bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Replication Stress for Glioma Stem Cell Specific Cytotoxicity
Authors: Clough Emily , Strathdee Karen , Carruthers Ross
Published: October 2022

AIMS

Glioma stem cells (GSC) show high levels of DNA replication stress and exhibit abnormal S phase in comparison to differentiated, non GSC tumour cells. We investigated the DNA replication phenotypes of GSC and mechanism of GSC specific cytotoxicity following DNA replication stress response inhibition with combined ATR/PARP inhibition (CAiPi).

METHOD

Paired GSC enriched (‘GSC’) and GSC deplete differentiated (‘bulk’) populations were cultured from resected GBM specimens and maintained in neurobasal media with growth factors or serum containing media respectively. Cell viability, neurosphere and clonogenic assays were used to assess cytotoxicity whilst DNA replication was interrogated utilising immunofluorescent repair foci, flow cytometry and DNA fibre assay. CAiPi consisted of VE821 (ATRi) with Olaparib (PARPi).

RESULTS

GSC show reduced DNA replication rates and alterations in cell cycle profile and demonstrate extreme sensitivity to CAiPi. CAiPi resulted in significantly elevated levels of 53BP1 nuclear bodies in GSC indicating genomic under- replication, however did not preferentially reduce fork speed compared to non-GSC. Analysis of replication fork structures revealed an increase in new origin firing in GSC dependent upon PARP trapping. GSC cytotoxicity was reduced by roscovitine induced inhibition of origin firing, suggesting an important role of dysregulated origin firing in CAiPi response. CAiPi is also potently radiosensitising by clonogenic assay.

CONCLUSION

Taken together these data suggest that GSC are vulnerable to dysregulation of origin firing which results in under-replication of their genome and reliance upon G1 cell cycle resolution of DNA damage. We propose that CAiPi is an attractive therapeutic strategy for translation to the clinic.
Improving the Odds - Long Term Survivors of Glioblastoma Multiforme (GBM)
Authors: Akbar Palwasha Khan , Lord Hannah
Published: October 2022

AIMS

To review the data of patients in NHS Tayside who survived >24 months from a diagnosis of GBM, identifying trends in: (i) fixed demographic features; (ii) genetic mutations; (iii) treatment pathways.

METHOD

A retrospective case note review of patients with a new diagnosis of GBM 2015-2020, identifying those with >2 year survival. Data analysed: demographics (gender, age), mutations (IDH1, MGMT), and treatment (surgical, chemotherapy/radiotherapy).

RESULTS

84 patients identified. 18 survived >24 months (2 year survival rate of 21.4%). Median survival = 31 months (range 24-110 months); 18 patients: M:F ratio = 1.6:1; Median age at diagnosis 54.5 (range 34-72 years); 13 methylated MGMT, 2 unmethylated (3 unknown); 2 mutated IDH1, 10 wildtype (6 unknown); 16 maximum surgical resection; 17 chemoradiation and adjuvant chemotherapy; 17 received radiation dose of 60Gy in 30#, 1 received 40Gy in 15#; 11 had disease progression requiring further treatment; 5 had no progression, 2 progressed but did not have further treatment.

CONCLUSION

In Stupp data a 2 year survival of 26.5% was reached. In our real world cohort, a 2 year survival of 21.4% is satisfactory. MGMT methylation was common, but not exclusively the case. Only 2 were IDH1 mutated, possibly reflecting the frequency of occurrence in the GBM population, but demonstrating that it is not a prerequisite for improved survival. Younger age, and maximal surgical resection followed by chemoradiation and adjuvant chemotherapy are associated with improved prognosis. Recognising our dataset is small, we recommend further studies using a larger cohort to improve understanding of better outcomes in this patient group.
The Impact of Molecular Analysis on Patient Waiting Time: A Neurosurgical Audit
Authors: Maducolil Jeremy Easow , Mustafa Mohammad Arish , Hayes Wallis , Williams Amanda , Pal Piyali , Rathi Nitika , Brodbelt Andrew
Published: October 2022

AIMS

The 2021 WHO classification includes molecular characterizations to a much greater degree. Molecular markers play an important role in deciding treatment choice and predicting prognosis. Molecular markers are often performed in separate laboratories. This has led to concerns about the amount of time taken to get further molecular markers and the delay in diagnosis. Therefore our aim was to determine the waiting time for molecular markers to be returned from the lab following surgery.

METHOD

We retrospectively collected data for patients who had molecular analysis conducted in 2020 for gliomas at The Walton Centre, Liverpool. Descriptive statistics were conducted using SPSS V27.0.

RESULTS

182 patients were included. 130 patients waited <4 weeks, 46 patients >4 weeks, and 6 patients >8 weeks for molecular marker results. The median waiting time was 21 days (range: 11-219, IQR: 17.00-31.00). For patients who waited >4 weeks and >8 weeks, there were 7 WHO Grade I, 7 Grade II, 2 Grade III, and 26 Grade IV tumours. The median time taken between surgery and treatment to begin was 15 working days (range: 7-86, IQR: 12.00- 25.00). M-array took the longest time to return with a median of 63.5 days (range: 48-93, IQR: 60.00-80.00). Following which was NGS results which took a median of 32 days (range: 21-219, IQR: 27.00-40.00)

CONCLUSION

Most patients received their results in less than 4 weeks, however nearly a third had a waiting time of greater than 4 weeks. Reasons for delays need to be explored further to allow for quicker intervention from the MDT.
COVID-19 Pandemic Neuro-Oncology Consultation Settings: Ensuring Services Address Patient Preferences
Authors: Galante Joao , Ben-Joseph Aaron , Forner Samantha , Kennaird Elaine , Durve Meeta , Glendenning Jennifer
Published: October 2022

Aims

The Covid-19 pandemic expanded the use of virtual consultations (telephone (T) or video (V)). Moving forward, Neuro-Oncology consultation settings require tailoring to optimally meet patient needs. This project aimed to evaluate patient perceptions of consultation settings to optimise service planning and ongoing incorporation of T and V options for patients with high grade brain tumours.

METHOD

From February 2022, patient perceptions on consultation settings were prospectively sought on follow-up/on- treatment appointments in Kent Oncology Centre. The peer-reviewed anonymised survey explored rationale for consultation setting, travelling (time, distance and arrangements) , satisfaction with appointment parameters (amount/ clarity of information, patient perception of support, assessment of symptoms and ability to ask questions) and setting preferences moving forward.

RESULTS

The majority of consultations were F2F, 1/3 had teleconsultations. 2/5 of patients were given a choice of consultation setting. Reason for teleconsultation included geographical distance, longer journey time, consultant decision, disability, work and active Covid-19 infection. All settings recorded good levels of satisfaction, however the majority (>2/3) would recommend F2F appointments to others for scan results, pre-chemotherapy/on-radiotherapy checks, specialist nurse reviews and end of treatment reviews.

CONCLUSION

Despite reassuring levels of satisfaction for both F2F and non-F2F appointments, F2F setting remains preferred regardless of the aim of the consultation. For a selected number of patients, teleconsultation has advantages due to geographical constraints, however the option of F2F consultations remains important and patients should be involved in these decisions.
10-Year Institutional Retrospective Case Series of WHO Grade II Gliomas and Correlation of Incidence of Seizures, Isocitrate Dehydrogenase No. 1 (IDH-1) Mutation and Lobar Location (2010-2020)
Authors: Lammy Simon , Bridgman Elsie , Johnson Hannah , Taylor Aaron , Grivas Athanasios
Published: October 2022

AIMS OBJECTIVES

To assess the correlation in World Health Organisation (WHO) Grade II gliomas of IDH-1 mutation, lobar location and seizures

DESIGN

10-year retrospective case series

SUBJECTS

Histopathological WHO Grade II gliomas

METHODS

We searched case notes in NHS Greater Glasgow & Clyde and Scottish National PACS.

RESULTS

84 patients underwent tissue diagnosis. Mean age 42rs (range: 21-77yrs]). Seizures (NB: pre-2017 International League against Epilepsy classification [ILAE]) occurred in 71% (52% generalised, 37% partial and 11% mixed). 31% had ongoing seizures postoperatively. 38% had headache (50% had headache and seizures). 21% had a focal neurological deficit (FND) (61% had a FND and seizure). Seizure, as an isolated pre-operative symptom occurred in 48% patients compared to isolated headache in 10% and isolated FND in 4%. Overall, 58% of lesions and 60% of seizures were frontal. Histologically, 60% were astrocytomas and 40% oligodendrogliomas (49% of astrocytomas and 71% of oligodendrogliomas arose from the frontal lobe). IDH-1 mutation occurred in 80% (75% had seizures) and 66% were frontal.

CONCLUSION

This confirms a correlation between IDH-1, incidence of seizures and frontal lesions (p = <0.05)

REFERENCES

Zhong et al. IDH1/2 Mutation is Associated with Seizure as an Initial Symptom in Low-Grade Glioma. Epilepsy Res. 2015 109:100-105
An Audit of Serial Stereotactic Biopsies at the WCFT Between 2018-2021
Authors: Gilder Connor , Pal Piyali
Published: October 2022

AIMS

(1) To assess how often serial stereotactic brain biopsies of gliomas perform at Walton Centre between 20018 and 2021 allow clinically requisite molecular results, within the expected turnaround times. (2)Assess reasons for delay or not obtaining molecular results.

METHOD

All data obtained from LIMS (TDHC) and electronic patient records (eP2) at the Walton Centre Foundation Trust, and analysed in MS Excel. High grade glioma cases explored in detail.

RESULTS

Of 61 cases included, 45 were gliomas. 37 (61%) were HGGs i.e. GBMs or AAs. All requested molecular data could be obtained on 74% GBMs and 40% of AAs. One Oligodendroglioma remained ungraded. All the 4 DMGs could be issued final histological diagnosis based on immunohistochemistry and required no extra molecular tests. All requested molecular data could be obtained in 71% of LGG cases. MGMT results were obtained in 89% of GBM cases. NGS results were obtained in 57% of GBM cases. The average turnaround time from date of biopsy to authorised report 13 – 97 days, with a mean of 26 days.

CONCLUSION

(1) The majority of GBM cases yielded all requested molecular results. (2) Sample size was a limiting factor in obtaining molecular results. (3) Turnaround times have been compounded by failed molecular tests, ultimately affecting patient waiting times in HGGs. (4) Histological grading by mitotic index is not possible on small biopsy fragments. (5) If viable tumour cells are present, immunohistochemical molecular markers have proved valuable.
Exploring a Link Between Alzheimer’s and Glioma by Investigating SORL1 Network
Authors: Montalbo Kristy , Bakker Emyr , Stasik Izabela , Smith Christopher
Published: October 2022

AIMS

Use bioinformatics methods to identify and validate associated proteins and genes in the SORL1 network. Generate a bank of patient derived cells in association with the Royal Preston Hospital BTNW tissue bank. Explore identified targets from the bioinformatics in patient derived cells.

METHOD

Proteins and genes associated with SORL1 and SORLA were identified on GeneCards. Connectivity mapping of known and predicted interactions linked to SORL1 was explored in STRING. For clinical validation differential expression was investigated by comparing genomic data from GTEX and TCGA, available at Xenabrowser. For survival analysis Kaplan-Meier curves were generated on cBioPortal. The five most differently expressed novel targets are taken forward for laboratory experiments using western blots for protein quantification and immunocytochemistry to identify and visualise target proteins.

RESULTS

A total of 73 genes (30 from GeneCards and 43 from STRING) were obtained. 63 genes from the generated SORL1-related network were shown to be differentially expressed whilst 40 were significantly different between low-surviving patients and high-surviving patients. The top five associated proteins are CKAP4, CTNND1, FN1, HSPA12A and SORCS3. CKAP4, CTNND1 and FN1 are highly expressed in both glioma and glioblastoma, but low expressed in healthy tissue. HSPA12A is low expressed in cancerous brain tissue and highly expressed in healthy samples. SORCS3 is differentially expressed in healthy samples and glioma, but significantly low expressed glioblastoma.

CONCLUSION

This project provides insight into SORL1 molecular relationships and function in tissue, cultured cells and serum from a patient cohort including demographics, disease progression and site.
Agreement Between Measures of Adherence to Isoniazid Preventive Therapy Among People With HIV in Uganda
Authors: Forman Leah S , Lodi Sara , Fatch Robin , Emenyonu Nneka I , Adong Julian , Ngabirano Christine , Jacobson Karen R , Gerona Roy , Reckers Andrew R , Gandhi Monica , Muyindike Winnie R , Hahn Judith A
Published: October 2022

Background

Isoniazid (INH) preventative therapy is recommended for people with HIV (PWH) in resource-constrained settings. Valid measures are needed to assess adherence. We aimed to examine agreement between measures overall and by level of social desirability.

Methods

PWH with latent tuberculosis (TB) were recruited in Mbarara, Uganda. Past 30-day adherence was measured by the number of days with pill bottle openings using a medication event monitoring system (MEMS) and self-reported number of days pills taken. INH concentration (INH plus acetyl INH and their ratio) in hair samples was measured. We used Bland-Altman plots to examine agreement between adherence measures and calculated the area under the receiver operating characteristics curve (AUROC) to determine if INH hair concentration predicted optimal MEMS-measured adherence (≥90%).

Results

A total of 301 participants enrolled; 92% were virologically suppressed, and adherence was high. The median (interquartile range [IQR]) number of pill bottle openings in 30 days was 28 (24–30) compared with 30 (28–30) via self-report. The median INH concentration (IQR) was 36.2 (17.2–62.4), and the INH:acetyl ratio was 2.43 (0.99–3.92). Agreement between self-reported and MEMS adherence was greater at more optimal adherence levels. INH:acetyl INH ratio was not predictive of optimal adherence according to MEMS (AUROC, 0.62; 95% CI, 0.52–0.72) in a subset (n = 161).

Conclusions

Lower MEMS adherence levels compared with self-report suggest the need for objective adherence measures. Biologic measures have potential, although in this study INH concentration was not predictive of MEMS measured adherence. More data are needed to assess the accuracy of biologic measures.
A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study
Authors: Chihara Yusuke , Takeda Takayuki , Goto Yasuhiro , Nakamura Yoichi , Tsuchiya-Kawano Yuko , Nakao Akira , Onoi Keisuke , Hibino Makoto , Fukuda Minoru , Honda Ryoichi , Yamada Takahiro , Taniguchi Ryusuke , Sakamoto Sinjiro , Date Koji , Nagashima Seiji , Tanzawa Shigeru , Minato Koichi , Nakatani Koichi , Izumi Miiru , Shimose Takayuki , Kishimoto Junji , Uchino Junji , Takayama Koichi
Published: October 2022

Background

Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear.

Methods

This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety.

Results

Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis.

Conclusion

Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).
Radiotherapy Plus Temozolomide With or Without Nimotuzumab Against the Newly Diagnosed EGFR-Positive Glioblastoma: A Retrospective Cohort Study
Authors: She Lei , Gong Xuan , Su Lin , Liu Chao
Published: October 2022

Background

Glioblastoma (GBM) has a poor prognosis, and patients with epidermal growth factor receptor (EGFR) amplification have an even worse prognosis. Nimotuzumab is an EGFR monoclonal antibody thought to play a significant role in the treatment of GBM. This paper presents a retrospective cohort study that evaluates the clinical efficacy and safety of nimotuzumab in GBM.

Materials and Methods

A total of 56 newly diagnosed patients with EGFR-positive GBM were included in our study. The patients were divided into radiotherapy (RT) + temozolomide (TMZ) + nimotuzumab (39 patients) and RT + TMZ (17 patients) groups based on whether or not nimotuzumab was added during RT. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed.

Results

The median follow-up time was 27.9 months (95% confidence interval [CI], 25.1-30.8). The median PFS was 12.4 months (95% CI, 7.8-17.0) and 8.2 months (95% CI, 6.1-10.3) in the 2 groups, respectively, P = .052. The median OS was 27.3 months (95% CI, 19.0-35.6) and 16.7 months (95% CI, 11.1-22.2), respectively, P = .018. In patients with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, the PFS and OS were significantly better in patients treated with nimotuzumab than in those without nimotuzumab (median PFS: 19.3 vs 6.7 months, P = .001; median OS: 20.2 vs 13.8 months, P = .026). During the treatment period, no statistically significant difference in toxicity was noted between the 2 groups.

Conclusion

Our retrospective cohort study suggests the efficacy of Nimotuzumab combined with concurrent RT with TMZ in patients with newly diagnosed EGFR-positive GBM, and specifically those with unmethylated MGMT promoter. Further prospective studies are warranted to validate our findings. Besides, nimotuzumab demonstrated good safety and tolerability.
Behavioral Political Science
Authors: James Patrick
Published: October 2022

Behavioral political science (BPS) is a research enterprise with many accomplishments in place already, such as rigorous concept formation and a wide range of theories that have performed well under various kinds of testing. This chapter, which evaluates the contents of the present volume, unfolds in eight sections. The first section provides an overview of how assessment of BPS will be carried out. Sections two through five review the accomplishments of the major sectors in the present volume: a) bounded rationality and heuristics, b) theories, c) attitudes, and d) methods. The sixth section introduces systemism, a graphic approach toward representation of cause and effect. The seventh section applies systemism in an effort to assemble the contributions from sectors a through d into a visual representation of cause and effect for BPS. An eighth and final section reflects on what has been achieved.
When Queer Theory Goes to Law School
Authors: Cossman Brenda
Published: October 2022

Queer theory developed as an interrogation of the multiple discursive productions of sexuality, seeking to denaturalize the assumed connections between sex, gender, and desire. It did so in part as a break from the prevailing analytic frameworks for theorizing around sexuality. This chapter outlines the emergence of queer theory and some of its distinctive themes and critical sensibilities, highlighting its shared genealogies with feminism as well as its break from it. We consider what queer theory is against, what queer theory is for, and what it has to say about law. The chapter explores how queer legal theory differs from a more rights-based approach to LGBT issues by focusing on the Supreme Court’s decisions in the sodomy challenges and the same-sex marriage challenge.
Dominance Feminism
Authors: Abrams Kathryn
Published: October 2022

Dominance feminism offered a new theorization of sex and gender inequality, which described sexualization and sexual coercion as the linchpin of women’s subordination and offered law as a tool for remedying it, notably through the Title VII claim for sexual harassment. However, critiques by feminists of color, sex-positive feminists, and others exposed the limits of dominance theory’s engagement with intersectional experiences of sexual violence and women’s agency under circumstances of constraint. The advent of #MeToo returned sexualized injury to the fore and bolstered dominance feminism’s predominantly sociological approach with plural, solidaristic experiential narratives. Although some proponents of #MeToo have demonstrated a greater appreciation of women’s sexual agency amidst their resistance to sexual injury, whether #MeToo can capture the varieties of sexualized violence, as they are experienced on the streets or in low-wage or nonprofessional workplaces, remains an ongoing question.
Hyper-CVAD-Based Stem Cell Microtransplant as Post-Remission Therapy in Acute Lymphoblastic Leukemia
Authors: Cai Bo , Wang Yi , Lei Yangyang , Shi Yanping , Sun Qiyun , Qiao Jianhui , Hu Kaixun , Lei Yaqing , Li Bingxia , Liu Tieqiang , Liu Zhiqing , Yao Bo , Zhao Xuecong , Li Xiaofei , Zhao Wen , Feng Xiujie , Xie Anli , Ning Xin , Feng Mingxing , Zhao Weiwei , Guo Jiayue , Ai Huisheng , Yu Changlin , Guo Mei
Published: October 2022

Post-remission strategies for patients with acute lymphoblastic leukemia (ALL) are limited to the multiagent chemotherapy and allogeneic stem cell transplant (allo-SCT), and cellular therapies are seldom involved. Although chemotherapy combined with mismatched granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell infusion (microtransplant, MST) has been studied in patients with acute myeloid leukemia, its efficacy in ALL is still undetermined. We enrolled 48 patients receiving hyper-CVAD-based MST between July 1, 2009, and January 31, 2018. No acute or chronic graft-versus-host disease occurred in patients receiving MST. Four-year overall survival (OS) and leukemia-free survival (LFS) were 62% and 35%, respectively, and the 4-year relapse rate was 65%. No patient experienced non–relapse mortality. Subgroup analysis showed that OS rates were comparable between groups with different age, risk stratification, minimal residual disease status prior to MST and immunophenotype. Adult patients tended to achieve better 4-year LFS (62% vs. 26%, P = .058) and lower hematologic relapse rate (38% vs. 74%, P = .058) compared with adolescent and young adult patients. Donor chimerism/microchimerism was detectable ranging from 0.002% to 42.78% in 78% (42/54) available samples within 14 days after each infusion and at 3 months or one year after the last cell infusion. Multivariate analyses demonstrated that white blood cells <30 × 109/L at diagnosis and sufficient hyper-CVAD cycles were prognostic factors for better 4-year OS and LFS, while the B-cell phenotype and higher number of infused CD34+ cells in the first cycle were predictors for favorable 4-year LFS. The hyper-CVAD-based MST was a feasible strategy for treating ALL patients with mild toxicity.
Biomechanical Analysis of Cortical Bone Trajectory Screw Versus Bone Cement Screw for Fixation in Porcine Spinal Low Bone Mass Model
Authors: Li Yifan , Wang Silian , Zhu Zhenbiao , Chen Liwei , Shi Zhangpeng , Ye Xiaojian , Xu Wei , Li Zhikun
Published: October 2022

Study Design:

A prospective study of in vitro animal.

Objection:

To compare the biomechanics of cortical bone trajectory screw (CBT) and bone cement screw (BC) in an isolated porcine spinal low bone mass model.

Summary of Background Data:

The choice of spinal fixation in patients with osteoporosis remains controversial. Is CBT better than BC? Research on this issue is lacking.

Methods:

Ten porcine spines with 3 segments were treated with EDTA decalcification. After 8 weeks, all the models met the criteria of low bone mass. Ten specimens were randomly divided into groups, group was implanted with CBT screw (CBT group) and the other group was implanted with bone cement screw (BC group). The biomechanical material testing machine was used to compare the porcine spine activities of the two groups in flexion, extension, bending, and axial rotation, and then insertional torque, pull-out force, and anti-compression force of the 2 groups were compared. Independent sample t test was used for comparison between groups.

Results:

Ten 3 segments of porcine spine models with low bone mass were established, and the bone mineral density of all models was lower than 0.75 g/cm2. There is no difference between the CBT and BC groups in flexion, extension, bending, and axial rotation angle,P>0.05. However, there were significant differences between the 2 groups and the control group, withP＜0.01. The 2 groups significantly differed between the insertional torque (P=0.03) and the screw pull-out force (P=0.021). The anti-compression forces between the 2 groups have no significant difference between the two groups (P=0.946).

Conclusions:

The insertional torque and pull-out force of the CBT were higher than those of the BC in the isolated low bone porcine spine model. The range of motion and anti-compression ability of the model was similar between the 2 fixation methods.
Low-dimensional organization of global brain states of reduced consciousness
Authors: Perl Yonatan Sanz , Pallavicini Carla , Piccinini Juan , Demertzi Athena , Bonhomme Vincent , Martial Charlotte , Panda Rajanikant , Alnagger Naji , Annen Jitka , Gosseries Olivia , Ibañez Agustin , Laufs Helmut , Sitt Jacobo , Jirsa Viktor , Kringelbach Morten , Laureys Steven , Deco Gustavo , Tagliazucchi Enzo
Published: October 2022

Brain states are frequently represented using a unidimensional scale measuring the richness of subjective experience (level of consciousness). This description assumes a mapping between the high-dimensional space of whole-brain configurations and the trajectories of brain states associated with changes in consciousness, yet this mapping and its properties remain unknown. We combined whole-brain modelling, data augmentation and deep learning for dimensionality reduction to determine a mapping representing states of consciousness in a low-dimensional space, where distances parallel similarities between states. An orderly trajectory from wakefulness to brain injured patients is revealed in a latent space whose coordinates represent metrics related to functional modularity and structure-function coupling, both increasing alongside loss of consciousness. Finally, we investigated the effects of model perturbations, providing geometrical interpretation for the stability and reversibility of states. We conclude that conscious awareness depends on functional patterns encoded as a low-dimensional trajectory within the vast space of brain configurations.
From comparative gene content and gene order to ancestral contigs, chromosomes and karyotypes
Authors: Xu Qiaoji , Jin Lingling , Zheng Chunfang , Zhang Xiaomeng , Leebens-Mack James , Sankoff David
Published: October 2022

To reconstruct the ancestral genome of a set of phylogenetically related descendant species, we use the Raccroche pipeline for organizing a large number of generalized gene adjacencies into contigs and then into chromosomes. Separate reconstructions are carried out for each ancestral node of the phylogenetic tree for focal taxa. The ancestral reconstructions are monoploids; they each contain at most one member of each gene family constructed from descendants, ordered along the chromosomes. We design and implement a new computational technique for solving the problem of estimating the ancestral monoploid number of chromosomes x. This involves a “g-mer” analysis to resolve a bias due long contigs, and gap statistics to estimate x. We find that the monoploid number of all the rosid and asterid orders is x = 9. We show that this is not an artifact of our method by deriving x ≈ 20 for the metazoan ancestor.
Detection of orthologous genes with expression shifts linked to nickel hyperaccumulation across Eudicots
Authors: Gallopin Mélina , Drevet Christine , de la Torre Vanesa S. Garcia , Jelassi Sarah , Michel Marie , Ducos Claire , Saule Cédric , Majorel Clarisse , Burtet-Sarramegna Valérie , Pillon Yohan , Bastide Paul , Lespinet Olivier , Merlot Sylvain
Published: October 2022

The remarkable capacity of plants to tolerate and accumulate tremendous amount of nickel is a complex adaptative trait that appeared independently in more than 700 species distributed in about fifty families. Nickel hyperaccumulation is thus proposed as a model to investigate the evolution of complex traits in plants. However, the mechanisms involved in nickel hyperaccumulation are still poorly understood in part because comparative transcriptomic analyses struggle to identify genes linked to this trait from a wide diversity of species. In this work, we have implemented a methodology based on the quantification of the expression of orthologous groups and phylogenetic comparative methods to identify genes which expression is correlated to the nickel hyperaccumulation trait. More precisely, we performed de novo transcriptome assembly and reads quantification for each species on its own transcriptome using available RNA-Seq datasets from 15 nickel hyperaccumulator and non-accumulator species. Assembled contigs were associated to orthologous groups built using proteomes predicted from completed plant genome sequences. We then analyzed the transcription profiles of 5953 orthologous groups from distant species using a phylogenetic ANOVA. We identified 31 orthologous groups with an expression shift associated with nickel hyperaccumulation. These orthologous groups correspond to genes that have been previously implicated in nickel accumulation, and to new candidates involved in this trait. We thus believe that this method can be successfully applied to identify genes linked to other complex traits from a wide diversity of species.
Tetraose steroidal glycoalkaloids from potato provide resistance againstAlternaria solaniand Colorado potato beetle
Authors: Wolters Pieter J. , Wouters Doret , Tikunov Yury M. , Ayilalath Shimlal , Kodde Linda P. , Strijker Miriam , Caarls Lotte , Visser Richard G. F. , Vleeshouwers Vivianne G. A. A.
Published: October 2022

Plants with innate disease and pest resistance can contribute to more sustainable agriculture. Natural defence compounds produced by plants have the potential to provide a general protective effect against pathogens and pests, but they are not a primary target in resistance breeding. Here, we identified a wild relative of potato,Solanum commersonii, that provides us with unique insight in the role of glycoalkaloids in plant immunity. We cloned two atypical resistance genes that provide resistance toAlternaria solaniand Colorado potato beetle through the production of tetraose steroidal glycoalkaloids. Moreover, we providein vitroevidence to show that these compounds have potential against a range of different (potato pathogenic) fungi. This research links structural variation in steroidal glycoalkaloids to resistance against potato diseases and pests. Further research on the biosynthesis of plant defence compounds in different tissues, their toxicity, and the mechanisms for detoxification, can aid the effective use of such compounds to improve sustainability of our food production.
Identify the origin and end cells and infer the trajectory of cellular fate automatically
Authors: Zeng Zehua , Xing Cencan , Hu Lei , Roshan Shah , Xiong Yuanyan , Du Hongwu
Published: October 2022

Cellular state identification and trajectory inference enable reconstructions of cell fate dynamics from single-cell RNA sequencing. However, the identification of cell fate trajectories requires a large number of computational resources or known biological process, and lack a method to alleviate both of these deficiencies at the same time. Here, we present scLTNN, a method that automatically infers origin and end cell state from scRNA-seq data and calculates the developmental trajectory and differentiation direction of cells with only a few computational resources and time consummation. We apply scLTNN to disentangling subpopulation kinetics in CD8+ T cell, pancreatic endocrinogenesis, and the development of zebrafish embryos. scLTNN displays a strong trajectory inference ability cross-species. scLTNN features a modular design that can be flexibly extended to any scRNA-seq analysis task. The complete package is available online at https://github.com/Starlitnightly/scltnn.
Combinations of genes at the 16p11.2 and 22q11.2 CNVs contribute to neurobehavioral traits
Authors: Vysotskiy Mikhail ,   Autism Working Group of the Psychiatric Genomics Consortium,   Bipolar Disorder Working Group of the Psychiatric Genomics Consortium,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Weiss Lauren A
Published: October 2022

The 16p11.2 and 22q11.2 copy number variants (CNVs) are associated with neurobehavioral traits including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, obesity, and intellectual disability. Identifying specific genes contributing to each disorder and dissecting the architecture of CNV-trait association has been difficult, inspiring hypotheses of more complex models, such as the effects of pairs of genes. We generated pairwise expression imputation models for CNV genes and then applied these models to GWAS for: ASD, bipolar disorder, schizophrenia, BMI (obesity), and IQ (intellectual disability). We compared the trait variance explained by pairs with the variance explained with single genes and with traditional interaction models. We also modeled polygene region-wide effects using summed ranks across all genes in the region. In all CNV-trait pairs except for bipolar disorder at 22q11.2, pairwise effects explain more variance than single genes, which was specific to the CNV region for all 16p11.2 traits and ASD at 22q11.2. We identified individual genes over-represented in top pairs that did not show single-gene signal. We also found that BMI and IQ have a significant association with a regionwide score. Genetic architecture differs by trait and region, but 9/10 CNV-trait combinations showed evidence for multigene contribution, and for most of these, the importance of combinatorial models appeared unique to CNV regions. Our findings suggest that mechanistic insights for CNV pathology may require combinational models.
Universal Amplicon Sequencing of North Imperial Valley Wetlands Microbiomes
Authors: Becker Scott , Graham Elaina , Sager Lindsay , Spreafico Roberto , McCarren Jay
Published: October 2022

DNA sequencing of complex microbial communities allows for the classification and quantification of thousands of distinct organisms in diverse environmental niches. We present a three domain “Universal Amplicon” (UA) method to simultaneously amplify DNA from the ribosomal small subunit locus from bacteria, archaea, and eukaryotes (and their organelles) using a single pair of amplification primers. We demonstrate the amenability of the UA to multiplexed Illumina library preparation and MiSeq-based sequencing. We validate the UA by sequencing a commercially available microbial community of known quantitative composition and through direct comparison to a shotgun metagenomics dataset. Following validation, we apply the UA to a time-course study of the wetlands of the Northern Imperial Valley in California and show substantial and variable microbial life in the Salton Sea and nearby waters. We demonstrate that the microbial ecology of the Salton Sea varies on at least a monthly basis and is distinct from the surrounding area. Finally, we contribute an open-source Shiny app for real-time analysis of complex metagenomic communities, with application to this study and far beyond.
Accurate measurement of inhibition and excitation in human motor pools during sensory stimulation
Authors: Soteropoulos Demetris S. , Del Vecchio Alessandro
Published: October 2022

Surface electromyography (sEMG) is a pivotal approach in clinical and basic neurophysiology, allowing us to extract the summed activity of motor units in a given muscle. Due to the bipolar nature of the motor unit action potential, the sEMG is a non-linear representation of their underlying motor unit activity and therefore affected by signal cancellation. It is not clear how this cancellation influences evoked responses in sEMG. The aim of our study was to characterise how representative an evoked sEMG response was to the firing behaviour of the underlying motor pool. To do this, we first simulated a population of motor units (and their action potentials) that responded to a stimulus with a change in firing probability. Their activity was summed then rectified to generate a simulated sEMG signal or was rectified and then summed, to generate a sEMG signal with no cancellation. By comparing the two responses to that of the underlying pool we would then compare for discrepancies. We repeated this process but by using the responses of tibialis anterior motor units to weak tibial nerve stimulation. We find that both for the simulated and experimental data the response measured through the sEMG is almost always an underestimate of the evoked response in the underlying motor pool. This is the case for both inhibitory and excitatory evoked responses. The magnitude of the inaccuracy depends on the size of the evoked response, but it cannot be accounted solely by signal cancellation, suggesting other factors may also contribute.
A chronic signaling TGFb zebrafish reporter identifies immune response in melanoma
Authors: Noonan Haley R. , Barbano Julia , Xifaras Michael , Baron Chloé S. , Yang Song , Koczirka Katherine , McConnell Alicia M. , Zon Leonard I.
Published: October 2022

Developmental signaling pathways associated with growth factors such as TGFb are commonly dysregulated in melanoma. Here we identified a human TGFb enhancer specifically activated in melanoma cells treated with TGFB1 ligand. We generated stable transgenic zebrafish with this TGFb Induced Enhancer driving green fluorescent protein (TIE:EGFP). TIE:EGFP was not expressed in normal melanocytes or early melanomas but was expressed in spatially distinct regions of advanced melanomas. Single cell RNA- sequencing revealed that TIE:EGFP+ melanoma cells down-regulated interferon response, while up-regulating a novel set of chronic TGFb target genes. ChIP-sequencing demonstrated that AP-1 factor binding is required for activation of chronic TGFb response. Overexpression of SATB2, a chromatin remodeler associated with tumor spreading, showed activation of TGFb signaling in melanoma precursor zones and early melanomas. Confocal imaging and flow cytometric analysis showed that macrophages are recruited to TIE:EGFP+regions and preferentially phagocytose TIE:EGFP+ cells. This work identifies a TGFb induced immune response and demonstrates the need for the development of chronic TGFb biomarkers to predict patient response to TGFb inhibitors.
Large-scale assessment of habitat quality and quantity change on declining European butterflies
Authors: Chazot Nicolas , Faurby Søren , van Swaay Chris , Ekroos Johan , Wahlberg Niklas , Bacon Christine D. , Antonelli Alexandre
Published: October 2022

The rapid decline of biodiversity as a consequence of increased environmental impact by human activities requires urgent action against the ongoing crisis. At the heart of conservation policy is the debate on quality versus quantity: should the post-2020 Global Biodiversity Framework focus on maximising total protected area, or pursue instead qualitative targets? To improve conservation practices, we need to both understand the current trend of biodiversity and the factors driving the decline. We address this by: (1) projecting current European butterfly population trends for the next 50 and 100 years, (2) comparing the decline in species richness, phylogenetic diversity and habitat specialization among different habitats, and (3) estimating the relationship between recent trends in habitat quality or quantity and the decline of multiple metrics of European butterfly diversity. We do not find any significant relationship between diversity loss and habitat area loss and conclude that neither long-term nor short-term changes in habitat area are primary predictors of large-scale butterfly decline in Europe. Habitat quality emerges as the most crucial factor in our analyses – both the area affected and the severity of habitat quality reduction. Habitat degradation causes vegetation changes in structure and diversity, which affect butterfly survival. We also estimate a higher decline of habitat specialists than generalist species. We conclude that habitat protection cannot focus solely on the maximization of habitat area but urgently needs to restore high quality ecosystems to provide the full range of ecological requirements for biodiversity.
Subchronic oral toxicity study of Aldicarb sulfoxide in Sprague-Dawley rats
Authors: Ji Yongchao , Liu Yi , Duan Juanjuan , Wang Yiting , Wang Yu , Wang Fan , Chen Chao , Zhang Wensheng
Published: October 2022

Aldicarb sulfoxide is the metabolite of the exceedingly deadly carbamate insecticide Aldicarb. Aldicarb sulfoxide is easily soluble in water and has been identified in groundwater. Moreover, Aldicarb sulfoxide is highly hazardous to mammals. However, the toxicity data of Aldicarb sulfoxide is scarce. Here, the effects of relatively low dosages of exposure to Aldicarb sulfoxide on the blood biochemical, hematological, and histopathological parameters were examined in SD rats. The rats were treated with Aldicarb sulfoxide orally at dosages of 0, 6.3, 18.9, and 56.7 μg per kg b.w. daily for 12 weeks. The results revealed that Aldicarb sulfoxide induced significant alterations in liver-related biochemical parameters, glucose level, cholesterol level, and uric acid level. Histopathological testing demonstrated cellular alterations in the liver of 18.9 and 56.7 μg/kg BW. Together, our data demonstrated that Aldicarb sulfoxide exposure causes liver injury. Furthermore, the no observed adverse effect level (NOAEL) was less than 6.3 μg/kg BW, and the lowest benchmark dose (BMD) value was 0.03 μg/kg BW. Accordingly, Aldicarb sulfoxide’s derived no-effect level (DNEL) was calculated as 0.00035 μg/kg BW. Thus, this work is an important reference for supervising Aldicarb sulfoxide in the environment and determining safe exposure limits for Aldicarb sulfoxide.
Diagnosis of type 2 Diabetes Mellitus (T2DM) using Paired microRNAs
Authors: Takada Yukichi , Ono Yasuhiro , Shibuta Tatsuki , Ishibashi Ayaka , Takamori Ayako , Fujimoto Kazuma , Hirooka Yoshitaka , Umemura Tsukuru
Published: October 2022

Type 2 Diabetes mellitus (T2DM) is one of the most common diseases in the world and its prevalence ratio is still increasing. Patients with T2DM have diverse pathophysiological changes like as macrovascular, microvascular diseases, cancers as well as abnormal glucose metabolism. Thus, there are urgent needs to develop relevant biomarkers for the broad range of pathophysiology in patients with T2DM. We analyzed the signatures of serum miRNAs with the miRNA array analysis and reverse-transcription based quantitative polymerase chain reaction (RT-qPCR) in 50 patients with type 2 DM (T2DM) and 15 normal subjects. Array analysis showed that 19 miRNAs were up-regulated more than 2-fold and 71 miRNAs were down-regulated less than 0.5 in T2DM in comparison with normal subjects. Top 5 of up-regulated miRNAs were miR-3619-3p, miR-557, miR-6850-5p, miR-3648, miR-4730, and 5 of most down-regulated miRNAs were miR-5100, miR-4454, miR-1260b, miR-7975, miR-6131. We selected 4 miRNAs for validation analysis with RT-qPCR based on the abundance enough for reliable analyses and disease-specificities reported in previous reports. Serum miR-126-3p was down-regulated (3.21-fold, p<0.05) in T2DM, and miR-10a up-regulated (1.94-fold, p<0.05). However, none of single miRNA had significant correlation with clinical data and state. Data of the paired miRNAs: miR-10a and miR-200c, or miR-126 and miR-10a, clearly differentiated T2DM patients from normal subjects (p<0.05). Our study showed the paired-miRNA analyses as the more effective diagnostics for T2DM than the single miRNA analysis.
Effects of antennal segments defects on blood-sucking behavior in Aedes albopictus
Authors: Zhou Yiyuan , Deng Dongyang , Chen Rong , Chen Qian
Published: October 2022

After mating, female mosquitoes need a blood meal to promote the reproductive process. The blood-feeding transmits extremely harmful infections including malaria, yellow fever, dengue fever, and other arboviruses, making mosquitoes one of the most harmful creatures to human health. The selection and localization of the host by mosquitoes mainly depends on the trace chemical cues emitted by the host into the environment, and the sense of smell is the main way to perceive these trace chemical cues. However, the knowledge of the olfactory mechanism is not enough to meet the needs of mosquito control. Unlike previous studies that focused on the olfactory receptor recognition spectrum to reveal the olfactory mechanism of mosquito host localization. In this paper, we proposed that artificial defects in mosquito antennal flagellomeres may affect their blood-feeding behavior, and through rationally designed behavioral experiments, we found that the 6th and 7th flagellomeres on Aedes albopictus antenna are important in the olfactory detection of host searching. Meanwhile, the morphology and distribution of sensilla on each antenna flagellomere were also analyzed and discussed in this paper.
Active Fixation as an Efficient Coding Strategy for Neuromorphic Vision
Authors: Testa Simone , Sabatini Silvio P. , Canessa Andrea
Published: October 2022

Contrary to a photographer, who puts a great effort in keeping the lens still, eyes insistently move even during fixation. This benefits signal decorrelation, which underlies an efficient encoding of visual information. Yet, camera motion is not sufficient alone; it must be coupled with a sensor specifically selective to temporal changes. Indeed, motion induced on standard imagers only results in burring effects. Neuromorphic sensors represent a valuable solution. Here we characterize the response of an event-based camera equipped with Fixational Eye Movements (FEMs) on both synthetic and natural images. Our analyses prove that the system starts an early stage of redundancy suppression, as a precursor of subsequent whitening processes on the amplitude spectrum. This does not come at the price of corrupting structural information contained in local spatial phase across oriented axes. Isotropy of FEMs ensures proper representations of image features without introducing biases towards specific contrast orientations.