noriyuki , Suzuki Seiichiro , Hozumi Hironao , Karayama Masato , Suzuki Yuzo , Furuhashi Kazuki , Fujisawa Tomoyuki , Nakamura Yutaro , Odagiri Keiichi , Ishikawa Takamichi , Kataoka Kensuke , Kondoh Yasuhiro , Maekawa Masato , Inui Naoki , Watanabe Hiroshi , Suda Takafumi
Published: July 2021

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p < 0.001), right ventricular diameter on echocardiography (r = 0.565, p = 0.035), and mean pulmonary arterial pressure (r = 0.449, p = 0.032) and pulmonary vascular resistance (r = 0.451, p = 0.031) on right-heart catheterization. ANGP-1 and ANGP-2 were expressed on lung vascular endothelial cells, as shown by immunohistochemistry. Patients with PH with higher ANGP-2 concentration (≥ 2.48 ng/mL) had significantly worse survival (p = 0.022). Higher ANGP-2 concentration was a significant worse prognostic factor (hazard ratio = 6.063, p = 0.037), while serum ANGP-1 concentration was not. In conclusion, serum ANGP-2 may be a useful diagnostic and prognostic biomarker in patients with PH, especially in patients with group 3 PH.
Exercise training mitigates ER stress and UCP2 deficiency-associated coronary vascular dysfunction in atherosclerosis
Authors: Hong Junyoung , Park Eunkyung , Lee Jonghae , Lee Yang , Rooney Bridgette V. , Park Yoonjung
Published: July 2021

Endoplasmic reticulum (ER) stress and uncoupling protein-2 (UCP2) activation are opposing modulators of endothelial dysfunction in atherosclerosis. Exercise reduces atherosclerosis plaques and enhances endothelial function. Our aim was to understand how exercise affects ER stress and UCP2 activation, and how that relates to endothelial dysfunction in an atherosclerotic murine model. Wild type (C57BL/6, WT) and apolipoprotein-E-knockout (ApoEtm1Unc, ApoE KO) mice underwent treadmill exercise training (EX) or remained sedentary for 12 weeks. Acetylcholine (ACh)-induced endothelium-dependent vasodilation was determined in the presence of an eNOS inhibitor (L-NAME), UCP2 inhibitor (genipin), and ER stress inducer (tunicamycin). UCP2, ER stress markers and NLRP3 inflammasome signaling were quantified by western blotting. p67phox and superoxide were visualized using immunofluorescence and DHE staining. Nitric oxide (NO) was measured by nitrate/nitrite assay. ACh-induced vasodilation was attenuated in coronary arterioles of ApoE KO mice but improved in ApoE KO-EX mice. Treatment of coronary arterioles with L-NAME, tunicamycin, and genipin significantly attenuated ACh-induced vasodilation in all mice except for ApoE KO mice. Exercise reduced expression of ER stress proteins, TXNIP/NLRP3 inflammasome signaling cascades, and Bax expression in the heart of ApoE KO-EX mice. Further, exercise diminished superoxide production and NADPH oxidase p67phox expression in coronary arterioles while simultaneously increasing UCP2 expression and nitric oxide (NO) production in the heart of ApoE KO-EX mice. Routine exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles in an eNOS, UCP2, and ER stress signaling specific manner, and resulting in reduced TXNIP/NLRP3 inflammasome activity and oxidative stress.
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood
Authors: Latorre-Pellicer Ana , Gil-Salvador Marta , Parenti Ilaria , Lucia-Campos Cristina , Trujillano Laura , Marcos-Alcalde Iñigo , Arnedo María , Ascaso Ángela , Ayerza-Casas Ariadna , Antoñanzas-Pérez Rebeca , Gervasini Cristina , Piccione Maria , Mariani Milena , Weber Axel , Kanber Deniz , Kuechler Alma , Munteanu Martin , Khuller Katharina , Bueno-Lozano Gloria , Puisac Beatriz , Gómez-Puertas Paulino , Selicorni Angelo , Kaiser Frank J. , Ramos Feliciano J. , Pié Juan
Published: July 2021

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.