bluuebunny/crossref_metadata_2025 huggingface dataset:
The Associations Between Alanine Aminotransferase and Other Biochemical Parameters in Lean PCOS
Authors: Liu Cai , Liu Kai , Zhao Xiao , Zhu Junhua , Liu Yang , Hao Lina , Gao Yanyun , Liu Peng
Published: July 2022

To explore the associations of alanine aminotransferase in lean women of polycystic ovary syndrome (PCOS) with other biochemical parameters and the potential risk factors. This is a retrospective cohort study with lean PCOS (n = 91) and healthy controls (n = 45); we reviewed the electrical records and databases of the PCOS patients in our infertility clinic between January 2019 and September 2021; independent t-test, linear correlation analysis, and multiple linear regression were used to explore the associations. Higher levels of luteinizing hormone, total testosterone, thyroid stimulating hormone, platelet count, lymphocyte count, homocysteine, alanine aminotransferase (ALT), and uric acid were identified in lean PCOS patients, while follicle-stimulating hormone level was lower in in lean PCOS as expected (P < 0.05). Of note, the linear correlation showed that BMI, total testosterone, white blood cell count, lymphocyte count, aspartate aminotransferase, and uric acid were positively associated with alanine aminotransferase (r = 0.232, 0.318, 0.218, 0.388, 0.602, 0.353 respectively, P < 0.05). After multiple linear regression was performed, total testosterone and aspartate aminotransferase were independently and positively correlated with alanine aminotransferase in lean PCOS (B = 0.251, 0.605 respectively, P < 0.05). Higher level of ALT was identified in the lean PCOS. BMI, white blood cell count, lymphocyte count, aspartate aminotransferase, uric acid, and total testosterone were positively correlated with ALT in lean PCOS. Total testosterone and aspartate aminotransferase were independently and positively associated with ALT in lean PCOS after multiple linear regression. There might exist a potential risk of afflicting liver impairment for the lean PCOS women in the earlier period. Early examination and intervention might be necessary to prevent or delay the progression of the liver disease as soon as the diagnosis of PCOS.
Quasi-Banach modulation spaces and localization operators on locally compact abelian groups
Authors: Bastianoni Federico , Cordero Elena
Published: July 2022

We introduce new quasi-Banach modulation spaces on locally compact abelian groups which coincide with the classical ones in the Banach setting and prove their main properties. Then, we study Gabor frames on quasi-lattices, significantly extending the original theory introduced by Gröchenig and Strohmer. These issues are the key tools in showing boundedness results for Kohn–Nirenberg and localization operators on modulation spaces and studying their eigenfunctions’ properties. In particular, the results in the Euclidean space are recaptured.
Sexual Dysfunctions Among People Living with HIV With Long-Term Treatment with Antiretroviral Therapy
Authors: Scanavino Marco De Tubino , Mori Emi , Nisida Vera Vichr , Avelino-Silva Vivian I. , Amaral Maria Luiza Sant'ana do , Messina Bruna , Segurado Aluisio Cotrim
Published: July 2022

Introduction

Sexuality plays an essential role in the psychosocial well-being of people living with HIV (PLHIV) but it is still less assessed by healthcare professionals during treatment.

Aim

To investigate the frequency of those screening positive for sexual dysfunction (SD) and associated factors according to gender/sexual orientation in PLHIV under long-term treatment with antiretroviral therapy (ART).

Methods

Between September 2013 and October 2016, 234 PLHIV adults in treatment in São Paulo were included. Participants were sexually active, did not present sexual orientation disorder or body dysmorphic disorder, and did not use sexual hormones. We performed clinical interviews and measured levels of depression, anxiety, and levels of sexual hormones. SD was assessed using a self-report questionnaire.

Main Outcome Measures

Proportion of participants screening positive for SD in the International Index of Erectile Function, the Index of Premature Ejaculation, and the Female Sexual Function Index. In the regression analyses, the outcome SD considered any SD presented with disregard to gender.

Results

70% of participants reported consistent adherence to ART and 96% had an undetectable viral load. The median (Md) duration of ART was 198 months (inter quartil range, IQR 111.6–230.4) and the median CD4 was 655 cells/mm3 (IQR 443–871). Screening positive for erectile dysfunction was 49.7%, premature ejaculation 16.9%, female sexual dysfunction 27.4% and hypoactive desire 45.1%. Lower testosterone and prolactin levels were associated with erectile dysfunction in heterosexual men (n = 58); lower levels of oestradiol and higher levels of follicle stimulating hormone were associated with female sexual dysfunction and hypoactive desire in female participants (n = 63). The multivariable model used included comorbidities and hormonal abnormality and found that age (odds ratio, OR = 1.04, 95% confidence interval, 95%CI 1.00–1.08, P = .026) and the presence of depression/anxiety (OR = 2.96; 95%CI 1.52–5.77; P = .001) were associated with SD. Also, men reporting engaging in sex with other men were associated with screening positive for SD (OR 2.66; 95%CI 1.52–5.77, P = .013).

During treatment of PLHIV, it is important to evaluate sexual health and symptoms of depression and anxiety specifically.

The strength of this study consists in evaluating PLHIV who have been in long-term treatment with ART and analyzing those screening positive for SD and associated factors for each group (heterosexual men, men reporting engaging in sex with other men, and women). Limitation includes the difficulty to generalize the findings of the study, and not exploring women's sexual orientation.

Conclusion

PLHIV in long-term treatment with ART presented alarming rates of depression/anxiety which in turn is correlated with sexual and physical health problems.
Sexual Activity, Function and Dysfunction After a Diagnosis of Bladder Cancer
Authors: Jubber Ibrahim , Rogers Zoe , Catto James WF , Bottomley Sarah , Glaser Adam , Downing Amy , Absolom Kate
Published: July 2022

Background

Sexual dysfunction is common in those affected by cancer and local and radical treatments for Bladder Cancer (BC) can affect sexual function directly.

Aim

To evaluate sexual function following a bladder cancer (BC) diagnosis.

Methods

Self-reported sexual function was collected 10 years after a diagnosis of BC as part of a cross-sectional patient reported outcome measure (PROM) survey exploring life after BC diagnosis and treatment.

Outcomes

Participants completed a combined EORTC QLQ-BLM30 and QLQ-NMIBC24 questionnaire, including questions on sexual activity, intimacy, erectile/ejaculatory function and vaginal dryness.

Results

A total of 1796 participants returned a completed survey out of 3279 eligible participants (55%). Of the participants who returned a completed survey, a total of 1530 (85%) participants answered sexual function questions. The median (IQR) age was 75 (70–81). Participants were predominantly men (78%) and married/in civil partnerships (66%). In total, 31% were sexually active. Vaginal dryness was common (66%) in women. Erectile and ejaculatory dysfunction (80% and 58% respectively) were common in men. Compared to TURBT +/- intravesical treatments, those who had radical treatment were less likely to be sexually active (adjusted OR 0.56, 95% CI: 0.44–0.72, P<0.001) and had worse mean scores for intimacy problems (29.1 [radical treatment] vs 12.1, P<0.001), male sexual problems (72.2 [radical treatment] vs 45.7, P<0.001) and overall sexual function (17.1 [radical treatment] vs 20.3, P=0.01).

Clinical Implications

These findings highlight the magnitude of sexual dysfunction in the BC patient cohort and can help inform patients during the pre-op counselling process and shared decision making prior to BC treatments.

Strengths and Limitations

This study provides the largest in-depth analysis of sexual activity and function after BC diagnosis and treatment, to date. Limitations include the lack of data on participants’ sexual function prior to BC treatment and the heterogeneity with respect to time passed since last BC treatment.

Conclusion

Sexual dysfunction in BC patients is common and rates appear higher following radical treatments compared to endoscopic. It is important to elicit these problems in clinics to enable counselling and treatment.
State Formation through Emulation
Authors: Huang Chin-Hao , Kang David C.
Published: July 2022

Neither war nor preparations for war were the cause or effect of state formation in East Asia. Instead, emulation of China—the hegemon with a civilizational influence—drove the rapid formation of centralized, bureaucratically administered, territorial governments in Korea, Japan, and Vietnam. Furthermore, these countries engaged in state-building not to engage in conflict or to suppress revolt. In fact, war was relatively rare and there was no balance of power system with regular existential threats—the longevity of the East Asian dynasties is evidence of both the peacefulness of their neighborhood and their internal stability. We challenge the assumption that the European experience with war and state-making was universal. More importantly, we broaden the scope of state formation in East Asia beyond the study of China itself and show how countries in the region interacted and learned from each other and China to develop strong capacities and stable borders.
The Origin Legends of Early Medieval Britain and Ireland
Authors: Brady Lindy
Published: July 2022

The inhabitants of early medieval Britain and Ireland shared the knowledge that the region held four peoples and the awareness that they must have originally come from 'elsewhere'. The Origin Legends of Early Medieval Britain and Ireland studies these peoples' origin stories, an important genre that has shaped national identity and collective history from the early medieval period to the present day. These multilingual texts share many common features that repay their study as a genre, but have previously been isolated as four disparate traditions and used to argue for the long roots of current nationalisms. Yet they were not written or read in isolation during the medieval period. Individual narratives were in constant development, written and rewritten to respond to other texts. This book argues that insular origin legends developed together to flesh out the history of the insular region as a whole.
Essentials of Hydraulics
Authors: Julien Pierre Y.
Published: July 2022

Written for a one-semester course in hydraulics, this concise textbook is rooted in the fundamental principles of fluid mechanics and aims to promote sound hydraulic engineering practice. Basic methods are presented to underline the theory and engineering applications, and examples and problems build in complexity as students work their way through the textbook.
Abundant worked examples and calculations, real-world case studies, and revision exercises, as well as precisely crafted end-of-chapter exercises ensure students learn exactly what they need in order to consolidate their knowledge and progress in their career.
Students learn to solve pipe networks, optimize pumping systems, design pumps and turbines, solve differential equations for gradually-varied flow and unsteady flow, and gain knowledge of hydraulic structures like spillways, gates, valves, and culverts. An essential textbook for intermediate to advanced undergraduate and graduate students in civil and environmental engineering.
Role of flexibility on the aerodynamic performance of a resonating hummingbird-inspired wing
Authors: Kumar D. , Singh G. , Mohite P.M. , Lau E.M. , Wang Y.-C.
Published: July 2022

This work investigates the role of flexibility and resonant excitation on the deformation mechanism and aerodynamic performance of flapping wings. A hummingbird-inspired wing (HIW) is considered and designed to have a bone-like stiffener made of carbon fibre/epoxy (CF/E) composite attached to a membrane made of carbon nanotubes/polypropylene (CNTs/PP) nanocomposite representing the flexible part of the natural wing. The designed HIW model is analysed through fluid-structure interaction simulations performed at frequencies near and at resonant frequency. It is found that HIW generates desired bending and twisting deformations that are coupled. These deformation mechanisms are studied in detail with the help of time-varying deflections and bending-twisting angles. Further, the simultaneous effect of these parameters on the aerodynamic performance of the wing is also investigated. It is observed that the coupled nature of bending and twisting deformations is critical in enhancing the aerodynamic performance of flapping wings. In addition to that, the resonance generates higher amplitude of desired structural deformations that further enhances thrust as well as lift generation capability of the wing. The underlying mechanism for this is also explained by studying the flow around the deflected surface of the wing. Compared to off-resonant frequencies, vorticity and pressures are substantially higher for the wing at resonance. A physical model of HIW is realised using CNTs/PP and CF/E composites to perform experimental wing motion analysis and to validate the computational results. In conclusion, the present study provides a basis to design efficient biomimetic flapping wings for micro aerial vehicles (MAVs) by exploring flexibility and resonant excitation.
Why Is the Accumulation of Knowledge So Hard? Exploring Econometric Research on the Determinants of Public Social Spending in Latin America
Authors: Flechtner Svenja , Sánchez-Ancochea Diego
Published: July 2022

Many areas in applied econometric research within political economy fail to come up with conclusive findings. This is the case, for example, with studies on the determinants of public social spending in Latin America, a key area of research given the impact of social programs on poverty, inequality, and welfare more generally. In this area, as in others, it is hard to identify clear answers regarding the impact of economic processes and political institutions. Two reasons explain this lack of knowledge accumulation. First, each study uses different data sources and analytical models. Second, some of the empirical strategies required to solve various econometric problems may affect the results. This article questions the role of econometric research as the only method to explore political economy questions and highlights the importance of promoting conversations between complementary methods of both quantitative and qualitative traditions.
“Saints” or “Scabs”: Contesting Feminized Labors, Social Needs, and the Welfare State in the Volunteering Wars of the 1970s
Authors: Turk Katherine
Published: July 2022

The fate of caring labor was up for grabs in the 1970s, when Americans debated how to value feminized work—paid or unpaid, professional or service-oriented, performed in one's own home or beyond it—as women's social roles shifted. President Richard Nixon and his allies proposed reassigning caregiving functions to volunteers as a way to resist new demands on the welfare state and shrug off unmet social needs. Although many women's groups objected, their varied approaches to feminized labors also kept them from forging a united response. Recovering these volunteering wars offers up a vital perspective on the conflict between postwar movements advancing broad rights claims and the New Right's frontal assault on the “undeserving.” Manipulating notions of benevolence, Nixon and his associates found new ways to puncture the social safety net—a process that political leaders from both major parties would emulate and accelerate.
Tectonic evolution of the northern Verkhoyansk Fold-and-Thrust Belt: insights from palaeostress analysis and U–Pb calcite dating
Authors: Pavlovskaia Elena A , Khudoley Andrey K , Ruh Jonas B , Moskalenko Artem N , Guillong Marcel , Malyshev Sergey V
Published: July 2022

A combined structural and geochronological study was carried out to identify the tectonic evolution of the northern Verkhoyansk Fold-and-Thrust Belt, formed on the east margin of the Siberian Craton during late Mesozoic collision. Fault and fold geometries and kinematics were used for palaeostress reconstruction along the Danil and Neleger rivers cross-cutting the central and western parts of the Kharaulakh segment of the northern Verkhoyansk. Three different stress fields (thrust, normal and strike-slip faulting) were identified after separation from heterogeneous fault-slip data. Thrust and normal faulting stress fields were found in both areas, whereas a strike-slip faulting stress field was only found in Neoproterozoic rocks of the Neleger River area. U–Pb laser ablation – inductively coupled plasma – mass spectrometry (LA-ICP-MS) dating of calcite slickenside samples reveals the following succession of major deformation events across the northern Verkhoyansk: (i) The oldest tectonic event corresponding to the strike-slip faulting stress field with NE–SW-trending compression axis is Early Permian (Cisuralian, 284 ± 7 Ma) and likely represents a far-field response to the late Palaeozoic collision of the Kara terrane with the northern margin of the Siberian Craton. (ii) A slickenfibrous calcite age of 125 ± 4 Ma is attributed to the Early Cretaceous compression event, when the fold-and-thrust structure was formed. (iii) U–Pb slickenfibre calcite ages of 76–60 Ma estimate the age of a Late Cretaceous – Palaeocene compression event, when thrusts were reactivated. Slickensides related to both (ii) and (iii) compressional tectonic events formed by similar stress fields with W–E-trending compression axes. (iv) From the Palaeocene onwards, extensional tectonics with approximately W–E extension predominated.
The display of wealth, status and power: two recently discovered mid-fourth-century BC pebble-mosaic floors from Sinope
Authors: Kaba Hazar , Aksoy Eray
Published: July 2022

In 2019, excavation in the Yalnızlar neighbourhood of Sinop, Turkey, revealed a small number of architectural remains, two stone-paved floors and two lavishly decorated pebble-mosaic floors. Both the architectural remains and the pebble-mosaic floors are rare finds in Sinop, even more so given that the floors were found largely intact within their architectural settings. These elements appear to have constituted a portion of a once-grand house of the mid-fourth century BC. This article focuses on the pebble-mosaic floors, which will be analysed in two parts. The first introduces the floors and considers their construction techniques and decorative programmes. Analogies form an essential part of the analysis in order to contextualise both pavements within the corpus of Greek pebble-mosaic floors. A holistic evaluation of the architectural remains and the mosaics follows, in order to consider the setting and use of the floors. In the second part of the article, the sociocultural context of the mosaics is addressed. The analysis considers the meaning and symbolism of their decorations, as well as the place they once occupied within the lives of their owners. Ultimately, the position of the examples from Sinope within the wider sphere of mid-fourth-century BC Greek pebble-mosaic floors will be considered, along with the significance of such lavishly decorated floors in Sinope at this time.
Adaptive fault-tolerant control for an autonomous underwater vehicle
Authors: Tabatabaee-Nasab Fahimeh S. , Moosavian S. Ali A. , Keymasi Khalaji Ali
Published: July 2022

In recent years, using autonomous underwater vehicles (AUVs) for submarine missions has increased substantially. One of the problems in controlling these nonlinear devices is the possibility of a fault in the system operators. Failure causes increased operating costs and reduced vehicle performance. Therefore, the use of fault tolerance control is essential to ensure the stability and ability of the device to continue its activity. The focus of this article is on the trajectory tracking control for an underactuated AUV with actuator faults using kinematics and dynamics modeling. An adaptive rule is used as an online estimation to compensate for malfunctions in robot performance. In this regard, the adaptive fault-tolerant control plan is proposed, so that the closed-loop system is stable, and all control objectives are achievable. At first, the dynamic model of AUV with actuator fault and disturbance is described. Next, the control algorithm is designed for trajectory tracking in the presence of time-varying disturbances and actuator faults. The proposed adaptive rules will overcome disturbances and actuator faults. Finally, to illustrate the effectiveness of the proposed method, the provided controller is compared with other common control methods.
Strategy for embryo transfer to improve pregnancy outcomes in advanced maternal age
Authors: Wang Xue , Xiao Yaling , Sun Zhengyi , Zhen Jingran , Yu Qi
Published: July 2022

The purpose of this retrospective study was to optimize the transplantation strategy for women of advanced maternal age to achieve live births within the shortest time. Data were collected from patients older than 40 years who underwent assisted reproductive therapy at our centre from 1 January 2009 to 31 December 2019. In total, 1023 cases of fresh cleavage embryo transfer (CET) cycles, 280 cases of frozen–thawed blastocyst transfer (FBT) cycles, and 26 cases of frozen–thawed CET (FCET) cycles were included. The main outcome was the live birth rate (LBR). The secondary outcomes were the clinical pregnancy rate (CPR) and neonatal outcomes. Multivariable logistic regression was performed to adjust for confounding factors. The blastocyst formation rate of patients older than 40 years was 23.5%, the freezing cycle rate was 19.8%, and the fresh-embryo transfer rate was 83.0%. The implantation rate, CPR, and LBR were significantly different among the CET, FCET, and FBT groups. There were no significant differences in multiple pregnancies and abortion rates among the groups, and neonatal outcomes were similar. Multivariate logistic regression analysis showed that, compared with the CET group, LBR did not increase in the FCET group, whereas LBR increased in the FBT group. For patients older than 40 years when having approximately eight embryos after fertilization, blastocyst transfer can be considered after fully discussing the advantages and disadvantages of blastocyst culture. Alternatively, CET can be performed first, followed by FBT if the cleavage embryo transfer is unsuccessful.
Party switching and policy disagreement: scaling analysis of experts' judgment
Authors: Kubo Hiroki , Matsumoto Tomoko , Yamamoto Kentaro
Published: July 2022

Under what conditions do policy disagreements cause parties to split? Before the general elections in 2017 in Japan, the Minshin, the largest opposition party, split, and the major opposition camp collapsed into three parties. Disagreement about defense policy was rapidly politicized by the founding leader of a new party, Hope. Some members were motivated to switch to Hope and split the Minshin. Why did the disagreement about defense policy, which had long existed but was inactive, become an issue that led to a major split? To answer these questions, we used Aldrich–Mckelvey and Blackbox transpose scalings to analyze the data from an expert survey about issue positions and the salience of party policies. The variance in experts' responses was also examined to consider whether parties consistently and clearly distinguish their policy positions. Party positions on defense policy were clearly distinguished and revealed a split among splinter parties. However, the party positions clearly converged on the environment, decentralization, and other policies in a two-dimensional space, which indicated the unity of the major opposition camp. Moreover, different item functioning (DIF) analysis revealed a high variance (i.e., negative weight) on the issue salience of defense policy, which indicated its politicization immediately before the split. Overall results indicated that the politicization of defense policy contributed to weakening party cohesion and the party was split over disagreement about it. This implies that party switching is caused by policy disagreement but also hinges critically on which policy is politicized as an issue for party unity.
Simulating Dropsondes to Assess Moist Static Energy Variability in Tropical Cyclones
Authors: Carstens Jacob D. , Wing Allison A.
Published: July 2022

Interactions between clouds, water vapor, radiation, and circulation influence tropical cyclone (TC) development. Many of these interactions can be quantified by understanding tendencies of the spatial variance of moist static energy (MSE). Dropsondes from aircraft reconnaissance sample profiles needed to compute MSE at fine vertical resolution, and may be useful in analyzing these feedbacks on TCs in situ. However, dropsondes are spatially sparse, and sample limited column depths depending on the type of reconnaissance mission. We use idealized convection‐permitting simulations to examine how MSE variability, and the feedbacks that influence it, are resolved using selected patterns of grid points meant to resemble dropsonde launch points in reconnaissance flight patterns. We first examine the column depth necessary to capture the MSE variability of the full atmosphere. We then study how these simulated flight patterns depict MSE variance and its relevant diabatic feedbacks in TCs of varying structure and intensity.
Structural Hillslope Connectivity Is Driven by Tectonics More Than Climate and Modulates Hydrologic Extremes and Benefits
Authors: Husic Admin , Michalek Alexander
Published: July 2022

Structural hydrologic connections, formed by the coaction of tectonic and climatic processes, facilitate the transfer of matter across Earth's surface. Large‐scale analysis of hillslope connectivity controls is lacking, thus limiting our understanding of the drivers of extremes, like floods and landslides, and benefits, like wetlands. Here, we model hillslope connectivity using the Index of Connectivity, at 10‐m resolution for the contiguous United States. We show the dominance of tectonic drivers, like river steepness (ρ = 0.84) and seismic activity (ρ = 0.48), over climatic drivers, like precipitation (ρ = −0.31) and aridity (ρ = −0.07), in controlling the strength of connectivity. Highly connected basins were associated with landslide occurrence (ρ = 0.69) while poorly connected basins had greater wetland density (ρ = −0.50). Lastly, we share our results in an open access data portal for land managers to leverage structural connectivity maps in their respective study domains.
Directly Generating Spatially Periodic, Heterogeneous Groundwater Flow Fields: A Finite Volume Approach
Authors: Zhou Lian , Hansen Scott K.
Published: July 2022

We present a finite volume approach for generating doubly‐periodic, 2D heterogeneous groundwater velocity fields, given an arbitrary hydraulic conductivity field discretized on a rectangular lattice. The method conserves mass, allows direct specification of any desired mean flow direction and computes the corresponding field with a single solve operation, and solves for inter‐cell fluxes that may be used directly for particle tracking with the Pollock method without further interpolation. We demonstrate an open‐source Python implementation of the approach that we created.
TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer
Authors: Gu Yayun , Gao Huanyao , Zhang Huan , John August , Zhu Xiujuan , Shivaram Suganti , Yu Jia , Weinshilboum Richard M. , Wang Liewei
Published: July 2022

The HER2 receptor modulates downstream signaling by forming homodimers and heterodimers with other members of the HER family. For patients with HER2-positive breast cancer, Trastuzumab, an anti-HER2 monoclonal antibody as first-line therapy has shown significant survival benefits. However, the development of acquired resistance to Trastuzumab continues to be a significant obstacle. TNF receptor-associated factor 4 (TRAF4) upregulation was discovered to be associated with a worse clinical outcome. Here we identified TRAF4 overexpression as one of the putative mechanisms for HER2-positive breast cancer cells to maintain HER2 signaling during Trastuzumab treatment, while TRAF4 knockdown reduced HER2 stability and improved Trastuzumab sensitivity. Mechanistically, TRAF4 regulates HER2 level through its impact on SMAD specific E3 ubiquitin protein ligase protein 2 (SMURF2). The development of a membrane-associated protein complex containing HER2, TRAF4, and SMURF2 has been observed. SMURF2 bound to the HER2 cytoplasmic domain, and directly ubiquitinated it leading to HER2 degradation, whereas TRAF4 stabilized HER2 by degrading SMURF2 and inhibiting the binding of SMURF2 to HER2. Moreover, downregulation of TRAF4 has decreased the AKT/mTOR signaling. In conclusion, we discovered a new HER2 signaling regulation that involves the TRAF4-SMURF2 complex, a possible mechanism that might contribute to anti-HER2 resistance, making TRAF4 a viable target for treating HER2 + breast cancer.
Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma—a pilot study
Authors: Stagno Matias J. , Schmidt Andreas , Bochem Jonas , Urla Cristian , Handgretinger Rupert , Cabanillas Stanchi Karin M. , Saup Rafael , Queudeville Manon , Fuchs Jörg , Warmann Steven W. , Schmid Evi
Published: July 2022

Background

Neuroblastoma (NB) is the most common paediatric extracranial solid malignancy. We analysed the role of the epitope detection in monocytes (EDIM) technique for liquid biopsy in NB patients.

Methods

Tumour epitopes transketolase-like 1 (TKTL1), Apo10 (DNaseX) and GD2 were assessed: expression levels in seven NB tumour samples and five NB cell lines were analysed using RT-PCR and flow cytometry. LAN-1 cells were co-cultured with blood and assessed using EDIM. Peripheral blood macrophages of patients with neuroblastoma (n = 38) and healthy individuals (control group, n = 37) were labelled (CD14+/CD16+) and assessed for TKTL1, Apo10 and GD2 using the EDIM technology.

Results

mRNA expression of TKTL1 and DNaseX/Apo10 was elevated in 6/7 NB samples. Spike experiments showed upregulation of TKTL1, Apo10 and GD2 in LAN-1 cells following co-culturing with blood. TKTL1 and Apo10 were present in macrophages of 36/38 patients, and GD2 in 15/19 patients. The 37 control samples were all negative. EDIM expression scores of the three epitopes allowed differentiation between NB patients and healthy individuals.

Conclusions

The EDIM test might serve as a non-invasive tool for liquid biopsy in children suffering from NB. Future studies are necessary for assessing risk stratification, tumour biology, treatment monitoring, and early detection of tumour relapses.
Modular scaffolding by lncRNA HOXA10-AS promotes oral cancer progression
Authors: Chen Yi-Tung , Kan Chia-Hua , Liu Hsuan , Liu Yu-Hao , Wu Chih-Ching , Kuo Yu-Ping , Chang Ian Yi-Feng , Chang Kai-Ping , Yu Jau-Song , Tan Bertrand Chin-Ming
Published: July 2022

Recent findings have implicated long noncoding RNAs (lncRNAs) as pivotal gene regulators for diverse biological processes, despite their lack of protein-coding capabilities. Accumulating evidence suggests the significance of lncRNAs in mediating cell signaling pathways, especially those associated with tumorigenesis. Consequently, lncRNAs have emerged as novel functional regulators and indicators of cancer development and malignancy. Recent transcriptomic profiling has recognized a tumor-biased expressed lncRNA, the HOXA10-AS transcript, whose expression is associated with patient survival. Functional cell-based assays show that the HOXA10-AS transcript is essential in the regulation of oral cancer growth and metastasis. LncRNA expression is also associated with drug sensitivity. In this study, we identify that HOXA10-AS serves as a modular scaffold for TP63 mRNA processing and that such involvement regulates cancer growth. These findings provide a functional interpretation of lncRNA-mediated molecular regulation, highlighting the significance of the lncRNA transcriptome in cancer biology.
Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer
Authors: Zhou Xiaoshu , Zhou Rui , Rao Xinrui , Hong Jiaxin , Li Qianwen , Jie Xiaohua , Wang Jian , Xu Yingzhuo , Zhu Kuikui , Li Zhenyu , Wu Gang
Published: July 2022

The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
Authors: Liu Ruxia , Xu Chunling , Zhang Weilin , Cao Yangpo , Ye Jingjing , Li Bo , Jia Shi , Weng Lin , Liu Yingying , Liu Lei , Zheng Ming
Published: July 2022

Hypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia regulates mitochondrial functions in many cells, however, it is not clear if mitophagy is involved in the pathogenesis of hypoxic PH. By employing the hypoxic mitophagy receptor Fundc1 knockout (KO) and transgenic (TG) mouse models, combined hypoxic PH models, the current study found that mitophagy is actively involved in hypoxic PH through regulating PASMC proliferation. In the pulmonary artery medium from hypoxic PH mice, mitophagy was upregulated, accompanied with the increased active form of FUNDC1 protein and the enhanced binding affinity of FUNDC1 with LC3B. In PASMCs, overexpression of FUNDC1 increased mitophagy and cell proliferation while knockdown of FUNDC1 inhibited hypoxia-induced mitophagy and PASMC proliferation. Stimulation of mitophagy by FUNDC1 in PASMCs elevated ROS production and inhibited ubiquitination of hypoxia inducible factor 1α (HIF1α), and inhibition of mitophagy by FUNDC1 knockdown or knockout abolished hypoxia-induced ROS-HIF1α upregulation. Moreover, Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling, and Fundc1 KO mice were much resistant to hypoxic PH. In addition, intraperitoneal injection of a specific FUNDC1 peptide inhibitor to block mitophagy ameliorated hypoxic PH. Our results reveal that during hypoxic PH, FUNDC1-mediated mitophagy is upregulated which activates ROS-HIF1α pathway and promotes PASMC proliferation, ultimately leads to pulmonary vascular remodeling and PH.
A phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma
Authors: Todo Tomoki , Ino Yasushi , Ohtsu Hiroshi , Shibahara Junji , Tanaka Minoru
Published: July 2022

Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 108 pfu (low dose) or 1 × 109 pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for “immunoprogression” characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development.
A metagenomic DNA sequencing assay that is robust against environmental DNA contamination
Authors: Mzava Omary , Cheng Alexandre Pellan , Chang Adrienne , Smalling Sami , Djomnang Liz-Audrey Kounatse , Lenz Joan Sesing , Longman Randy , Steadman Amy , Gómez-Escobar Luis G. , Schenck Edward J. , Salvatore Mirella , Satlin Michael J. , Suthanthiran Manikkam , Lee John R. , Mason Christopher E. , Dadhania Darshana , De Vlaminck Iwijn
Published: July 2022

Metagenomic DNA sequencing is a powerful tool to characterize microbial communities but is sensitive to environmental DNA contamination, in particular when applied to samples with low microbial biomass. Here, we present Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) a metagenomic sequencing assay that is robust against environmental DNA contamination introduced during sample preparation. The core idea of SIFT-seq is to tag the DNA in the sample prior to DNA isolation and library preparation with a label that can be recorded by DNA sequencing. Any contaminating DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. We applied SIFT-seq to screen for infections from microorganisms with low burden in blood and urine, to identify COVID-19 co-infection, to characterize the urinary microbiome, and to identify microbial DNA signatures of sepsis and inflammatory bowel disease in blood.
Subsurface ocean warming preceded Heinrich Events
Authors: Max Lars , Nürnberg Dirk , Chiessi Cristiano M. , Lenz Marlene M. , Mulitza Stefan
Published: July 2022

Although the global environmental impact of Laurentide Ice-Sheet destabilizations on glacial climate during Heinrich Events is well-documented, the mechanism driving these ice-sheet instabilities remains elusive. Here we report foraminifera-based subsurface (~150 m water depth) ocean temperature and salinity reconstructions from a sediment core collected in the western subpolar North Atlantic, showing a consistent pattern of rapid subsurface ocean warming preceding the transition into each Heinrich Event identified in the same core of the last 27,000 years. These results provide the first solid evidence for the massive accumulation of ocean heat near the critical depth to trigger melting of marine-terminating portions of the Laurentide Ice Sheet around Labrador Sea followed by Heinrich Events. The repeated build-up of a subsurface heat reservoir in the subpolar Atlantic closely corresponds to times of weakened Atlantic Meridional Overturning Circulation, indicating a precursor role of ocean circulation changes for initiating abrupt ice-sheet instabilities during Heinrich Events. We infer that a weaker ocean circulation in future may result in accelerated interior-ocean warming of the subpolar Atlantic, which could be critical for the stability of modern, marine-terminating Arctic glaciers and the freshwater budget of the North Atlantic.
Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
Authors: Gomez-Sintes Raquel , Xin Qisheng , Jimenez-Loygorri Juan Ignacio , McCabe Mericka , Diaz Antonio , Garner Thomas P. , Cotto-Rios Xiomaris M. , Wu Yang , Dong Shuxian , Reynolds Cara A. , Patel Bindi , de la Villa Pedro , Macian Fernando , Boya Patricia , Gavathiotis Evripidis , Cuervo Ana Maria
Published: July 2022

Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.
Surrogate- and invariance-boosted contrastive learning for data-scarce applications in science
Authors: Loh Charlotte , Christensen Thomas , Dangovski Rumen , Kim Samuel , Soljačić Marin
Published: July 2022

Deep learning techniques have been increasingly applied to the natural sciences, e.g., for property prediction and optimization or material discovery. A fundamental ingredient of such approaches is the vast quantity of labeled data needed to train the model. This poses severe challenges in data-scarce settings where obtaining labels requires substantial computational or labor resources. Noting that problems in natural sciences often benefit from easily obtainable auxiliary information sources, we introduce surrogate- and invariance-boosted contrastive learning (SIB-CL), a deep learning framework which incorporates three inexpensive and easily obtainable auxiliary information sources to overcome data scarcity. Specifically, these are: abundant unlabeled data, prior knowledge of symmetries or invariances, and surrogate data obtained at near-zero cost. We demonstrate SIB-CL’s effectiveness and generality on various scientific problems, e.g., predicting the density-of-states of 2D photonic crystals and solving the 3D time-independent Schrödinger equation. SIB-CL consistently results in orders of magnitude reduction in the number of labels needed to achieve the same network accuracies.
Biallelic and gene-wide genomic substitution for endogenous intron and retroelement mutagenesis in human cells
Authors: Ohno Tomoyuki , Akase Taichi , Kono Shunya , Kurasawa Hikaru , Takashima Takuto , Kaneko Shinya , Aizawa Yasunori
Published: July 2022

Functional annotation of the vast noncoding landscape of the diploid human genome still remains a major challenge of genomic research. An efficient, scarless, biallelic, and gene-wide mutagenesis approach is needed for direct investigation of the functional significance of endogenous long introns in gene regulation. Here we establish a genome substitution platform, the Universal Knock-in System or UKiS, that meets these requirements. For proof of concept, we first used UKiS on the longest intron of TP53 in the pseudo-diploid cell line HCT116. Complete deletion of the intron, its substitution with mouse and zebrafish syntenic introns, and specific removal of retrotransposon-derived elements (retroelements) were all efficiently and accurately achieved in both alleles, revealing a suppressive role of intronic Alu elements in TP53 expression. We also used UKiS for TP53 intron deletion in human induced pluripotent stem cells without losing their stemness. Furthermore, UKiS enabled biallelic removal of all introns from three human gene loci of ~100 kb and longer to demonstrate that intron requirements for transcriptional activities vary among genes. UKiS is a standard platform with which to pursue the design of noncoding regions for genome writing in human cells.
Biodegradable germanium electronics for integrated biosensing of physiological signals
Authors: Zhao Haonan , Xue Zhongying , Wu Xiaozhong , Wei Zhihuan , Guo Qiuyu , Xu Miao , Qu Chunyan , You Chunyu , Mei Yongfeng , Zhang Miao , Di Zengfeng , Guo Qinglei
Published: July 2022

Transient electronics that can disappear or degrade via physical disintegration or chemical reaction over a pre-defined operational period provide essential for their applications in implantable bioelectronics due to the complete elimination of the second surgical extraction. However, the dissolution of commonly utilized bioresorbable materials often accompanies hydrogen production, which may cause potential or irreparable harm to the human body. This paper introduces germanium nanomembrane-based bioresorbable electronic sensors, where the chemical dissolution of all utilized materials in biofluidic theoretically have no gaseous products. In particular, the superior electronic transport of germanium enables the demonstrated bioresorbable electronic sensors to successfully distinguish the crosstalk of different physiological signals, such as temperature and strain, suggesting the significant prospect for the construction of dual or multi-parameter biosensors. Systematical studies reveal the gauge factor and temperature coefficient of resistance comparable to otherwise similar devices with gaseous products during their dissolution.
A general design of caging-group-free photoactivatable fluorophores for live-cell nanoscopy
Authors: Lincoln Richard , Bossi Mariano L. , Remmel Michael , D’Este Elisa , Butkevich Alexey N. , Hell Stefan W.
Published: July 2022

The controlled switching of fluorophores between non-fluorescent and fluorescent states is central to every super-resolution fluorescence microscopy (nanoscopy) technique, and the exploration of radically new switching mechanisms remains critical to boosting the performance of established, as well as emerging super-resolution methods. Photoactivatable dyes offer substantial improvements to many of these techniques, but often rely on photolabile protecting groups that limit their applications. Here we describe a general method to transform 3,6-diaminoxanthones into caging-group-free photoactivatable fluorophores. These photoactivatable xanthones (PaX) assemble rapidly and cleanly into highly fluorescent, photo- and chemically stable pyronine dyes upon irradiation with light. The strategy is extendable to carbon- and silicon-bridged xanthone analogues, yielding a family of photoactivatable labels spanning much of the visible spectrum. Our results demonstrate the versatility and utility of PaX dyes in fixed and live-cell labelling for conventional microscopy, as well as the coordinate-stochastic and deterministic nanoscopies STED, PALM and MINFLUX.