bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.68.A Hemangiopericytoma, case series and clinic-pathological analysis
Authors: Redaelli V , Calatozzolo C , Marucci G , Pinzi V , Gaviani P , Botturi A , Simonetti G , Mattei L , Pollo B , Silvani A
Published: September 2022

Background

Hemangiopericytoma (HPC) is an extremely rare aggressive tumor of mesenchymal origin, which constitutes less than 1% of primary tumors of the central nervous system. Typically it occurs in young adults (mean age at diagnosis 30-50 years). Initially described as gemmangiomas, was first called hemangiopericytoma in 1942 but it was considered as a variant of meningioma until 1993 when it was finally recognized as a distinct clinical-pathological entity by the World Health Organization (WHO). In 2016, there was the unification of both HPC and Solitary Fibrous Tumor (SFT) in a single spectrum of rare and thick mesenchymal tumors due to the identification, in both tumoral types, of a molecular alteration called NAB2-STAT6 fusion.

Material and Methods

The present study is a case series of patients that received a pathological diagnosis of SFT/HPC at our Institute from 1981 to 2020. Clinical data included: demographic data, tumor characteristics and treatment modality. Hystological diagnosis and immunohistochemistry allowed to confirm diagnosis, based on the 2016 WHO classification. Haematoxylin staining was completed with immunohistochemistry with primary antibodies for STAT 6 and evaluation of presence of tumor necrosis. Statistical analysis was conducted considering age at first diagnosis, treatment modality, extent of tumor resection, presence of necrosis in histological analysis compared to PFS-1, OS and relapses number.

Results

The case series was composed by 82 patients (46 men and 36 women) with median age of 43 (± 20) that accede to our Institute from 1981 to 2020. Our statistical analysis showed significative correlation between age, extend of tumor resection and presence of necrosis with OS and relapses number.

Conclusion

Hemangiopericytoma is a very rare cerebral tumors, and for this reason large case series are not disposable in literature. In our study we collected all disposable data of every patient with pathological diagnosis of SFT/HPC acceded to our hospital in the long period of 39 years in the aim to verify the presence of significative correlations. We observed strong correlation between tumor resection and presence of necrosis in tumor tissue with prognosis parameters (OS and number of relapses). This result it could be important to conduct the decisional process about treatment after surgical resection, considering also pathological features, rather than only surgical resection.
P12.04.A Exosomes from glioma associated sphere forming cells induce a transition of invasive phenotype via transfer of EMP2 and CA9
Authors: Kang S , Ryu B , Sa J , Kim H , Park K , Yu S , Hong D , Kim K
Published: September 2022

Background

Glioblastoma multiforme (GBM) mostly occurs local recurrence at normal parenchyme adjacent tumor despite of conventional treatment. Glioma stem like cells (GSC) forming intratumoral heterogeneity within the GBM acquired the microenvironmental adaptation by inter-exosomal contents exchange between heterogenic cells. In addition, GSC has an invasive potential as like human GBM. Therefore, we investigate whether exosomal proteins of GSC affect the normal tissue invasion in GBM.

Material and Methods

Exosomes were isolated by Size-Exclusion method from conditioned media and validated by Electron microscope and Immunoblot assay. Exosomal proteomics were examined with Liquid Chromatography-Mass Spectrometry (LC/MS). To produce the fluorescent exosome, bi-cistron vectors were cloned with shRNA and CD63-GFP. To identify the effect of tranfected exosome, the isolated exosomes were treated to recipient cells and examined the invasion by 3D invasion assay and mouse intracranial model.

Results

Firstly, we dichotomized two groups following tumor invasion at matrigel assay and GSC derived orthotopic mouse model. CSC2 and X01 GSCs revealed highly invasive phenotype whereas 83NS and 528NS GSCs did not. Exosome was isolated in each group and identified by CD63 expression or electron microscopy. In proteomics analysis, hypoxia, extracellular matrix organization, GTPase cycle related proteins were enriched in highly invasive cell’s exosome. Among them, we focused the carbonic anhydrase IX (CA9) and the epithelial membrane protein 2 (EMP2) on its permissive role to glioblastoma invasion respectively. CA9 and EMP2 mRNA and protein levels were verified in GSCs and their exosomes and the high expression levels were detected in CSC2 and X01 compared to the low one in 83NS and 528NS GSCs. To evaluate the effects of CA9 and EMP2 on exosome mediated invasion potential, viral bi-cistron vectors was composed with the target gene knockdown and the CD63 fluorescence was used to detect intracellular exosome transfer. Interestingly, the decreased expression of phosphorylated FAK, a key invasive marker, was observed after Lentiviral mediated CA9- and EMP2-knockdown in highly invasive CSC2. To identify whether CA9 and EMP2 proteins are the intracellular effector protein responsible for exosome mediated glioma invasion, the donor exosomes (Exo-CSC2-sh-CA9 and Exo-CSC2-EMP2, after Lentiviral transfection to CSC2s) were isolated and treated to the non invasive 528NS cells as recipient cells. In 3D invasion assay, Exo-CSC2-shCA9 or Exo-CSC2-shEMP2 mediated tumor invasion was significantly decreased at 528NS GSCs compared to Exo-CSC2-shEV. These features were found at mouse intracranial model as well.

Conclusion

Together with these, we conclude that exosome derived from GSCs induces a transition of invasive phenotype via transfer of EMP2 and CA9 proteins.
An SNW/SKI-INTERACTING PROTEIN influences endoreduplication and cell growth in Arabidopsis
Authors: Jiang Shan , Meng Bolun , Zhang Yilan , Li Na , Zhou Lixun , Zhang Xuan , Xu Ran , Guo Siyi , Song Chun-Peng , Li Yunhai
Published: September 2022

Endoreduplication plays an important role in cell growth and differentiation, but the mechanisms regulating endoreduplication are still elusive. We have previously reported that UBIQUITIN-SPECIFIC PROTEASE14 (UBP14) encoded by DA3 interacts with ULTRAVIOLETB INSENSITIVE4 (UVI4) to influence endoreduplication and cell growth in Arabidopsis (Arabidopsis thaliana). The da3-1 mutant possesses larger cotyledons and flowers with higher ploidy levels than the wild-type. Here, we identify the suppressor of da3-1 (SUPPRESSOR OF da3-1 3; SUD3), which encodes SNW/SKI-INTERACTING PROTEIN (SKIP). Biochemical studies demonstrate that SUD3 physically interacts with UBP14/DA3 and UVI4 in vivo and in vitro. Genetic analyses support that SUD3 acts in a common pathway with UBP14/DA3 and UVI4 to control endoreduplication. Our findings reveal an important genetic and molecular mechanism by which SKIP/SUD3 associates with UBP14/DA3 and UVI4 to modulate endoreduplication.
Long-term outcomes in Rheumatoid Arthritis: Review of data from the ‘Basildon Inflammatory Arthritis Cohort’
Authors: Jain Kanishk , Laila Deena , Nandagudi Anupama , Bharadwaj Anurag
Published: September 2022

Objective

The aim was to determine outcomes in RA with long-term analysis of a real-world inception cohort.

Methods

We carried out a retrospective cohort analysis of 184 patients with a new diagnosis of RA (ACR/EULAR 2010 criteria) between 2009 and 2013. Measured parameters included patient demographics, serological markers, disease activity (DAS28-CRP), treatment regimen, development of new co-morbidities and all-cause mortality.

Results

Complete data were available for analysis in 171 patients, 60 men and 111 women, with a median age of 57 years and median follow-up time of 7.5 years. DAS-28 remission was achieved in 73%, with the majority continuing to require pharmacological therapy. Drug-free remission was achieved in 11.7%, whereas 3.5% remained refractory to treatment. Analysis of new co-morbidities revealed malignancy in 12.9% (n = 22), with lung cancer having the highest incidence (n = 9). Cardiovascular, pulmonary and cerebrovascular disease developed in 11.1% (n = 19), 5.8% (n = 10) and 5.3% (n = 9), respectively. The crude mortality rate was 19.3% (33 of 171), incidence mortality rate 174 per 10 000 person-years of follow-up and standardized mortality ratio 1.57 (95% CI 1.10, 2.17). More deaths were recorded from underlying malignancy [7.6% (n = 13)] than with cardiovascular disease [4.7% (n = 8)]. The majority of deaths occurred ≥5 years after initial diagnosis (67%).

Conclusion

Long-term analysis reveals that mortality in RA remains significantly elevated compared with the general population. Additionally, this real-world study underlines malignancy as the predominant cause of morbidity and mortality in RA.
Contribution of Organ-Based Tube Current Modulation to the Reduction of Lens Exposure Dose in Head 4D CT Imaging: A Phantom Study
Authors: Nagamoto Keisuke , Watanabe Ryo , Kawachino Tomonori , Ohishi Yoshitaka , Yamamoto Aina , Moritake Takashi , Nihei Shun-ichi , Kamochi Masayuki , Kunugita Naoki
Published: September 2022

The purpose of this study was to evaluate the effectiveness of organ effect modulation (OEM) in reducing the lens dose in 4D computed tomography (CT) of the head in volume-acquisition (NVA) mode. Six radiophotoluminescent dosemeters were placed on the head of a RANDO phantom. The doses absorbed by the organs and image noise change rate were determined. The lens doses without OEM (i.e. in the OEMoff case) were higher than those with the same target standard deviation and volume-computed tomography dose index (CTDIvol) as in the OEMoff case (p < 0.01). The image noise change rate was 11%. OEM reduced the lens dose during head 4D CT imaging in the NVA mode by 18%. Furthermore, the feasibility of lens dose reduction while ensuring sufficient image quality was confirmed under the condition in which OEM was employed with the same CTDIvol as in the OEMoff case.
On Understanding in Mathematics
Authors: Schaathun Hans Georg
Published: September 2022

It is often difficult to teach mathematics for understanding. Many students seem to prefer to learn computational skills by rote, and seem to remember very little of the course contents the following semester. The reasons for this are surely manifold. This paper reviews the concept of understanding, looking particularly towards the meaning it has in hermeneutic philosophy. The known distinction between hermeneutical and epistemological understanding is resituated in mathematics, and we argue that it is the hermeneutic understanding which is most relevant when mathematics is taught as a support subject for engineering and other professions.
Resveratrol alleviates Ang II-induced vascular smooth muscle cell senescence by upregulating E2F1/SOD2 axis
Authors: Liu Lei , Yang Xiuhua , Liao Yiyang , Wang Chuanhua , Wang Yuanliang
Published: September 2022

Background

Vascular smooth muscle cells (VSMCs) senescence is a crucial factor relevant to accelerate cardiovascular diseases. Resveratrol (RES) has been reported that could obstruct vascular senescence. However, the detailed molecular mechanisms of RES in VSMCs senescence are still indistinct and deserve further investigations.

Methods and Results

In this study, VSMCs were treated with 100 nM angiotensin II (Ang II) for 3 days and then followed with a range of different concentrations of RES (0.5, 5, 15, 25, 35, 50 μM), and 25 μM of RES was chose for following experiments. We found that the E2F1 and SOD2 expressions were reduced in Ang II-induced VSMCs. RES treatment impeded Ang II-induced oxidative stress and mitochondrial dysfunction through elevating E2F1 and SOD2 expression, thereby alleviating VSMCs senescence. Additionally, E2F1 knockdown reversed the protective effects of RES on VSMCs senescence caused by Ang II administration. Ch-IP assay and dual luciferase reporter gene assay validated that E2F1 could bind to the promoter region of SOD2. Furthermore, E2F1 or SOD2 overexpression blocked Ang II-induced on VSMCs senescence.

Conclusion

In conclusion, RES mitigated Ang II-induced VSMCs senescence by suppressing oxidative stress and mitochondrial dysfunction through activating E2F1/SOD2 axis. Our study disclosed that RES might be a potential drug and the axis of its regulatory mechanism might be therapeutic targets for postponing vascular senescence.
Occurrence of Brown Rot of American Plum Caused by Monilinia fructicola in Missouri
Authors: Patel Jaimin S. , Tian Peng , Navarrete-Tindall Nadia , Bartelette W. Sue
Published: September 2022

Prunus americana (wild plum) is commonly found in Missouri and many other U.S. states from Texas to Massachusetts. In May 2022, P. americana fruits exhibiting brown rot symptoms were observed in Cole County, Missouri. The symptoms include brown rot and mummified fruits. Advanced symptoms include fruits covered with fungal growth. A single-spore isolate (PAM-1) was recovered from fruits showing brow rot symptoms. The PAM-1 isolate cultured on potato dextrose agar (PDA) grew a 100 mm diameter Petri dish in seven days. The colony was off-white to light brown in color, circular, and showed concentric rings. The colony had entire margins and produced abundant conidia on PDA. The conidia ( n = 50) were 12.07 µm long and 7.64 µm wide. The conidia are oblong to lemon-shaped and hyaline. The polymerase chain reaction with ITS1 and ITS4 primers generated 508 bp DNA sequence which showed 100% identity to Monilinia fructicola (GenBank accession nos. FJ515894.1 and EF207419.1). Pathogenicity tests on both wounded and unwounded fruits exhibited similar symptoms. Control fruits did not show any symptoms. Based on the disease symptoms, pathogen morphology, molecular characterization, and pathogenicity test the pathogen was identified as M. fructicola. To our knowledge, this is the first scientific report showing M. fructicola as a causal organism of brown rot of wild plum in Missouri.
RHEGMATOGENOUS RETINAL DETACHMENT AFTER INJECTION OF TISSUE PLASMINOGEN ACTIVATOR AND GAS FOR SUBMACULAR HEMORRHAGE SECONDARY TO AGE-RELATED MACULAR DEGENERATION
Authors: Manrique-Lipa Roslyn , Jasim Haneen , Safi Antoine , Liyanage Sidath E. , Keller Johannes
Published: September 2022

Purpose:

The purpose of this study was to describe the rate, clinical characteristics, and outcomes of rhegmatogenous retinal detachment (RRD) after injection of tissue plasminogen activator (TPA) and gas for submacular hemorrhage displacement.

Methods:

Retrospective analysis of consecutive cases developing RRD after TPA injection and gas for submacular hemorrhage displacement. The rate of RRD was calculated, and a description of RRD clinical characteristics was performed. Anatomic and visual outcomes after RRD repair were analyzed.

Results:

Ninety eyes of 90 patients were analyzed. Tissue plasminogen activator was given intravitreally in 53 eyes (59%) and subretinally in 37 eyes (41%). RRD occurred in 6 of 90 eyes (7%). Of these, one had intravitreal TPA and five had vitrectomy with subretinal TPA (P = 0.04). The mean age was 75 (64–93) years. The median time of RRD occurrence was 42 (1–134) days. All cases had macular involvement. Two cases had PVR at presentation. Vitrectomy was performed in all cases and silicone oil used in five, all of which resulted in permanent silicone oil retention. One case (17%) achieved primary single surgery success. The median final visual acuity was 1.8 logMAR (20/1,260 Snellen).

Conclusion:

The RRD rate after submacular hemorrhage displacement was 7% in our case series. Rhegmatogenous retinal detachment occurred more commonly after vitrectomy with subretinal TPA injection. The visual and anatomic outcomes were poor, with a high rate of retained silicone oil and recurrent RRD.
Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn’s disease
Authors: ten Bokkel Huinink Sebastiaan , de Jong Djuna C. , Nieboer Daan , Thomassen Doranne , Steyerberg Ewout W. , Dijkgraaf Marcel G.W. , Bodelier Alexander G.L. , West Rachel L. , Römkens Tessa E.H. , Hoentjen Frank , Mallant Rosalie C. , van Tuyl Bas A.C. , Mares Wout G.N. , Wolfhagen Frank H.J. , Dijkstra Gerard , Reijnders Jurriën G.P. , de Boer Nanne K. , Tan Adriaan C.I.T.L. , van Boeckel Petra G.A. , Tack Greetje J. , van Asseldonk Dirk P. , D’Haens Geert R.A.M. , van der Woude C Janneke , Duijvestein Marjolijn , de Vries Annemarie C
Published: September 2022

Background

Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn’s disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy.

Methods

We performed a retrospective cohort study in 17 Dutch hospitals. Crohn’s disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis.

Results

486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54–0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28–0.76)]. After an update, a c-statistic of 0.60 (0.58–0.63) and calibration slope of 0.89 (0.69–1.09) were reported in internal-external validation.

Conclusion

Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn’s disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.
Validating the prognostic value of Freiburg index of posttransjugular intrahepatic portosystemic shunt survival score and classic scores in Chinese patients with implantation of transjugular intrahepatic portosystemic shunt
Authors: Song Jinlei , Wang Xiaoze , Yan Yuling , Xiang Tong , Luo Xuefeng
Published: September 2022

Background and aims

It is important and challenging to evaluate the survival of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). We aimed to validate the Freiburg index of post-TIPS survival (FIPS) score and classic scores for predicting mortality in Chinese patients after TIPS creation.

Methods

A total of 709 consecutive patients with cirrhosis from December 2011 to July 2018 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the FIPS score, the model for end-stage liver disease (MELD) score, Child-Pugh score and Chronic Liver Failure Consortium Acute Decompensation score was validated with the receiver operating characteristic (ROC) curve and DeLong et al. test.

Results

The MELD-Na score was superior to the FIPS score in predicting 1-month mortality [AUROC, 0.727 (0.692–0.759) vs. 0.588 (0.551–0.625); P = 0.048]. The MELD and MELD-Na scores were significant superior to the FIPS score in predicting 3-month mortality [AUROC, 0.730 (0.696–0.762) vs. 0.598 (0.561–0.634); P = 0.044 and 0.740 (0.706–0.772) vs. 0.598 (0.561–0.634); P = 0.028]. Subgroup analyses revealed that Child-Pugh score was better than FIPS score in predicting 3-month mortality [AUROC, 0.797 (0.745–0.843) vs. 0.578 (0.517–0.637); P = 0.049] in nonviral cirrhosis group.

Conclusion

Classic scores still had good risk stratification and predictive ability of post-TIPS mortality. The FIPS score was not superior to the classic scores in the current Chinese cohort. The MELD and MELD-Na scores were significantly superior to the FIPS score in predicting 3-month mortality.
Comparison of the safety and efficacy of YEARS, PEGeD, 4PEPS or the sole item “PE is the most likely diagnosis” strategies for the diagnosis of pulmonary embolism in the emergency department: post-hoc analysis of two European cohort studies
Authors: Roussel Mélanie , Gorlicki Judith , Douillet Delphine , Moumneh Thomas , Bérard Laurence , Cachanado Marine , Chauvin Anthony , Roy Pierre-Marie , Freund Yonathan
Published: September 2022

Background

The optimal strategy for the diagnosis of pulmonary embolism (PE) in the emergency department (ED) remains debated. To reduce the need of imaging testing, several rules have been recently validated using an elevated D-dimer threshold.

Objective:

To validate the safety of different diagnostic strategies and compare the efficacy in terms of chest imaging testing.

Design and patients:

Post-hoc analysis of individual data of 3330 adult patients without a high clinical probability of PE in the ED followed-up at 3 months in France and Spain (1916 from the PROPER cohort, 1414 from the MODIGLIANI cohort).

Exposure:

Four diagnostic strategies with an elevated D-dimer threshold if PE is unlikely. The YEARS combined with Pulmonary Embolism Rule-out Criteria (PERC) the pulmonary embolism graduated D-dimer (PEGeD) combined with PERC and the 4-level pulmonary embolism probability score (4PEPS) rules were assessed. A modified simplified (MODS) rule with a simplified YEARS reduced to the sole item of “Is PE the most likely diagnosis” combined with PERC was also tested.

Outcome measure and analysis:

The primary outcome was the proportion of diagnosed PE or deep venous thrombosis at 3 months in patients in whom PE could have been excluded without chest imaging according to the tested strategy. The safety of a strategy was confirmed if the failure rate was less than 1.85%. The secondary outcome was the use of imaging testing according to each rule.

Results:

Among 3330 analyzed patients, 150 (4.5%) had a PE. The number of missed PEs were 25, 29, 30 and 26 for the PERC+YEARS, PERC+PEGeD, 4PEPS and MODS rules respectively, with a failure rate of 0.75% (95% CI 0.51% to 1.10%), 0.87% (0.61% to 1.25%), 0.90% (0.63% to 1.28%) and 0.78% (0.53% to 1.14%) respectively. There was no significant difference in the failure rate between rules. Except for a significant lower use of chest imaging for 4PEPS compared to YEARS (14.9% vs 16.3%, difference -1.4% [95%CI -2.1% to -0.8%]), there was no difference in the proportion of imaging testing.

Conclusion:

In this post-hoc analysis of patients with suspicion of PE, YEARS and PEGeD combined with PERC, and 4PEPS were safe to exclude PE. The safety of the modified simplified MODS strategy was also confirmed. There was no significant difference of the failure rate between strategies.
Hip subluxation in Italian cerebral palsy children and its determinants: a retrospective cohort study
Authors: Faccioli Silvia , Sassi Silvia , Ferrari Adriano , Corradini Elena , Toni Francesca , Kaleci Shaniko , Lombardi Francesco , Benedetti Maria Grazia
Published: September 2022

The study’s aim was two-fold: to describe the trend of hip subluxation in the largest sample of Italian nonambulatory cerebral palsy (CP) children ever published; to investigate its determinants. This single-centre retrospective cohort study included patients with spastic or dyskinetic CP, Gross Motor Function Classification System (GMFCS) level IV or V, age 0–18 years, having been referred to our unit before March 2020. The hip subluxation was measured by means of the migration percentage (MP). Other data were gathered such as sex, CP subtype, GMFCS level, presence of drug-resistant epilepsy, age, use of walkers with weight relief or standing devices, previous botulinum injection or hip surgery, oral or intrathecal baclofen and hip pain. Multiple linear stepwise regression was performed and descriptive statistics are provided. Spastic CP had MP maximum increase in early ages, with GMFCS level V values persistently higher than level IV. The dyskinetic subtype showed a slower increase of the MP, with GMFCS level IV presenting similar or higher values, compared to level V. Age, CP severity and spastic subtype are the main determinants. The stepwise multiple regression analysis demonstrated that weight relief walking and standing assistive devices, combined with botulinum contributed to reduce the MP progression. Dyskinetic CP showed overall lower MP values and a more variable behaviour relative to age and GMFCS level, compared to the spastic subtype. Standing and walking assistive devices, with partial or total weight relief, combined with individually targeted botulinum injections, should be considered in the management of bilateral nonambulatory CP patients, to prevent hip subluxation or its recurrence after surgery.
Tlx3 controls the development of C-low threshold mechanoreceptors
Authors: Wang Haoyong , Cao Zheng , Jiang Xuequan , Huang Chengcheng , Cao Cheng , Liu Zijing
Published: September 2022

Somatosensory information is signaled by primary sensory neurons located in dorsal root ganglia (DRG) or trigeminal ganglia. Type C-low threshold mechanoreceptors (C-LTMRs) are proposed to sense light touch. The differentiation and maturation of C-LTMRs are regulated by multiple transcript factors, including Zfp521 and Runx1. However, the molecular mechanism of C-LTMR development still remains largely unclear. RNA sequencing (RNA-seq) was performed to detect transcriptional changes in Tlx3cko DRGs compared to controls. In situ hybridization and RNAscope were used to verify RNA-seq data. RNA-seq identified 203 up- and 372 downregulated genes in DRG by loss of Tlx3 function. KEGG and Gene ontology analysis indicated that the biological properties and molecular functions were closely associated with neural signal processing and transmitting somatosensory information. In addition, the expression of marker genes of C-LTMRs was significantly decreased in Tlx3 mutants. However, Tlx3cko mice exhibited normal response to static and dynamic touch. Furthermore, Tlx3 was required to regulate the expression of Zfp521 and Runx1. Tlx3, Runx1 and Zfp521 may form a hierarchical regulation pathway to control C-LTMR development.
Optimized N-methyl-D-aspartate receptor antagonist exhibits hippocampal proneurogenic effects in aged senescence-accelerated mouse prone 8 mice
Authors: Companys-Alemany Júlia , Roig-Soriano Joan , Turcu Andreea L. , Chillón Miguel , Vázquez Santiago , Pallàs Mercè , Griñán-Ferré Christian
Published: September 2022

N-methyl-D-aspartate (NMDA) receptor antagonists mediate adult neurogenic effects. Here, the neurogenic effect of a new NMDA receptor antagonist endowed with neuroprotective effects in Alzheimer’s disease mice model. Nine-month-old senescence-accelerated mouse prone 8 (SAMP8) with UB-ALT-EV were orally treated. 5-Bromo-2-deoxyuridine (BrdU) (50 mg/kg) was 3× injected I.P. every 2 h. After 28 days of treatment, SAMP8-treated group improved working memory. Moreover, the number of BrdU+ cells and DCX+ cells in the SAMP8 dentate gyrus (DG) was significantly increased. GFAP+ cells were not affected by treatment. Together, these results provided evidence that UB-ALT-EV promotes the survival and proliferation of neural progenitor cells in the aged SAMP8 hippocampus.
How does negative evidence impact argument strength during semantic category-based induction? An event-related potential study
Authors: Zhang Jiantao , Sun Tie
Published: September 2022

Negative evidence may influence category-based inductive reasoning, but the underlying time course of cognitive brain processing is unclear. This study adopted event-related potentials (ERPs) to investigate this effect by manipulating the category type (related vs. unrelated) and argument type (positive vs. negative) in a semantic category-based induction task. The behavioral results showed that, under unrelated conditions, a negative argument produced greater argument strength and shorter reaction time than a positive argument did. Meanwhile, the ERP results found a negative argument elicited larger P300, N400, and slow negative component amplitudes than a positive argument, which could possibly embody the expectation-related processing produced by memory updating, semantic integration, and the more complex inference-driven information integration and interpretation processes and cognitive load in hypothesis generation. This study provides novel evidence on the temporal course of how negative evidence influences argument strength during semantic category-based induction.
Understanding emergence of antimycobacterial dose dependent resistance
Authors: Kloprogge Frank , Canseco Julio Ortiz , Phee Lynette , Sadouki Zahra , Kipper Karin , Witney Adam A. , Stoker Neil , McHugh Timothy D.
Published: September 2022

Concentration dependency of phenotypic and genotypic isoniazid-rifampicin resistance emergence was investigated to obtain a mechanistic understanding on how anti-mycobacterial drugs facilitate the emergence of bacterial populations that survive throughout treatment. Using static kill curve experiments, observing two evolution cycles, it was demonstrated that rifampicin resistance was the result of non-specific mechanisms and not associated with accumulation of drug resistance encoding SNPs. Whereas, part of isoniazid resistance could be accounted for by accumulation of specific SNPs, which was concentration dependent. Using a Hollow Fibre Infection Model it was demonstrated that emergence of genotypic resistance only occurs when antibiotic levels fall below MIC although MICs are typically maintained following clinical dosing provided that adherence to the regimen is good. This study showed that disentangling and quantifying concentration dependent emergence of resistance provides improved rational for drug and dose selection although further work on understanding underlying mechanisms is needed to improve the drug development pipeline.

One Sentence Summary

Disentangling and quantifying concentration dependent emergence of resistance will contribute to better informed drug and dose selection for anti-mycobacterial combination therapy.
Unravelling drivers of local adaptation through Evolutionary Functional-Structural Plant modelling
Authors: de Vries Jorad , Fior Simone , Pålsson Aksel , Widmer Alex , Alexander Jake M.
Published: September 2022

Local adaptation to contrasting environmental conditions along environmental gradients is a widespread phenomenon in plant populations, yet we lack a mechanistic understanding of how individual agents of selection contribute to local adaptation.

Here, we developed a novel evolutionary functional-structural plant (E-FSP) model that simulates local adaptation of virtual plants along an environmental gradient. First, we validate the model by testing if it can recreate two elevational ecotypes of Dianthus carthusianorum occurring in the Swiss Alps. Second, we use the E-FSP model to disentangle the relative contribution of abiotic (temperature) and biotic (competition and pollination) selection pressures to elevational adaptation in D. carthusianorum.

The model reproduced the qualitative differences between the elevational ecotypes in two phenological (germination and flowering time) and one morphological trait (stalk height), as well as qualitative differences in four performance variables that emerge from GxE interactions (flowering time, number of stalks, rosette area and seed production). Our results suggest that elevational adaptation in D. carthusianorum is predominantly driven by the abiotic environment.

Our approach shows how E-FSP models incorporating physiological, ecological and evolutionary mechanisms can be used in combination with experiments to examine hypotheses about patterns of adaptation observed in the field.
Three new genome assemblies of blue mussel lineages: North and South EuropeanMytilus edulisand MediterraneanMytilus galloprovincialis
Authors: Simon Alexis
Published: September 2022

The blue mussel species complex (Mytilus edulls) is of particular interest both as model species in population genetics and ecology, but also as an economic resource in many regions. Using 10X genomics pseudo-long reads, I assembled genomes of three closely related blue mussel lineages from theMytllusspecies complex in the Northern hemisphere. Given the huge diversity within and between lineages in this complex, the objective was to produce affordable genomic resources for population and evolutionary genomic studies to broaden the coverage of this diverse species complex. I used transcriptome guided corrections and scaffolding on a chromosome scale genome of a close species to reduce the fragmentation of the genomes. The result is a set of partially fragmented genomes of equivalent completeness to already published genomes. Three new draft genomes are added to the fast increasing genomic resources of this complex for the MediterraneanM. galloprovlnclalls, the South-EuropeanM. edullsand the the North-EuropeanM. edulls.
Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
Authors: Yang Chunsong , Wierbiłowicz Krzysztof , Dworak Natalia M , Bae Song Yi , Tengse Sachi B. , Abianeh Nicki , Drake Justin M. , Abbas Tarek , Ratan Aakrosh , Wotton David , Paschal Bryce M
Published: September 2022

The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor-positive and androgen receptor-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the androgen receptor, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergentresistant fraction within the nucleus, which is reminiscent of how inhibitors such as Talazoparib affect PARP1 fractionation. Because PARP7 is expressed in AR negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer.

Significance

RBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically-used PARP1 inhibitors.
Quantifying and Visualizing Uncertainty for Source Localization in Electrocardiographic Imaging
Authors: Njeru Dennis K. , Athawale Tushar M. , France Jessie J. , Johnson Chris R.
Published: September 2022

Electrocardiographic imaging (ECGI) presents a clinical opportunity to noninvasively understand the sources of arrhythmias for individual patients. To help increase the effectiveness of ECGI, we provide new ways to visualize associated measurement and modeling errors. In this paper, we study source localization uncertainty in two steps: First, we perform Monte Carlo simulations of a simple inverse ECGI source localization model with error sampling to understand the variations in ECGI solutions. Second, we present multiple visualization techniques, including confidence maps, level-sets, and topology-based visualizations, to better understand uncertainty in source localization. Our approach offers a new way to study uncertainty in the ECGI pipeline.
Slow and not so furious: de novo stomatal pattern formation during plant embryogenesis
Authors: Smit Margot E , Vatén Anne , Mair Andrea , Northover Carrie A M , Bergmann Dominique C
Published: September 2022

The fates of cells on the leaf surface depend on positional cues and environmental signals. New stomata are formed away from existing ones to prevent disadvantageous clustering, but how are the initial precursors positioned? Mature embryos do not have stomata, but we provide transcriptomic, imaging, and genetic evidence that Arabidopsis embryos engage known stomatal fate and patterning factors to create regularly spaced stomatal precursor cells. Analysis of embryos from 35 plant species indicates this trait is conserved across angiosperm clades. Embryonic stomatal patterning in Arabidopsis is established in three stages: first broad SPEECHLESS (SPCH) expression, then coalescence of SPCH and its targets into discrete domains, and finally one round of symmetric division to create stomatal precursors. Lineage progression is then halted until after germination. We show that embryonic stomatal pattern enables quick stomatal differentiation and photosynthetic activity upon germination but also guides the formation of additional stomata as the leaf expands. In addition, key stomatal regulators are prevented from driving the fate transitions they can induce after germination, revealing stage-specific layers of regulation that control lineage progression during embryogenesis.
Dynamic regulation of gonadal transposon control across the lifespan of the naturally short-lived African turquoise killifish
Authors: Teefy Bryan B. , Adler Ari , Xu Alan , Hsu Katelyn , Singh Param Priya , Benayoun Bérénice A.
Published: September 2022

Although germline cells are considered to be functionally “immortal”, both the germline and supporting somatic cells in the gonad within an organism will experience aging. With increased age at parenthood, the age-related decline in reproductive success has become an important biological issue for an aging population. However, molecular mechanisms underlying reproductive aging across sexes in vertebrates remain poorly understood. To decipher molecular drivers of vertebrate gonadal aging across sexes, we perform longitudinal characterization of the gonadal transcriptome throughout lifespan in the naturally short-lived African turquoise killifish(Nothobranchius furzeri). By combining mRNA-seq and small RNA-seq from 26 individuals, we characterize the aging gonads of young adult, middle-aged, and old female and male fish. We analyze changes in transcriptional patterns of genes, transposable elements (TEs), and piRNAs. We find that testes seem to undergo only marginal changes during aging. In contrast, in middle-aged ovaries, the timepoint associated with peak female fertility in this strain, PIWI pathway components are transiently downregulated, TE transcription is elevated, and piRNA levels generally decrease, suggesting that egg quality may already be declining at middle-age. Furthermore, we show that piRNA ping-pong biogenesis declines steadily with age in ovaries, while it is maintained in aging testes. To our knowledge, this dataset represents the most comprehensive transcriptomic dataset for vertebrate gonadal aging. This resource also highlights important pathways that are regulated during reproductive aging in either ovaries or testes, which could ultimately be leveraged to help restore aspects of youthful reproductive function.
G-quadruplex landscape and its regulation revealed by a new antibody capture method
Authors: Datta Subhamoy , Patel Manthan , Sathyaseelan Chakkarai , Ghosh Chandrama , Mudgal Akanksha , Patel Divyesh , Rathinavelan Thenmalarchelvi , Singh Umashankar
Published: September 2022

Our understanding of DNA G-quadruplexes (G4s) fromin vitrostudies has been complemented by genome-wide G4 landscapes from cultured cells. Conventionally, the formation of G4s is accepted to depend on G-repeats such that they form tetrads. However, genome-wide G4s characterized through high-throughput sequencing suggest that these structures form at a large number of regions with no such canonical G4-forming signatures. Many G4-binding proteins have been described with no evidence for any protein that binds to and stabilizes G4s. It remains unknown what fraction of G4s formed in human cells are protein-bound. The G4-chromatin immunoprecipitation (G4-ChIP) method hitherto employed to describe G4 landscapes preferentially reports G4s that get crosslinked to proteins in their proximity. Our current understanding of the G4 landscape is biased against representation of G4s which escape crosslinking as they are not stabilized by protein-binding and presumably transient. We report a protocol that captures G4s from the cells efficiently without any bias as well as eliminates the detection of G4s formed artifactually on crosslinked sheared chromatin post-fixation. We discover that G4s form sparingly at SINEs. An application of this method shows that depletion of a repeat-binding protein CGGBP1 enhances net G4 capture at CGGBP1-dependent CTCF-binding sites and regions of sharp interstrand G/C-skew transitions. Thus, we present an improved method for G4 landscape determination and by applying it we show that sequence property-specific constraints of the nuclear environment mitigate G4 formation.
Structural Reorganization and Relaxation Dynamics of Axially Stressed Chromosomes
Authors: Ruben Benjamin S. , Brahmachari Sumitabha , Contessoto Vinícius G. , Cheng Ryan R. , Oliveira Junior Antonio B. , Pierro Michele Di , Onuchic José N.
Published: September 2022

Micromechanical studies of mitotic chromosomes have revealed them to be remarkably extensible objects and informed early models of mitotic chromosome organization. We use a data-driven, coarsegrained polymer modeling approach, capable of generating ensembles of chromosome structures that are quantitatively consistent with experiments, to explore the relationship between the spatial organization of individual chromosomes and their emergent mechanical properties. In particular, we investigate the mechanical properties of our model chromosomes by axially stretching them. Simulated stretching led to a linear force-extension curve for small strain, with mitotic chromosomes behaving about ten-fold stiffer than interphase chromosomes. Studying the relaxation dynamics we found that chromosomes are viscoelastic solids, with a highly liquid-like, viscous behavior in interphase that becomes solid-like in mitosis. This emergent mechanical stiffness in our model originates from lengthwise compaction, an effective potential capturing the activity of loop-extruding SMC complexes. Chromosomes denature under large strains via unraveling, which is characterized by opening of large-scale folding patterns. By quantifying the effect of mechanical perturbations on the chromosome’s structural features, our model provides a nuanced understanding of in vivo mechanics of chromosomes.
DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing N6-methyladenosine binding
Authors: Li Mengyao , Li Jie , Yuan Aiyun , Dong Weidong , Dong Suwei , Yang Yun-Gui , Wang Yibo , Wu Chen , Li Jing
Published: September 2022

N6-methyladenosine (m6A) is the most prevalent RNA modification, and its regulators include writers, readers and erasers. m6A is under stringent control and takes part in many biological events, but it is not known whether there is an interplay between m6A and glycosylation. Here we investigated an m6A reader, YTHDC1, which has been shown to be recruited to the DNA-RNA hybrid at DNA damage sites and regulate homologous recombination (HR) during DNA damage repair. We found that YTHDC1 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification at Ser396 upon DNA damage, which is pivotal for YTHDC1 chromatin binding and ionization radiation induced foci (IRIF) formation. RNA immunoprecipitation (RIP) and molecular dynamics (MD) simulations indicate that O-GlcNAcylation is vital for YTHDC1 to bind with m6A RNA. Fluorescence recovery after photo bleaching (FRAP) analysis revealed that YTHDC1 O-GlcNAcylation is essential for DNA damage-induced YTHDC1-m6A condensate formation. We further demonstrate that YTHDC1 O-GlcNAcylation promotes HR-mediated DNA damage repair and cell survival, probably through recruitment of Rad51 to the damage sites. We propose that YTHDC1 O-GlcNAcylation is instrumental for HR and genome stability.
Delayed SARS-CoV-2 Spread and Olfactory Cell Lineage Impairment in Close-Contact Infection Syrian Hamster Models
Authors: Ueha Rumi , Ito Toshihiro , Ueha Satoshi , Furukawa Ryutaro , Kitabatake Masahiro , Ouji-Sageshima Noriko , Uranaka Tsukasa , Tanaka Hirotaka , Nishijima Hironobu , Kondo Kenji , Yamasoba Tatsuya
Published: September 2022

Objectives

Close contact with patients with COVID-19 is speculated to be the most common cause of viral transmission, but the pathogenesis of COVID-19 by close contact remains to be elucidated. In addition, despite olfactory impairment being a unique complication of COVID-19, the impact of SARS-CoV-2 on the olfactory cell lineage has not been fully validated. This study aimed to elucidate close-contact viral transmission to the nose and lungs and to investigate the temporal damage in the olfactory receptor neuron (ORN) lineage caused by SARS-CoV-2.

Methods

Syrian hamsters were orally administered SARS-CoV-2 as direct-infection models. On day 7 after inoculation, infected and uninfected hamsters were housed in the same cage for 30 minutes. These uninfected hamsters were subsequently assigned to a close-contact group. First, viral presence in the nose and lungs was verified in the infection and close-contact groups at several time points. Next, the impacts on the olfactory epithelium, including olfactory progenitors, immature ORNs, and mature ORNs, were examined histologically. Then, the viral transmission status and chronological changes in tissue damage were compared between the direct-infection and close-contact groups.

Results

In the close-contact group, viral presence could not be detected in both the nose and lungs on day 3, and the virus was identified in both tissues on day 7. In the direct-infection group, the viral load was highest in the nose and lungs on day 3, decreased on day 7, and was no longer detectable on day 14. Histologically, in the direct-infection group, mature ORNs were most depleted on day 3 (p < 0.001) and showed a recovery trend on day 14, with similar trends for olfactory progenitors and immature ORNs. In the close-contact group, there was no obvious tissue damage on day 3, but on day 7, the number of all ORN lineage cells significantly decreased (p < 0.001).

Conclusion

SARS-CoV-2 was transmitted even after brief contact and subsequent olfactory epithelium and lung damage occurred more than 3 days after the trigger of infection. The present study also indicated that SARS-CoV-2 damages all ORN lineage cells, but this damage can begin to recover approximately 14 days post infection.
Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response
Authors: Arora Rohit , Cao Christian , Kumar Mehul , Sinha Sarthak , Chanda Ayan , McNeil Reid , Samuel Divya , Arora Rahul K. , Matthew T. Wayne , Chandarana Shamir , Hart Robert , Dort Joseph C. , Biernaskie Jeff , Neri Paola , Hyrcza Martin D. , Bose Pinaki
Published: September 2022

We performed the first integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, cellular compositions, and ligand-receptor interactions. We demonstrate that LE regions are conserved across multiple cancers while TC states are more tissue specific. Additionally, we found our LE gene signature is associated with worse clinical outcomes while the TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biologies, a platform for data exploration (http://www.pboselab.ca/spatial_OSCC/) and is foundational for developing novel targeted therapies.