bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19)
Authors: Kim Jason , Zhang Jenny , Cha Yoonjeong , Kolitz Sarah , Funt Jason , Escalante Chong Renan , Barrett Scott , Kusko Rebecca , Zeskind Ben , Kaufman Howard
Published: June 2020

Background

The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19).

Methods

We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform.

Results

Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2.

Conclusions

While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.
Correction to: Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1
Authors: Okła Karolina , Rajtak Alicja , Czerwonka Arkadiusz , Bobiński Marcin , Wawruszak Anna , Tarkowski Rafał , Bednarek Wiesława , Szumiło Justyna , Kotarski Jan
Published: June 2020

An amendment to this paper has been published and can be accessed via the original article.
Tanshinone IIA alleviates brain damage in a mouse model of neuromyelitis optica spectrum disorder by inducing neutrophil apoptosis
Authors: Gong Ye , Zhang Ya-ling , Wang Zhen , Song Huan-huan , Liu Yuan-chu , Lv Ao-wei , Tian Li-li , Zhu Wen-li , Fu Ying , Ding Xiao-li , Cui Lang-jun , Yan Ya-ping
Published: June 2020

Background

Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune astrocytopathic disease associated with the anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions primarily located on the optic nerves and spinal cord. Tanshinone IIA (TSA), an active natural compound extracted from Salvia miltiorrhiza Bunge, has profound immunosuppressive effects on neutrophils.

Objective

The present study aimed to evaluate the effect of TSA on NMOSD mice and explore the underlying mechanisms. Mice were initially administered TSA (pre-TSA group, n = 20) or vehicle (vehicle group, n = 20) every 8 h for 3 days, and then NMOSD model was induced by intracerebral injection of NMOSD-immunoglobulin G (NMO-IgG) and human complement (hC). In addition, post-TSA mice (n = 10) were administered equal dose of TSA at 8 h and 16 h after model induction. At 24 h after intracerebral injection, histological analysis was performed to assess the inhibitory effects of TSA on astrocyte damage, demyelination, and neuroinflammation in NMOSD mice, and western blotting was conducted to clarify the effect of TSA on the NF-κB and MAPK signaling pathways. Furthermore, flow cytometry and western blotting were conducted to verify the proapoptotic effects of TSA on neutrophils in vitro.

Results

There was a profound reduction in astrocyte damage and demyelination in the pre-TSA group and post-TSA group. However, prophylactic administration of TSA induced a better effect than therapeutic treatment. The number of infiltrated neutrophils was also decreased in the lesions of NMOSD mice that were pretreated with TSA. We confirmed that prophylactic administration of TSA significantly promoted neutrophil apoptosis in NMOSD lesions in vivo, and this proapoptotic effect was mediated by modulating the caspase pathway in the presence of inflammatory stimuli in vitro. In addition, TSA restricted activation of the NF-κB signaling pathway in vivo.

Conclusion

Our data provide evidence that TSA can act as a prophylactic agent that reduces NMO-IgG-induced damage in the mouse brain by enhancing the resolution of inflammation by inducing neutrophil apoptosis, and TSA may serve as a promising therapeutic agent for neutrophil-associated inflammatory disorders, such as NMOSD.
Investigation of Atyp.C using UF-5000 flow cytometer in patients with a suspected diagnosis of urothelial carcinoma: a single-center study
Authors: Ren Chunyun , Wang Xing , Yang Chunwei , Li Shengchao , Liu Shuangchun , Cao Hongcui
Published: June 2020

Background

This study evaluated the predictive power of Atyp.C (a parameter of UF-5000 flow cytometer) for patients with a suspected diagnosis of urothelial carcinoma.

Methods

We analyzed 163 urine specimens from 128 patients with suspected urothelial carcinoma using a fully automated fluorescence flow cytometry analyzer (UF-5000) and evaluated its performance on identifying atypical/malignant urothelial cells. From January 1, 2019 to April 4, 2019, all consecutive specimens for urinary cytopathology were enrolled.

Results

Of the specimens with urinary cytopathology, 67 specimens (41.1%) revealed abnormal findings in cytology analysis. Among them, 20 specimens (12.3%) were diagnosed as atypical urothelial cells, 26 specimens (16.0%) as suspicious for malignancy (S-malignancy), and 21 specimens (12.9%) as confirmed malignancy. The UF-5000 findings were positive in 59 specimens (36.2%); therefore, the agreement with cytopathology was 73.0%. Using follow-up histologic diagnosis of urothelial carcinoma with or without urinary tract cytology (UTCy) as a reference standard (suspicious and confirmed malignancy were the positive criteria for UTCy), the sensitivity was 59.0%, specificity was 82.1%, positive predictive value was 75.0%, negative predictive value was 68.8%, and the agreement was 71.1%.

Conclusions

It is worth knowing and reporting that the Atyp.C assay may be used as an accessory test for patients with suspected urothelial carcinoma, based on its ability to identify high-risk patients who might need closer follow-up or additional medical treatment.
The predictive value of variables measurable in the ambulance and the development of the Predict Sepsis screening tools: a prospective cohort study
Authors: Wallgren Ulrika Margareta , Sjölin Jan , Järnbert-Pettersson Hans , Kurland Lisa
Published: June 2020

Background

Despite sepsis being a time critical condition with a high mortality, it is often not identified in a timely fashion. The aim of the current study was to create a screening tool based on bedside measurable variables predictive of sepsis among ambulance patients with infection according to clinical judgment by ambulance personnel.

Methods

Prospective cohort study of 551 adult patients presenting with suspected infection, performed in the ambulance setting of Stockholm during 2017–2018. 18 variables were measured in the ambulance (8 keywords related to medical history, 6 vital signs, 4 point-of-care blood tests, in addition to age, gender, and comorbidity. Logistic regression, area under the curve (AUC) and classification trees were used to study the association with sepsis. The AUC, sensitivity, specificity, predictive values and likelihood ratios were used to evaluate the predictive ability of sepsis screening models.

Results

The six variables with the strongest association with sepsis were: systolic blood pressure ≤ 100 mmHg, temperature > 38.5 °C, GCS < 15, lactate > 4 mmol/L, gastrointestinal symptoms, and a history of acute altered mental status. These were combined into the Predict Sepsis screening tool 1, with a sensitivity of 0.90, specificity 0.41, AUC 0.77; 95% confidence interval [CI] 0.73–0.81, PPV 0.52, and NPV 0.86. Combining a history of acute altered mental status with GCS < 15 and excluding lactate in the Predict Sepsis screening tool 2 did not noticeably affect the AUC. In addition, the AUCs of these models did not differ noticeably when compared to a model including vital signs alone, with novel calculated cut-offs; the Predict Sepsis screening tool 3.

Conclusions

Systolic blood pressure ≤ 100 mmHg, temperature > 38.5 °C, GCS < 15, lactate > 4 mmol/L, gastrointestinal symptoms, and a history of acute altered mental status demonstrated the strongest association with sepsis. We present three screening tools to predict sepsis with similar sensitivity. The results indicated no noticeable increase of predictive ability by including symptom-variables and blood tests to a sepsis screening tool in the current study population.

Trial registration

NCT03249597.
Mitochondria transfer enhances proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell and promotes bone defect healing
Authors: Guo Yusi , Chi Xiaopei , Wang Yifan , Heng Boon Chin , Wei Yan , Zhang Xuehui , Zhao Han , Yin Ying , Deng Xuliang
Published: June 2020

Background

Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is considered a promising therapeutic approach for bone defect repair. However, during the transplantation procedure, the functions and viability of BMSCs may be impaired due to extended durations of in vitro culture, aging, and disease conditions of patients. Inspired by spontaneous intercellular mitochondria transfer that naturally occurs within injured tissues to rescue cellular or tissue function, we investigated whether artificial mitochondria transfer into pre-transplant BMSCs in vitro could improve cellular function and enhance their therapeutic effects on bone defect repair in situ.

Methods

Mitochondria were isolated from donor BMSCs and transferred into recipient BMSCs of the same batch and passage. Subsequently, changes in proliferative capacity and cell senescence were evaluated by live cell imaging, Cell Counting Kit-8 assay, cell cycle analysis, Ki67 staining, qPCR and Western blot analysis of c-Myc expression, and β-galactosidase staining. Migration ability was evaluated by the transwell migration assay, wound scratch healing, and cell motility tests. Alkaline phosphatase (ALP) staining, Alizarin Red staining, and combined with qPCR and Western blot analyses of Runx2 and BMP2 were performed to elucidate the effects of mitochondria transfer on the osteogenic potential of BMSCs in vitro. After that, in vivo experiments were performed by transplanting mitochondria-recipient BMSCs into a rat cranial critical-size bone defect model. Micro CT scanning and histological analysis were conducted at 4 and 8 weeks after transplantation to evaluate osteogenesis in situ. Finally, in order to establish the correlation between cellular behavioral changes and aerobic metabolism, OXPHOS (oxidative phosphorylation) and ATP production were assessed and inhibition of aerobic respiration by oligomycin was performed.

Results

Mitochondria-recipient BMSCs exhibited significantly enhanced proliferation and migration, and increased osteogenesis upon osteogenic induction. The in vivo results showed more new bone formation after transplantation of mitochondria-recipient BMSCs in situ. Increased OXPHOS activity and ATP production were observed, which upon inhibition by oligomycin attenuated the enhancement of proliferation, migration, and osteogenic differentiation induced by mitochondria transfer.

Conclusions

Mitochondria transfer is a feasible technique to enhance BMSC function in vitro and promote bone defect repair in situ through the upregulation of aerobic metabolism. The results indicated that mitochondria transfer may be a novel promising technique for optimizing stem cell therapeutic function.
Endothelial colony-forming cells reduced the lung injury induced by cardiopulmonary bypass in rats
Authors: Sun Haibin , Zhao Xiaoqing , Tai Qihang , Xu Guangxiao , Ju Yingnan , Gao Wei
Published: June 2020

Background

Cardiopulmonary bypass (CPB) results in severe lung injury via inflammation and endothelial injury. The aim of this study was to evaluate the effect of endothelial colony-forming cells (ECFCs) on lung injury in rats subjected to CPB.

Methods

Thirty-two rats were randomized into the sham, CPB, CPB/ECFC and CPB/ECFC/L-NIO groups. The rats in the sham group received anaesthesia, and the rats in the other groups received CPB. The rats also received PBS, ECFCs and L-NIO-pre-treated ECFCs. After 24 h of CPB, pulmonary capillary permeability, including the PaO2/FiO2 ratio, protein levels in bronchoalveolar lavage fluid (BALF) and lung tissue wet/dry weight were evaluated. The cell numbers and cytokines in BALF and peripheral blood were tested. Endothelial injury, lung histological injury and apoptosis were assessed. The oxidative stress response and apoptosis-related proteins were analysed.

Results

After CPB, all the data deteriorated compared with those obtained in the S group (sham vs CPB vs CPB/ECFC vs CPB/ECFC/L-NIO: histological score 1.62 ± 0.51 vs 5.37 ± 0.91 vs 3.37 ± 0.89 vs 4.37 ± 0.74; PaO2/FiO2 389 ± 12 vs 233 ± 36 vs 338 ± 28 vs 287 ± 30; wet/dry weight 3.11 ± 0.32 vs 6.71 ± 0.73 vs 4.66 ± 0.55 vs 5.52 ± 0.57; protein levels in BALF: 134 ± 22 vs 442 ± 99 vs 225 ± 41 vs 337 ± 53, all P < 0.05). Compared to the CPB treatment, ECFCs significantly improved pulmonary capillary permeability and PaO2/FiO2. Similarly, ECFCs also decreased the inflammatory cell number and pro-inflammatory factors in BALF and peripheral blood, as well as the oxidative stress response in the lung tissue. ECFCs reduced the lung histological injury score and apoptosis and regulated apoptosis-related proteins in the lung tissue. Compared with the CPB/ECFC group, all the indicators were partly reversed by the L-NIO.

Conclusions

ECFCs significantly reduced lung injury induced by inflammation after CPB.
Shrimp miR-965 induced the human melanoma stem-like cell apoptosis and inhibited their stemness by disrupting the MCL-1-ER stress-XBP1 feedback loop in a cross-species manner
Authors: Wu Wenlin , Xu Chenxi , Zhang Xiaobo , Yu An , Shu Le
Published: June 2020

Background

Melanoma is a type of aggressive skin cancer with a poor survival rate. The resistance to conventional therapy of this disease is, at least in part, attributed to its cancer stem cell population. However, the mechanism of survival and stemness maintenance of cancer stem cells remains to be investigated.

Methods

Tumorsphere formation assay was used to study the stem-like property of melanoma stem-like cells (MSLC). Chromatin immunoprecipitation (ChIP), promoter luciferase reporter assay were included for exploring the role of MCL-1 in MSLC and electrophoretic mobility shift assay were used to evaluate the interaction between shrimp miR-965 and human Ago2 protein. Melanoma xenograft nude mice were used to study the inhibition of tumor development.

Results

In the present study, our results showed that myeloid cell leukemia sequence 1 (MCL-1) knocking down induced ER stress and apoptosis, and the expression reduction of stemness associated genes in MSLC, which implied a significant role of MCL-1 in MSLC. Further study indicated that ER stress agonist (tunicamycin) treatment in MSLC results in the translocation of XBP1, an ER stress sensor, into the nucleus to induce MCL-1 expression through direct binding to the − 313- to − 308-bp region of MCL-1 promoter. In addition, we found that a shrimp-derived miRNA (shrimp miR-965) could interact with the human Ago2 protein and suppressed the human MCL-1 expression by binding to the 3′ UTR of MCL-1 mRNA, thereby inhibiting the MSLC proliferation and stemness in vitro and in vivo in a cross-species manner.

Conclusion

In conclusion, we identified an important role of MCL-1-ER stress-XBP1 feedback loop in the stemness and survival maintenance of MSLC, and shrimp miR-965, a natural food derived miRNA, could regulate MSLC stemness and survival by targeting MCL-1 and disrupting the balance of MCL-1-ER stress-XBP1 feedback loop. In conclusion, this study indicated an important mechanism of the regulation of MSLC stemness and survival, otherwise it also demonstrated the significance of cross-species-derived miRNA as promising natural drugs in melanoma therapy.
Existence and Ulam stability results of a coupled system for terminal value problems involving ψ-Hilfer fractional operator
Authors: Abdo Mohammed S. , Shah Kamal , Panchal Satish K. , Wahash Hanan A.
Published: June 2020

The work reported in this paper deals with the study of a coupled system for fractional terminal value problems involving ψ-Hilfer fractional derivative. The existence and uniqueness theorems to the problem at hand are investigated. Besides, the stability analysis in the Ulam–Hyers sense of a given system is studied. Our discussion is based upon known fixed point theorems of Banach and Krasnoselskii. Examples are also provided to demonstrate the applicability of our results.
Generalization of movements in quadruped robot locomotion by learning specialized motion data
Authors: Yamamoto Hiroki , Kim Sungi , Ishii Yuichiro , Ikemoto Yusuke
Published: June 2020

Machines that are sensitive to environmental fluctuations, such as autonomous and pet robots, are currently in demand, rendering the ability to control huge and complex systems crucial. However, controlling such a system in its entirety using only one control device is difficult; for this purpose, a system must be both diverse and flexible. Herein, we derive and analyze the feature values of robot sensor and actuator data, thereby investigating the role that each feature value plays in robot locomotion. We conduct experiments using a developed quadruped robot from which we acquire multi-point motion information as the movement data; we extract the features of these movement data using an autoencoder. Next, we decompose the movement data into three features and extract various gait patterns. Despite learning only the “walking” movement, the movement patterns of trotting and bounding are also extracted herein, which suggests that movement data obtained via hardware contain various gait patterns. Although the present robot cannot locomote with these movements, this research suggests the possibility of generating unlearned movements.
Consumer resistance to innovation: smart clothing
Authors: Ju Naan , Lee Kyu-Hye
Published: June 2020

Smart clothing is believed to have an enormous growth potential, but at present, it is not so attractive in terms of sales. This study identified various obstacles affecting consumers’ interest in smart clothing. Interviews were conducted with consumers who are resistant to innovation, those who would continue to use their phones and wearable devices of which safety and functionality have already been proven but reject smart clothing. Availability, which refers to the extent to which consumers can use a product or service, is also a significant factor influencing the innovation resistance of smart clothing. It was also observed that consumers reject smart clothing as an act of resisting innovation; many stated that they would not buy smart clothing unless a trustable brand produces it with appropriate functions and lower prices. Some people said that they refuse to purchase smart clothing due to aesthetic dissatisfaction despite the improved quality and performance. These results indicate that manufacturers should consider what functionality or technology would be appropriate to incorporate in clothing while ensuring fashionable styles and availability in many sizes.
Healthcare utilisation prior to suicide in persons with alcohol use disorder: national cohort and nested case–control study
Authors: Crump Casey , Edwards Alexis C. , Kendler Kenneth S. , Sundquist Jan , Sundquist Kristina
Published: June 2020

Background

Alcohol use disorder (AUD) is common and associated with increased risk of suicide.

Aims

To examine healthcare utilisation prior to suicide in persons with AUD in a large population-based cohort, which may reveal opportunities for prevention.

Method

A national cohort study was conducted of 6 947 191 adults in Sweden in 2002, including 256 647 (3.7%) with AUD, with follow-up for suicide through 2015. A nested case–control design examined healthcare utilisation among people with AUD who died by suicide and 10:1 age- and gender-matched controls.

Results

In 86.7 million person-years of follow-up, 15 662 (0.2%) persons died by suicide, including 2601 (1.0%) with AUD. Unadjusted and adjusted relative risks for suicide associated with AUD were 8.15 (95% CI 7.86–8.46) and 2.22 (95% CI 2.11–2.34). Of the people with AUD who died by suicide, 39.7% and 75.6% had a healthcare encounter <2 weeks or <3 months before the index date respectively, compared with 6.3% and 25.4% of controls (adjusted prevalence ratio (PR) and difference (PD), <2 weeks: PR = 3.86, 95% CI 3.50–4.25, PD = 26.4, 95% CI 24.2–28.6; <3 months: PR = 2.03, 95% CI 1.94–2.12, PD = 34.9, 95% CI 32.6–37.1). AUD accounted for more healthcare encounters within 2 weeks of suicide among men than women (P = 0.01). Of last encounters, 48.1% were in primary care and 28.9% were in specialty out-patient clinics, mostly for non-psychiatric diagnoses.

Conclusions

Suicide among persons with AUD is often shortly preceded by healthcare encounters in primary care or specialty out-patient clinics. Encounters in these settings are important opportunities to identify active suicidality and intervene accordingly in patients with AUD.
Advanced Radiation Therapy Technology Use in the Treatment of Bone Metastases in a Public, Salary-Funded, Non-Incentivized Health Care System
Authors: Chan Matthew , Olson Robert , Lefresne Shilo , McKenzie Michael
Published: June 2020

PURPOSE:

There is limited evidence to support the routine use of conformal radiotherapy (RT) techniques in the treatment of bone metastases. This study evaluated trends in advanced technique use within the province of British Columbia.

MATERIALS AND METHODS:

Data on patients who received RT for bone metastases between 2009 and 2016 (with the exception of 2012) at 6 regional cancer centers were reviewed. Descriptive statistics summarized radiation technique patterns. Logistic regression assessed the influence of patient, treatment, and provider variables on receipt of RT technique.

RESULTS:

A total of 24,215 RT courses were identified; 97% were planned by simple RT and 3% by advanced techniques (3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic body radiotherapy). The use of advanced techniques was significantly higher in recent years compared with in 2009 (odds ratios [ORs], 2.2, 4.2, 4.2, and 6.3, respectively, for the years 2013 to 2016; P < .001). Patients with thyroid, sarcoma, and neuroendocrine malignancies (ORs, 10.3, 5.5, and 5.2, respectively; P < .005) were more likely to be treated with advanced techniques, as were skull, sternum, rib, and pelvic metastases (ORs, 8.0, 5.2, 2.2, and 2.2, respectively; P < .001). Advanced techniques were most commonly used in the setting of re-irradiation (38%). They were associated with slightly higher incompletion rates (3.0% v 1.5%, P < .005) and less use within 30 days of death (6% v 15%, P < .001).

CONCLUSION:

Within our publicly funded, salary-based provincial health care system, we found that the majority of bone metastases are still being treated by simple RT; however, the use of advanced techniques is increasing, and we identified select patterns in which they are being prescribed. Additional study into clinical benefit is required.
Palbociclib in Patients With Non–Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study
Authors: Ahn Eugene R. , Mangat Pam K. , Garrett-Mayer Elizabeth , Halabi Susan , Dib Elie G. , Haggstrom Daniel E. , Alguire Kathryn B. , Calfa Carmen J. , Cannon Timothy L. , Crilley Pamela A. , Gaba Anu G. , Marr Alissa S. , Sangal Ashish , Thota Ramya , Antonelli Kaitlyn R. , Islam Samiha , Rygiel Andrew L. , Bruinooge Suanna S. , Schilsky Richard L.
Published: June 2020

PURPOSE

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non–small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported.

METHODS

Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon’s two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety.

RESULTS

Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting.

CONCLUSION

Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.
A Dispute over Patrimonial Property in Huaquechula, Mexico: The Chimalhua Case, 1738–1740
Authors: Mysyk Avis , Martínez Edgar de Ita
Published: June 2020

Throughout the colonial period, disputes over the inheritance of property were common among indigenous peoples, both nobles and commoners. From the outset, they became familiar with and adept at negotiating their interests from within the colonial legal system. Based on the corresponding archival document and map, this article explores how the Chimalhuas used this system to resolve an intrafamilial dispute over patrimonial property. The dispute was not one between equals but, because the Spanish legal system was flexible, its legal decisions arbitrary, both sides attempted to use late-colonial modes of argumentation, legal strategies, and status- and class-based rhetoric to their advantage. This article also considers how the wider context of indigenous population recovery and Spanish pressure on resources within which the dispute occurred had implications for two separate but related issues. First, the status of the Chimalhuas had declined and, second, the dispute was largely confined to the negotiation of individual interests.
Subjects under Duress: The Greek Rant
Authors: Reuter Victoria A.
Published: June 2020

The literary rant is a unique mode of expression employed by dispossessed subjects to performatively highlight the mechanisms of their oppression and to create a rhetorical and political subject position from which to speak. The rant relies on the reader’s complicity to witness the speech of the other, and as such, it is like Judith Butler’s rhetorical “scene of address” in which a listener judges the speaker as a recognizable member of society, or not. The ranter’s language moves outside the domain of speakability, risking misunderstanding in order to confront the limitations of language and the sociopolitical system that has cast them out. It is a risk that challenges both the identity of the speaker and the social norms and responsibilities of the listener. Building on Dina Al-Kassim’s scholarship on the rant, this article uses examples from Greek journalism and prose to demonstrate how ranting narrators usurp and redeploy sovereign speech to create a spectacle of their own abjection. Examination of Dimitris Dimitriadis’s “Abomination” and selected stories from Christos Iconomou’s Good Will Come from the Sea foregrounds the ranter’s dispossession and explores the disruptive power that this speaking position offers.
Carceral Entanglement in the Work of Leila Abdelrazaq
Authors: Feldman Keith P.
Published: June 2020

This essay considers how the graphic arts of Leila Abdelrazaq give form to Palestine’s contemporary worldliness and to the worldliness of Palestinian difference. It argues that Abdelrazaq’s work illustrates the entanglement of diaspora, memory, and futurity within the interconnected structures of enclosure and expulsion.
Indefinite Detention
Authors: Butler Judith
Published: June 2020

Indefinite detention is a legal norm and practice that is increasingly acceptable throughout the world. It consists of arrest and forcible detention without a clear communication of crimes committed, and it can last indefinitely, since it deprives the detained of recourse to courts for review and release. Kafka’s Trial, which brought this kind of legal nightmare into focus, proves relevant for understanding the temporal sequence by which the expectation of justice through law is confounded and negated. Over and against the expectation that a set of legal procedures sequentially followed will deliver a fair verdict, if not justice, Kafka’s reordering of space and time exposes a world in which the allegation becomes punishment and the expected release becomes the renewal of detention itself. The relation between fictional and legal sequence proves salient for understanding the indefinite postponement of justice through law, exposing in the end a form of legal violence indistinguishable from criminality.
Critical (Dis)pleasure
Authors: Penteado Bruno
Published: June 2020

Recent developments in literary studies that can be grouped under the umbrella term postcritique purport to restore, in our disciplinary practices, attention to affect, pleasure, and attachment, which postcritics believe the critical tradition has silenced and neglected. Postcritics depict critique as a violent hermeneutic practice of excavating a text’s hidden truths. This essay claims that postcritique’s understanding of critical theory is misguided and caricatural. By focusing on key thinkers of the critical tradition, particularly French philosophers, it argues that hermeneutic openness and nonmastery is a constant in many critical writings—and so is the question of pleasure. It suggests that many of postcritique’s propositions, which postcritics affirm are innovative and claim critique has disavowed, have always been a recurring topic in the work of critical theorists.
Blanchot and Lautréamont
Authors: Allen William S.
Published: June 2020

Blanchot’s readings of Lautréamont are among the most important writings on this challenging author, and they are also crucial for the development of his own thinking, but they have never been discussed in depth. This essay surveys the whole range of Blanchot’s writings on Lautréamont and shows how they constitute the first considered attempt within his thinking to examine the notions of the fantastic and the image in relation to the experience of metaphor. This survey not only enables a renewed understanding of the significance of Lautréamont’s writings but also reveals how Blanchot transforms the Hegelian thinking of experience by way of its passage through literature.
Universal History Upside Down
Authors: Buck-Morss Susan
Published: June 2020

Universal history as traditionally understood emerged out of the semi-secularization of Biblical history that followed Georg Wilhelm Friedrich Hegel’s attempt to think the whole of religion, philosophy, and history as a cosmological system of modernity. That was the nineteenth century. In the twentieth century, universal history became an attempt to include all so-called civilizations within an academic canon. By unearthing the central significance of the Haitian Revolution for Hegel’s idea of freedom, the author argues for an inversion of historical understanding: the alleged margins of history are central, the alleged divisions between histories are mythical, and the goal of a universal history of humanity is to be achieved by dismantling the topology in which the past has been framed and passed down to us. The goal is to disrupt the intellectual order by exposing the blind spots that hinder conceptual, hence political, imagination—a writing of universal history upside down. A universal history worthy of the name will go far beyond the notion of correcting the Eurocentricity of history writing; it will need to be based on a deprivatized, denationalized structure of collective memory, effecting nothing short of a different world order. If the present is imagined not as the culmination of the past but rather as its rescue, then a radical pedagogy practices this gesture in its mode of historical recuperation. Theoretical pragmatics as a method of universal history, the transitory visibility of truth, respects the past’s lack of closure and welcomes the past’s intrusion in the present. It views history as a gift, given to all of us, without restrictions.
Nudity and Pleasure
Authors: Diabate Naminata
Published: June 2020

Cultural products and discourses about erotic pleasure have recently proliferated, leading to what the author calls “the pleasure turn.” In studies of African culture, “the pleasure turn” can be read as decentering the dominant paradigm that has mostly associated black nakedness with negative emotions: sorrow, pain, and humiliation. Illustrative of the turn is the 2009 exhibition Beauty and Pleasure in South African Contemporary Art, which considered pain and suffering as overrated and sought to provide a more accurate picture of life on the continent as a mix of pleasure and pain. This article closely reads the South African multimedia artist Dineo Bopape’s 2008 Silent Performance, alongside Berni Searle’s 2001 politically charged Snow White, to point out their generative potential for the intersection of the visual media, erotic pleasure, and nudity. Traditional views of pleasure have avoided the nexus of erotic pleasure and the visual because of their historical association with nineteenth-century scientific racism. The author argues Bopape’s and Searle’s images exceed a single and stable interpretation. By inserting their (semi-)naked bodies as central images, they invite yet resist unwanted readings of erotic pleasure in their works. Incorporating her analysis of these works into her conceptualization of images of black female nudity in art, the author proposes that a robust attention be given the visual image in the rising conversation on pleasure in African studies.
Cortical distribution of GABAergic interneurons is determined by migration time and brain size
Authors: Fazzari Pietro , Mortimer Niall , Yabut Odessa , Vogt Daniel , Pla Ramon
Published: June 2020

Cortical interneurons (CINs) originate in the ganglionic eminences (GEs) and migrate tangentially to the cortex guided by different attractive and repulsive cues. Once inside the cortex, the cellular and molecular mechanisms determining the migration of CINs along the rostrocaudal axis are less well understood. Here, we investigated the cortical distribution of CINs originating in the medial and caudal GEs at different time points. Using molecular and genetic labeling, we showed that, in the mouse, early- and late-born CINs (E12 versus E15) are differentially distributed along the rostrocaudal axis. Specifically, late-born CINs are preferentially enriched in cortical areas closer to their respective sites of origin in the medial or caudal GE. Surprisingly, our in vitro experiments failed to show a preferential migration pattern along the rostrocaudal axis for medial- or caudal-born CINs. Moreover, in utero transplantation experiments suggested that the rostrocaudal dispersion of CINs depends on the developmental stage of the host brain and is limited by the migration time and the increasing size of the developing brain. These data suggest that the embryonic expansion of the cortex contributes to the rostrocaudal distribution of CINs.
C-terminal phosphorylation modulates ERM-1 localization and dynamics to control cortical actin organization and support lumen formation during Caenorhabditis elegans development
Authors: Ramalho João J. , Sepers Jorian J. , Nicolle Ophélie , Schmidt Ruben , Cravo Janine , Michaux Grégoire , Boxem Mike
Published: June 2020

ERM proteins are conserved regulators of cortical membrane specialization that function as membrane-actin linkers and molecular hubs. The activity of ERM proteins requires a conformational switch from an inactive cytoplasmic form into an active membrane- and actin-bound form, which is thought to be mediated by sequential PIP2 binding and phosphorylation of a conserved C-terminal threonine residue. Here, we use the single Caenorhabditis elegans ERM ortholog, ERM-1, to study the contribution of these regulatory events to ERM activity and tissue formation in vivo. Using CRISPR/Cas9-generated erm-1 mutant alleles, we demonstrate that a PIP2-binding site is crucially required for ERM-1 function. By contrast, dynamic regulation of C-terminal T544 phosphorylation is not essential but modulates ERM-1 apical localization and dynamics in a tissue-specific manner, to control cortical actin organization and support lumen formation in epithelial tubes. Our work highlights the dynamic nature of ERM protein regulation during tissue morphogenesis and the importance of C-terminal phosphorylation in fine-tuning ERM activity in a tissue-specific context.
Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia
Authors: Fil Daniel , Chacko Balu K. , Conley Robbie , Ouyang Xiaosen , Zhang Jianhua , Darley-Usmar Victor M. , Zuberi Aamir R. , Lutz Cathleen M. , Napierala Marek , Napierala Jill S.
Published: June 2020

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, whereas a fraction of patients are compound heterozygotes, with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring an Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure-to-thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA lesions and fragmentation are accompanied by marked amplification of mitochondrial DNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life, and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.
Rabbit model of Staphylococcus aureus implant-associated spinal infection
Authors: Gordon Oren , Miller Robert J. , Thompson John M. , Ordonez Alvaro A. , Klunk Mariah H. , Dikeman Dustin A. , Joyce Daniel P. , Ruiz-Bedoya Camilo A. , Miller Lloyd S. , Jain Sanjay K.
Published: June 2020

Post-surgical implant-associated spinal infection is a devastating complication commonly caused by Staphylococcus aureus. Biofilm formation is thought to reduce penetration of antibiotics and immune cells, contributing to chronic and difficult-to-treat infections. A rabbit model of a posterior-approach spinal surgery was created, in which bilateral titanium pedicle screws were interconnected by a plate at the level of lumbar vertebra L6 and inoculated with a methicillin-resistant S. aureus (MRSA) bioluminescent strain. In vivo whole-animal bioluminescence imaging (BLI) and ex vivo bacterial cultures demonstrated a peak in bacterial burden by day 14, when wound dehiscence occurred. Structures suggestive of biofilm, visualized by scanning electron microscopy, were evident up to 56 days following infection. Infection-induced inflammation and bone remodeling were also monitored using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and computed tomography (CT). PET imaging signals were noted in the soft tissue and bone surrounding the implanted materials. CT imaging demonstrated marked bone remodeling and a decrease in dense bone at the infection sites. This rabbit model of implant-associated spinal infection provides a valuable preclinical in vivo approach to investigate the pathogenesis of implant-associated spinal infections and to evaluate novel therapeutics.
Photoperiodic induction without light-mediated circadian entrainment in a high arctic resident bird
Authors: Appenroth Daniel , Melum Vebjørn J. , West Alexander C. , Dardente Hugues , Hazlerigg David G. , Wagner Gabriela C.
Published: June 2020

Organisms use changes in photoperiod to anticipate and exploit favourable conditions in a seasonal environment. While species living at temperate latitudes receive day length information as a year-round input, species living in the Arctic may spend as much as two-thirds of the year without experiencing dawn or dusk. This suggests that specialised mechanisms may be required to maintain seasonal synchrony in polar regions.

Svalbard ptarmigan (Lagopus muta hyperborea) are resident at 74-81° north latitude. They spend winter in constant darkness (DD) and summer in constant light (LL); extreme photoperiodic conditions under which they do not display overt circadian rhythms.

Here we explored how arctic adaptation in circadian biology affects photoperiodic time measurement in captive Svalbard ptarmigan. For this purpose, DD-adapted birds, showing no circadian behaviour, either remained in prolonged DD, were transferred into a simulated natural photoperiod (SNP) or were transferred directly into LL. Birds transferred from DD to LL exhibited a strong photoperiodic response in terms of activation of the hypothalamic thyrotropin-mediated photoperiodic response pathway. This was assayed through expression of the Eya3, Tshβ and deiodinase genes, as well as gonadal development. While transfer to SNP established synchronous diurnal activity patterns, activity in birds transferred from DD to LL showed no evidence of circadian rhythmicity.

These data show that the Svalbard ptarmigan does not require circadian entrainment to develop a photoperiodic response involving conserved molecular elements found in temperate species. Further studies are required to define how exactly arctic adaptation modifies seasonal timer mechanisms.
Functional effect of vaterite – the presence of an alternative crystalline structure in otoliths alters escape kinematics of the brown trout
Authors: Vignon Matthias , Aymes Jean-Christophe
Published: June 2020

The fast-start escape response is the main locomotor behaviour observed in fish to evade predatory attacks and thereby increase their probability of survival. Thus far, this high-speed sensory motor control has been extensively studied in relation to extrinsic factors. In contrast, there has been surprisingly little consideration of intrinsic individual factors that can mediate sensorial perception, such as inter-individual variability in mechanosensory systems. The inner ear of teleost fishes is composed of otoliths that play an important role in hearing and balance functions. While sagittal otoliths are normally composed of aragonite in many fish species, the inclusion of vaterite (an abnormal crystalline structure) has been reported in a number of individuals from different environments. There is currently strong theoretical and empirical evidence that vaterite deposition has a negative impact on auditory sensitivity in fishes. While the functional/behavioural implications of this defect on otolith-related hearing function has been hypothesised, it has remained largely untested experimentally. Here, using juvenile (0+ years) Salmo trutta originating from the wild in experimental conditions, we report for the first time that the deposition of calcium carbonate in its crystalline vateritic polymorph has significant pervasive effects on the escape kinematics of fish. The presence of an alternative crystalline structure in otoliths is likely to alter fish behaviour in ways that decrease survival. We also report that altered behaviour in individuals with vateritic otoliths is partially compensated for by the presence of a functional lateral line. Such functional compensation suggests more slight consequences, if any, in the wild.
Aquatic and terrestrial takeoffs require different hindlimb kinematics and muscle function in mallard ducks
Authors: Taylor-Burt Kari R. , Biewener Andrew A.
Published: June 2020

Mallard ducks are capable of performing a wide range of behaviors including nearly vertical takeoffs from both terrestrial and aquatic habitats. The hindlimb plays a key role during takeoffs from both media. However, because force generation differs in water versus on land, hindlimb kinematics and muscle function are likely modulated between these environments. Specifically, we hypothesize that hindlimb joint motion and muscle shortening are faster during aquatic takeoffs, but greater hindlimb muscle forces are generated during terrestrial takeoffs. In this study, we examined the hindlimb kinematics and in vivo contractile function of the lateral gastrocnemius (LG), a major ankle extensor and knee flexor, during takeoffs from water versus land in mallard ducks. In contrast to our hypothesis, we observed no change in ankle angular velocity between media. However, the hip and metatarsophalangeal joints underwent large excursions during terrestrial takeoffs but exhibited almost no motion during aquatic takeoffs. The knee extended during terrestrial takeoffs but flexed during aquatic takeoffs. Correspondingly, LG fascicle shortening strain, shortening velocity, and pennation angle change were greater during aquatic takeoffs than terrestrial takeoffs due to the differences in knee motion. Nevertheless, we observed no significant differences in LG stress or work, but did see an increase in muscle power output during aquatic takeoffs. Because differences in the physical properties of aquatic and terrestrial media require differing hindlimb kinematics and muscle function, animals such as mallards may be challenged to tune their muscle properties for movement across differing environments.