bluuebunny/crossref_metadata_2025 huggingface dataset:
Mainstreaming Marxism: on the anarchic structure of world economy
Authors: Morton Adam David
Published: March 2023

This article carves out a focus on certain authorized mainstream perspectives and their theorizations of world order, and how they have become dominant at the expense of excluded and silenced contributions. This task begins, first, by asserting that the anarchic conditions of world order have been mainstreamed at the expense of contributions to Marxist political economy. Here, my focus extends the methodological approach of juxtaposition to explore competing understandings of anarchic orders in Kenneth Waltz's and Nikolai Bukharin's work to disclose, in the latter, the anarchic structure of world capitalism. Second, the method of juxtaposition enables me to cast attention to the parallel profiles of E. H. Carr and C. L. R. James and their weighty understandings of world revolution to reveal, in the latter, neglected classed conditions of racial capitalism. In a fresh manner, then, my approach juxtaposes key figures that have been present (Waltz, Carr) and absent (Bukharin, James) in understanding world order through the anarchic structure of the world economy and racial capitalism. In conclusion, the argument left for academic study and the elucidation of policy is the extent to which a necessarily historical materialist moment to understanding world order can and should be further extended and deepened.
A Randomized, Double-Blind, Midazolam-Controlled Trial of Low-Dose Ketamine Infusion in Patients With Treatment-Resistant Depression and Prominent Suicidal Ideation
Authors: Su Tung-Ping , Li Cheng-Ta , Lin Wei-Chen , Wu Hui-Ju , Tsai Shih-Jen , Bai Ya-Mei , Mao Wei-Chung , Tu Pei-Chi , Chen Li-Fen , Li Wei-Chi , Chen Mu-Hong
Published: March 2023

Background

The benefits of low-dose ketamine for patients with treatment-resistant depression (TRD) and prominent suicidal ideation require further investigation. The effects of treatment refractoriness, the duration of the current depressive episode, and the number of prior antidepressant failures on ketamine efficacy also require clarification.

Methods

We recruited 84 outpatients with TRD and prominent suicidal ideation—defined as a score ≥4 on item 10 of the Montgomery–Åsberg Depression Rating Scale (MADRS)—and randomized them into 2 groups to receive 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. We assessed depressive and suicidal symptoms prior to infusion; 240 minutes post infusion; and 2, 3, 5, 7, and 14 days post infusion.

Results

According to the MADRS scores, the antidepressant effect (P = .035) was significantly noted in the ketamine group up to 14 days than in the midazolam group. However, the antisuicidal effect of ketamine, as measured by the Columbia-Suicide Severity Rating Scale Ideation Severity Subscale (P = .040) and MADRS item 10 (P = .023), persisted only 5 days post infusion. Furthermore, the antidepressant and antisuicidal effects of ketamine infusion were noted particularly in patients whose current depressive episode lasted <24 months or whose number of failed antidepressants was ≤4.

Conclusions

Low-dose ketamine infusion is a safe, tolerable, and effective treatment for patients with TRD and prominent suicidal ideation. Our study highlights the importance of timing; specifically, ketamine is more likely to achieve therapeutic response when the current depressive episode lasted <24 months and the number of failed antidepressants is ≤4.
Financial strain of COVID-19 and its impact on willingness-to-pay for equine care
Authors: Thompson Jada M , Kibler Michelle L , Ivey Jennie L Z
Published: March 2023

The novel COVID-19 virus caused a global pandemic disrupting lives, industries, and economies. The result was an impact on prices due to challenges with production and supply chain distribution. This study investigates the financial strain COVID-19 had on equine owners and leasers, what the market for equine care would bear if costs for care increased, and what factors contribute to their willingness to pay (WTP) for increasing cost of equine care. An online survey was distributed for 4 weeks to adult U.S. residents. Respondents reported their involvement in the equine industry, financial response to COVID-19, and responses to a double-bound dichotomous choice question on their WTP for care given a randomized increase (1%–20%) in their current cost (n = 506). Data were analyzed using interval regression models where a = 0.05 (Stata15). Respondents were separated into three groups: owner keeping their horse at their residence, owner boarding their equids, and leaser. Boarders reported mean monthly payments of 23.33 ± 90.37 USD (n = 15) for free board, 236.47 ± 151.92 USD, (n = 75) for partial board, and 514.75 ± 291.71 USD (n = 181) for full board. Results show all owners, leaser, and boarders have different WTP values which range from 18.5% to 26.2% increase in current care costs which extends beyond the presented range due to many respondents responding “yes” to both WTP questions (71% of owners, 6% of boarders, 65% of leasers). Equine owners, with on farm equids from the southern US were WTP 11% less than from other regions (P = 0.015). The current boarding fees from owners that board their equids lowered their WTP by 0.01% (P = 0.029) for each additional dollar paid, whereas current care costs were not a significant factor for other owners (P = 0.370) or leasers (P = 0.395). Those that had a full lease for their equids, housed on farm or at a facility, were WTP 15% higher (P = 0.036) than those that had a partial or no lease. In comparison, boarding status (full, partial, or no boarding) did not significantly (P = 0.51) impact boarder’s WTP. Age of respondent and annual household income heterogeneously affected WTP across all groups. These results indicate the market for equine care can bear the increases in cost associated with financial distress related to COVID-19, and may aid equine owners, caregivers, and associated individuals in making informed decisions regarding essential care. Results from this study should be taken in context of the global pandemic and the restrictions in place, or lack thereof, at the time the survey was administered.
Effects of α-lipoic acid on growth performance, antioxidant capacity, and immune function in sheep
Authors: Yang Xinlu , Zhang Hongrui , Pang Fanglin , Zhang Lijie , Fu Tong , Wang Linfeng , Liu Kaizhen , Gao Tengyun
Published: March 2023

α-Lipoic acid (α-LA) was usually applied to improve the ability of removing the reactive oxygen species of host. The affection of α-LA on ruminants was mainly focused on the variation of serum antioxidant and immune indexes, but the research on tissues or organs remained limited. The aim of this study was to explore the effects of dietary supplementation with different levels of α-LA on growth performance, antioxidant status, and immune indexes of serum and tissues in sheep. One hundred Duhu F1 hybrid (Dupo♀ × Hu sheep♂) sheep aged 2 to 3 mo with similar body weight (27.49 ± 2.10 kg) were randomly allocated into five groups. Five diets supplemented with 0 (CTL), 300 (LA300), 450 (LA450), 600 (LA600), and 750 (LA750) mg/kg α-LA were fed to sheep for 60 d. The results showed that α-LA supplementation significantly increased the average daily feed intake (P < 0.05); however, no significant variation was found in the average daily gain, feed conversion rate, carcass weight, and slaughter rate among groups (P > 0.05). Compared with CTL group, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities in serum of LA600 and LA750 groups were increased (P < 0.05). At LA450–LA750 groups, SOD, CAT activities in liver and ileum tissues and GSH-Px activities in ileum tissues were increased than CTL group (P < 0.05), while malondialdehyde (MDA) contents in serum and muscle tissue were decreased than CTL group (P < 0.05). The total antioxidant capacity contents in liver, muscle, and ileum tissues of LA600 group were increased compared with CTL group (P < 0.05). Additionally, the interleukin-10 (IL-10) contents of serum in LA450–LA750 groups were increased than CTL group (P < 0.05); the contents of interleukin-1β (IL-1β) in serum, interleukin-2 (IL-2) in liver, and interleukin-6, IL-1β in muscle were decreased than CTL group (P < 0.05). The content of immunoglobulin A in serum of LA600 group, ileum, and muscle of LA750 group was increased than CTL group (P < 0.05). Based on the quadratic regression analysis of GSH-Px, MDA, IL-2, IL-10, and IL-1β, the optimal dietary α-LA levels were estimated to be 495.75, 571.43, 679.03, 749.75, and 678.25 mg/kg, respectively. This research will provide certain contribution for the effective utilization of α-LA in sheep production.
An finite element analysis surrogate model with boundary oriented graph embedding approach for rapid design
Authors: Fu Xingyu , Zhou Fengfeng , Peddireddy Dheeraj , Kang Zhengyang , Jun Martin Byung-Guk , Aggarwal Vaneet
Published: March 2023

In this work, we present a boundary oriented graph embedding (BOGE) approach for the graph neural network to assist in rapid design and digital prototyping. The cantilever beam problem has been solved as an example to validate its potential of providing physical field results and optimized designs using only 10 ms. Providing shortcuts for both boundary elements and local neighbor elements, the BOGE approach can embed unstructured mesh elements into the graph and performs an efficient regression on large-scale triangular-mesh-based finite element analysis (FEA) results, which cannot be realized by other machine-learning-based surrogate methods. It has the potential to serve as a surrogate model for other boundary value problems. Focusing on the cantilever beam problem, the BOGE approach with 3-layer DeepGCN model achieves the regression with mean square error (MSE) of 0.011 706 (2.41% mean absolute percentage error) for stress field prediction and 0.002 735 MSE (with 1.58% elements having error larger than 0.01) for topological optimization. The overall concept of the BOGE approach paves the way for a general and efficient deep-learning-based FEA simulator that will benefit both industry and Computer Aided Design (CAD) design-related areas.
Timed concurrent language for argumentation with maximum parallelism
Authors: Bistarelli Stefano , Chiara Meo Maria , Taticchi Carlo
Published: March 2023

The timed concurrent language for argumentation (tcla) is a framework to model concurrent interactions between communicating agents that reason and take decisions through argumentation processes, also taking into account the temporal duration of the performed actions. Time is a crucial factor when dealing with dynamic environments in real-world applications, where agents must act in a coordinated fashion to reach their own goals. However, modelling complex interactions and concurrent processes may be challenging without the help of proper languages and tools. In this paper, we discuss the use of tcla for practical purposes and provide a working implementation of the language, endowed with a user interface available online, that serves the dual purpose of aiding the research in this field and facilitating the development of multi-agent systems based applications.
3D radiative transfer modelling and virial analysis of starless cores in the B10 region of the Taurus molecular cloud
Authors: Scibelli Samantha , Shirley Yancy , Schmiedeke Anika , Svoboda Brian , Singh Ayushi , Lilly James , Caselli Paola
Published: March 2023

Low-mass stars like our Sun begin their evolution within cold (10 K) and dense (∼105 cm−3) cores of gas and dust. The physical structure of starless cores is best probed by thermal emission of dust grains. We present a high-resolution dust continuum study of the starless cores in the B10 region of the Taurus Molecular Cloud. New observations at 1.2 and 2.0 mm (12 and 18 arcsec resolution) with the NIKA2 instrument on the IRAM 30m have probed the inner regions of 14 low-mass starless cores. We perform sophisticated 3D radiative transfer modelling for each of these cores through the radiative transfer framework pandora, which utilizes RADMC-3D. Model best-fits constrain each cores’ central density, density slope, aspect ratio, opacity, and interstellar radiation field strength. These ‘typical’ cores in B10 span central densities from 5 × 104 to 1 × 106 cm−3, with a mean value of 2.6 × 105 cm−3. We find the dust opacity laws assumed in the 3D modelling, as well as the estimates from Herschel, have dust emissivity indices, β’s, on the lower end of the distribution constrained directly from the NIKA2 maps, which averages to β = 2.01 ± 0.48. From our 3D density structures and archival NH3 data, we perform a self-consistent virial analysis to assess each core’s stability. Ignoring magnetic field contributions, we find nine out of the 14 cores (64  per cent) are either in virial equilibrium or are bound by gravity and external pressure. To push the bounded cores back to equilibrium, an effective magnetic field difference of only ∼15 $\mu$G is needed.
The energetic particle environment of a GJ 436 b-like planet
Authors: Rodgers-Lee D , Rimmer P B , Vidotto A A , Louca A J , Taylor A M , Mesquita A L , Miguel Y , Venot O , Helling C , Barth P , Lacy E
Published: March 2023

A key first step to constrain the impact of energetic particles in exoplanet atmospheres is to detect the chemical signature of ionization due to stellar energetic particles and Galactic cosmic rays. We focus on GJ 436, a well-studied M dwarf with a warm Neptune-like exoplanet. We demonstrate how the maximum stellar energetic particle momentum can be estimated from the stellar X-ray luminosity. We model energetic particle transport through the atmosphere of a hypothetical exoplanet at orbital distances between $a=0.01\text{ and }0.2\,$au from GJ 436, including GJ 436 b’s orbital distance (0.028 au). For these distances, we find that, at the top of atmosphere, stellar energetic particles ionize molecular hydrogen at a rate of $\zeta _{\rm StEP,H_2} \sim 4\times 10^{-10}\text{ to }2\times 10^{-13}\, \mathrm{s^{-1}}$. In comparison, Galactic cosmic rays alone lead to $\zeta _{\rm GCR, H_2}\sim 2\times 10^{-20}\!-\!10^{-18} \, \mathrm{s^{-1}}$. At 10 au, we find that ionization due to Galactic cosmic rays equals that of stellar energetic particles: $\zeta _{\rm GCR,H_2} = \zeta _{\rm StEP,H_2} \sim 7\times 10^{-18}\, \rm {s^{-1}}$ for the top-of-atmosphere ionization rate. At GJ 436 b’s orbital distance, the maximum ion-pair production rate due to stellar energetic particles occurs at pressure $P\sim 10^{-3}\,$bar, while Galactic cosmic rays dominate for $P\gt 10^2\,$bar. These high pressures are similar to what is expected for a post-impact early Earth atmosphere. The results presented here will be used to quantify the chemical signatures of energetic particles in warm Neptune-like atmospheres.
Jupiter’s equatorial X-ray emissions over two solar cycles
Authors: Wibisono A D , Branduardi-Raymont G , Coates A J , Dunn W R , French R J
Published: March 2023

Jupiter’s disc is bright in X-rays as H2 molecules in the atmosphere are very effective at scattering solar X-rays. K-shell fluorescence from carbon atoms in atmospheric methane is thought to also provide a minor contribution. XMM–Newton has now observed Jupiter over a span of nearly two solar cycles from 2003 to 2021, offering the opportunity to determine whether Jupiter’s disc emissions are driven by solar activity or not. We compare the count rates of X-rays of energies 0.2–10.0, 0.2–2.0, 2.1–5.0, and 5.1–10.0 keV from the planet’s equatorial region, with the sunspot number and F10.7 adjusted solar radio flux. The respective Pearson’s correlation coefficients for both are 0.88/0.84, 0.86/0.83, 0.40/0.34, and 0.29/0.22 for each energy demonstrating that the low-energy X-ray disc emissions are indeed controlled by the Sun’s activity. This relationship is less clear for the higher energy emissions, raising questions around the source of these emissions.
A detailed analysis of X-ray emission-line velocities of Capella from over 20 yr of Chandra/HETG spectroscopy
Authors: Bozzo E , Huenemoerder D P , Produit N , Falanga M , Paltani S , Costantini E
Published: March 2023

Capella is the brightest chromospherically active binary in the sky, hosting a cooler G8III giant (Aa) and a hotter G1III companion (Ab). The source has been extensively observed in the X-rays in the past decades not only for its astrophysical interest in the field of corona sources, but also for in-flight calibrations of space-based X-ray instruments. In 2006, it was demonstrated using Chandra/High Energy Transmission Grating (HETG) observations that Aa is the main contributor to Capella’s X-ray emission, as the centroid energies of the emission lines are Doppler shifted along the orbit of the G8III giant (an aspect that has to be taken into consideration for calibration activities of X-ray instruments). In this paper, we extend the previous analysis performed in 2006 by re-analysing in a homogeneous way all Chandra/HETG observations performed in the direction of Capella. By doubling the amount of data available, we strengthened the conclusion that Capella Aa is the dominant emitter in soft X-rays. We did not find any evidence of a statistically significant contribution to this emission by the Ab giant. Our findings are discussed also in light of the incoming launch of the X-Ray Imaging and Spectroscopy Mission (XRISM) mission (spring 2023).
Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: a comparison of folic acid and 5-methyltetrahydrofolate
Authors: Wang Han , Ni Juan , Guo Xihan , Xue Jinglun , Wang Xu
Published: March 2023

Telomere length (TL), which is maintained by human telomerase reverse transcriptase (hTERT; component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay. Results showed that abnormal TL elongation was observed in FA and 5-MeTHF deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA-deficient condition but was significantly elongated under the 5-MeTHF-deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and -positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.
Industry survey of added vitamins and trace minerals in U.S. swine diets
Authors: Faccin Jamil E G , Tokach Mike D , Goodband Robert D , DeRouchey Joel M , Woodworth Jason C , Gebhardt Jordan T
Published: March 2023

From November 2021 to February 2022, 37 swine nutritionists representing 29 production systems and 8 nutrition supplier companies in the United States were surveyed about added vitamin and trace mineral concentrations in swine diets. Respondents were asked to provide vitamin premix and trace mineral concentrations, inclusion rates, and weight ranges associated with feeding phases. Survey participants represented 4.38 million sows, or 72% of the U.S. industry. Data were compiled into three nursery phases (phase 1, weaning to 7 kg; phase 2, 7 to 11 kg; and phase 3, 11 to 23 kg), three finishing phases (23 to 55 kg; 55 to 100 kg; 100 kg to market), gilt development, gestation, lactation, and boar. Within each dietary phase, the vitamins and trace minerals of interest included: vitamins A, D, E, and K, thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, choline, vitamin C, carnitine, copper, iodine, iron, manganese, selenium, zinc, cobalt, and chromium. Descriptive statistics used included: average, weighted average (determined by the total number of sows represented), median, minimum, maximum, 25th percentile (lowest quartile), and 75th percentile (highest quartile). In addition, all average supplementation rates for vitamins and trace minerals within each phase of production were compared to the requirement estimates reported in the NRC (2012). Nutritionists generally supplemented vitamins and trace minerals well above the NRC (2012) requirement estimates. However, great variation among respondents was observed in all vitamins and trace minerals, particularly in the fat-soluble vitamins. Also, the use of alternative sources of vitamin D [25(OH)D3], E (natural, d-alpha-tocopherol), and organic or chelated minerals like copper, manganese, selenium, and zinc were being used by approximately 40% of the respondents, primarily in breeding herd and nursery diets. Understanding current supplementation practices may help develop research trials to test different vitamin and trace mineral inclusions and provide an industry benchmark of vitamin and trace mineral usage.
Challenges in the management of relapsed germ cell tumors
Authors: Salous Tareq , Adra Nabil
Published: March 2023

Purpose of review

Despite the remarkable advances in the treatment of germ cell tumors (GCTs), a significant number of patients relapse after first line treatment. This review aims to highlight the challenges in management of relapsed GCT, discuss treatment options, and review novel therapeutics in development.

Recent findings

Patients with relapsed disease after first line cisplatin-based chemotherapy can still be cured and should be referred to centers with expertise in GCTs. Patients with anatomically confined relapse should be considered for salvage surgery. The systemic treatment of patients with disseminated disease at the time of relapse after first line treatment remains unsettled. Treatment options include using salvage standard-dose cisplatin-based regimens with drugs not previously used or high-dose chemotherapy. Patients who relapse after salvage chemotherapy have poor outcomes and development of novel treatment options is required in this setting.

Management of patients with relapsed GCT requires a multidisciplinary approach. Patients should be preferably evaluated at tertiary care centers with expertise in the management of these patients. There remains a subset of patients who relapse after salvage therapy and development of novel therapeutic approaches is needed in this setting.
Molecular testing of DNA damage response pathways in prostate cancer patients
Authors: Patel Lalit , Pritchard Colin C.
Published: March 2023

Purpose of review

Personalizing prostate cancer therapy requires germline and tumor molecular tests that predict who will respond to specific treatments and who may not. The review covers molecular testing of DNA damage response pathways, the first biomarker-driven precision target with clinical utility for treatment selection in patients with castration resistant prostate cancer (CRPC).

Recent findings

Recurrent somatic and germline variants cause deficiency of the mismatch repair (MMR) or homologous recombination (HR) pathways in about a quarter of CRPC patients. In prospective clinical trials, patients with deleterious variants in the MMR pathway more frequently experience a therapeutic response to immune checkpoint inhibitors (ICI). Similarly, somatic and germline events affecting HR predict response to poly(ADP) ribose polymerase inhibitor (PARPi) therapy. Molecular testing of these pathways currently involves assaying for loss of function variants in individual genes and for the genome-wide consequences of repair deficiency.

DNA damage response pathways are the first major area of molecular genetic testing in CRPC settings and offer insights into this new paradigm. Our hope is that eventually an arsenal of molecularly-guided therapies will be developed across many pathways to enable precision medicine options for most men with prostate cancer.
Liquid biopsy in head neck cancer: ready for clinical routine diagnostics?
Authors: Tinhofer Ingeborg , Staudte Stephanie , George Stephen
Published: March 2023

Purpose of review

The bodily fluids of patients with solid cancers representing a minimally-invasive source of clinically exploitable biomarkers have attracted an increasing amount of attention in recent years. In patients with head and neck squamous cell carcinoma (HNSCC), cell-free tumour DNA (ctDNA) belongs to the most promising liquid biomarkers for monitoring disease burden and identifying patients at high risk of recurrence. In this review, we highlight recent studies, evaluating the analytical validity and clinical utility of ctDNA as a dynamic biomarker in HNSCC, especially as it relates to risk stratification and contrasting human papilloma virus (HPV+ and HPV-) and carcinomas.

Recent findings

The clinical potential of minimal residual disease monitoring through viral ctDNA in identifying HPV+ oropharyngeal carcinoma patients at higher risk of recurrence has recently been demonstrated. Furthermore, accumulating evidence supports a potential diagnostic value of ctDNA dynamics in HPV-negative HNSCC. Altogether, recent data suggest that ctDNA analysis may be a valuable tool in guiding (de)escalation of surgical interventions as well as adaptation in radiotherapy dosage, both in the definitive and adjuvant settings.

Rigorous clinical trials with patient-relevant endpoints are critical in order to demonstrate that treatment decisions based on ctDNA dynamics result in better outcomes in HNSCC.
Chemotherapy postimmunotherapy for recurrent metastatic head and neck squamous cell carcinoma
Authors: Ducoulombier Agnes , Guigay Joel , Etienne-Grimaldi Marie-Christine , Saada-Bouzid Esma
Published: March 2023

Purpose of review

Clinical data on salvage chemotherapy used after checkpoints inhibitors in oncology are reviewed, with a special focus on recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Recent findings

Converging evidence is emerging about high response and/or disease control rates associated with salvage chemotherapy after immunotherapy failure in advanced solid tumours. This phenomenon is mainly reported in retrospective studies for “hot tumours” such as R/M HNSCC, melanoma, lung, urothelial or gastric cancers, but also in haematological malignancies. Some physiopathological hypotheses have been raised.

Several independent series show increased response rates associated with postimmuno chemotherapy when compared with retrospective series in similar settings. Several mechanisms could be involved such as a “carry-over” allowed by a persistence of the checkpoint inhibitor, a modulation of tumour microenvironment components but also an intrinsic immunomodulatory effect of chemotherapy, increased by a specific immunologic state induced by the therapeutic pressure of checkpoint inhibitors. These data establish a rationale for prospectively evaluating the features of postimmunotherapy salvage chemotherapy.
How to prevent human papillomavirus-related oropharyngeal cancer?
Authors: Ferrando-Díez Angelica , Pavón Miguel Angel , Cirauqui Beatriz , Alemany Laia , Mesía Ricard
Published: March 2023

Purpose of review

Human papillomavirus (HPV) is responsible of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in high-income countries. This significant epidemiological change requires several and diverse prevention strategies.

Recent findings

The cervical cancer prevention model is the paradigm of HPV-related cancer, and its success provides encouragement for the development of similar methods to prevent HPV-related OPSCC. However, there are some limitations that hinder its application in this disease. Here, we review the primary, secondary and tertiary prevention of HPV-related OPSCC and discuss some directions for future research.

The development of new and targeted strategies to prevent HPV-related OPSCC is needed since they could definitely have a direct impact on the reduction of morbidity and mortality of this disease.
Targeting Harvey rat sarcoma viral oncogene homolog in head and neck cancer: how to move forward?
Authors: Ben Yahia Hédi , Petit François M. , Saada-Bouzid Esma
Published: March 2023

Purpose of review

Despite recent advances, treatment personalization remains an issue for recurrent metastatic head and neck squamous cell carcinoma (RM HNSCC) patients. After human papilloma virus (HPV) and programmed death ligand 1 (PDL1) expression, Harvey rat sarcoma viral oncogene homolog (HRAS) appears as an emerging target in this field. In this review, we summarize the features of HRAS-mutated HNSCC and its targeting by farnesyl transferase inhibitors.

Recent findings

HRAS mutations define a small subgroup of RM HNSCC patients with a poor prognosis and often refractory to the standard treatments. Posttranslational processing of HRAS being dependent on farnesylation, farnesyl transferase inhibitors have been evaluated in HRAS-mutated tumors. Tipifarnib, a first in class farnesyl transferase inhibitor, has shown efficacy in phase 2 trials with HRAS-mutated tumors. Despite reported high response rates in selected population, the efficacy of Tipifarnib is inconsistent and always transient, probably because of limiting hematological toxicities leading to dose reduction and occurrence of secondary resistance mutations.

Tipifarnib is the first in the class of farnesyl transferase inhibitors to show efficacy in HRAS-mutated RM HNSCC. The understanding of mechanisms of resistance will pave the way for the design of second-generation farnesyl transferases inhibitors.
CenTauR: Towards a Universal Scale and Masks for Standardizing Tau Imaging Studies
Authors: Villemagne Victor L. , Leuzy Antoine , Bohorquez Sandra Sanabria , Bullich Santiago , Shimada Hitoshi , Rowe Christopher C. , Bourgeat Pierrick , Lopresti Brian , Huang Kun , Krishnadas Natasha , Fripp Jurgen , Takado Yuhei , Gogola Alexandra , Minhas Davneet , Weimer Robby , Higuchi Makoto , Stephens Andrew , Hansson Oskar , Doré Vincent ,   the Alzheimer’s Disease Neuroimaging Initiative,   the AIBL research group
Published: March 2023

INTRODUCTION

Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale.

METHOD

1045 participants underwent tau scans with either18F-Flortaucipir,18F-MK6240,18F-PI2620,18F-PM-PBB3,18F-GTP1 or18F-RO948. The mask was generated from cognitively unimpaired Aβ-subjects and AD patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the global mask. A universal scale, the CenTauRz, was constructed.

RESULTS

None of the regions known to display off-target signal were included in the masks. The CenTauRzallows robustly discrimination between low and high levels of tau deposits.

DISCUSSION

We constructed several tau-specific cortical masks*for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centres.

Research in Context

Systematic review:The authors reviewed the literature using traditional (e.g., PubMed) sources and meeting abstracts and presentations. While the use of tau PET imaging rapidly increased in research and in clinical trials over the past few years, there is no standardization pipeline for the quantification of tau imaging across tau tracers and quantification software.

Interpretation:We built a global and several regional universal masks for the sampling of tau PET scans based on the most commonly used tau PET tracers. We then derived a universal scale across tracers, the CenTauRz, to measure the tau signal.

Future directions:Standardised quantification will facilitate the derivation of universal cut-off values, merging of large cohorts, and comparison of longitudinal changes across tracers and cohorts both in clinical studies and therapeutic trials.
Role of Lactate in the Regulation of Transcriptional Activity of Breast Cancer-Related Genes and Epithelial-to-Mesenchymal Transition Proteins: A Compassion of MCF7 and MDA-MB-231 Cancer Cell Lines
Authors: San-Millan Inigo , Martinez Janel L. , Pickard Shivaun Lueke , Yu Hui , Hirsch Fred R. , Rivard Christopher J. , Brooks George A.
Published: March 2023

The Warburg Effect is characterized by accelerated glycolytic metabolism and lactate production and under fully aerobic conditions is a hallmark of cancer cells. Recently, we have demonstrated the role of endogenous, glucose-derived lactate as an oncometabolite which regulates gene expression in the estrogen receptor positive (ER+) MCF7 cell line cultivated in glucose media. Presently, with the addition of a triple negative breast cancer (TNBC) cell line, MDA-MB-231, we further confirm the effect of lactate on gene expression patterns and extend results to include lactate effects on protein expression. As well, we report effects of lactate on the expression of E-cadherin and vimentin, proteins associated with epithelial-to-mesenchymal transition (EMT). Endogenous lactate regulates the expression of multiple genes involved in carcinogenesis. In MCF7 cells, lactate increased the expression of EGFR, VEGF, HIF-1a, KRAS, MIF, mTOR, PIK3CA, TP53, and CDK4 as well as decreased the expression of ATM, BRCA1, BRCA2, E2F1, MET, MYC, and RAF mainly after 48h of exposure. On the other hand, in the MDA-MB-231 cell line, lactate increased the expressions of PIK3CA, VEGF, EGFR, mTOR, HIF-1α, ATM, E2F1, TP53 and decreased the expressions of BRCA1, BRCA2, CDK4, CDK6, MET, MIF, MYC, and RAF after 48h of exposure. In response to endogenous lactate, changes in protein expression of representative genes corroborated changes in mRNA expressions. Finally, lactate exposure decreased E-cadherin protein expression in MCF7 cells and increased vimentin expression in MDA-MB-231 cells. Further-more, by genetically silencing LDHA in MCF7 cells, we show suppression of protein expression of EGFR and HIF-1α, while full protein expression occurred under glucose and glucose + exogenous lactate exposure. Hence, endogenous, glucose-derived lactate, and not glucose, elicited changes in gene and protein expression levels.

In this study, we demonstrate that endogenous lactate produced under aerobic conditions (Warburg Effect) elicits important changes in gene and protein expression in both ER+ and TNBC cell lines. The widespread regulation of multiple genes by lactate and involves those involved in carcinogenesis including DNA repair, cell growth, proliferation, angiogenesis, and metastasis. Furthermore, lactate affected the expression of two relevant EMT biomarkers, E-cadherin and vimentin, which could contribute to the complex process of EMT and a shift towards a more mesenchymal phenotype in the two cancer cell lines studied.
THE FACTOR STRUCTURE OF THE PATIENT HEALTH QUESTIONNAIRE-9 IN STROKE: A COMPARISON WITH A NON-STROKE POPULATION
Authors: Blake J.J. , Munyombwe T. , Fischer F. , Quinn T.J , Van der Feltz-Cornelis C.M. , De Man-van Ginkel J.M. , Santos I.S. , Jeon H.J. , Köhler S. , Schram M.T. , Stehouwer C.D.A. , Wang Jianli , Levin-Aspenson H.F. , Whooley M.A. , Hobfoll S.E , Patten S.B. , Simning A. , Gracey F. , Broomfield N.M.
Published: March 2023

Background

There are concerns that the measurement of depression by the Patient Health Questionnaire-9 (PHQ-9), a self-report screening questionnaire, is biased by comorbid stroke sequelae. We, therefore, aimed to investigate these concerns in stroke, benchmarked against a non-stroke comparison sample, using factor analysis.

Methods

The secondary data sample constituted 787 stroke and 12,016 non-stroke participants, in a cross-sectional design. A subsample of 1,574 non-stroke participants was selected via propensity score matching. Dimensionality was assessed by comparing fit statistics of one-factor, two-factor, and bi-factor models. Between-group differences in factor structure were identified using measurement invariance.

Results

A two-factor model, consisting of somatic and cognitive-affect factors, had a superior fit to a unidimensional model (CFI = .984 versus CFI =.974, p<.001), but the high correlation between the factors indicated unidimensionality (r = .866). Configural invariance between stroke and non-stroke was supported (CFI = .983, RMSEA = .080), as were invariant thresholds (p = .092) and loadings (p = .103) for all items. Strong invariance was violated (p < .001, ΔCFI = -.003), indicating non-invariant item intercepts. Partially invariant models indicated responsibility of the tiredness and appetite intercepts, and latent depression severity was significantly overestimated in stroke, relative to the general population, using a summed score approach (Cohen’s d=.434).

Conclusions

The findings suggest that the PHQ-9 measures a single latent factor in stroke. However, the presence of non-invariant intercepts means that PHQ-9 total scores may be disproportionately influenced by fatigue in post-stroke vs. non-stroke patients and that total scores are incomparable between groups.
Non-linearity in motor unit velocity twitch dynamics: Implications for ultrafast ultrasound source separation
Authors: Lubel Emma , Sgambato Bruno Grandi , Rohlén Robin , Ibáñez Jaime , Barsakcioglu Deren Y , Tang Meng-Xing , Farina Dario
Published: March 2023

Ultrasound (US) muscle image series can be used for peripheral human-machine interfacing based on global features, or even on the decomposition of US images into the contributions of individual motor units (MUs). With respect to state-of-the-art surface electromyography (sEMG), US provides higher spatial resolution and deeper penetration depth. However, the accuracy of current methods for direct US decomposition, even at low forces, is relatively poor. These methods are based on linear mathematical models of the contributions of MUs to US images. Here, we test the hypothesis of linearity by comparing the average velocity twitch profiles of MUs when varying the number of other concomitantly active units. We observe that the velocity twitch profile has a decreasing peak-to-peak amplitude when tracking the same target motor unit at progressively increasing contraction force levels, thus with an increasing number of concomitantly active units. This observation indicates non-linear factors in the generation model. Furthermore, we directly studied the impact of one MU on a neighboring MU, finding that the effect of one source on the other is not symmetrical and may be related to unit size. We conclude that a linear approximation is limiting the decomposition methods to decompose full velocity twitch trains from velocity images, highlighting the need for more advanced models and methods for US decomposition than those currently employed.
xTrimoGene: An Efficient and Scalable Representation Learner for Single-Cell RNA-Seq Data
Authors: Gong Jing , Hao Minsheng , Zeng Xin , Liu Chiming , Ma Jianzhu , Cheng Xingyi , Wang Taifeng , Zhang Xuegong , Song Le
Published: March 2023

Abstract

The advances in high-throughput sequencing technology have led to significant progress in measuring gene expressions in single-cell level. The amount of publicly available single-cell RNA-seq (scRNA-seq) data is already surpassing 50M records for human with each record measuring 20,000 genes. This highlights the need for unsupervised representation learning to fully ingest these data, yet classical transformer architectures are prohibitive to train on such data in terms of both computation and memory. To address this challenge, we propose a novel asymmetric encoder-decoder transformer for scRNA-seq data, called xTrimoGene, which leverages the sparse characteristic of the data to scale up the pre-training. This scalable design of xTrimoGene reduces FLOPs by one to two orders of magnitude compared to classical transformers while maintaining high accuracy, enabling us to train the largest transformer models over the largest scRNA-seq dataset today. Our experiments also show that the performance of xTrimoGene improves as we increase the model sizes, and it also leads to SOTA performance over various downstream tasks, such as cell classification, perturb-seq effect prediction, and drug combination prediction.
Structural development of the human fetal kidney: new stages and cellular dynamics in nephrogenesis
Authors: Schumacher Anika , Nguyen Tri Q. , Broekhuizen Roel , van Griensven Martijn , LaPointe Vanessa
Published: March 2023

Research on the ultrastructural development of the kidney is limited, and research on rodent kidneys prevails. Yet, large differences between rodent and human nephrogenesis exist and therefore translation between species is not desirable. At the same time, there is an increasing demand for human research, in addition to assessing the potential of novel therapies such as renal organoids. We therefore generated an interactive atlas of large transmission electron microscopy tile scans of first trimester human kidneys, specifically Carnegie stage 20 until post-conceptional week 12. Analysis identified key ultrastructural features of proximal and distal progenitor cells such as cell shape, microvilli and luminal budding in the renal vesicle. Regarding glomerular development, we identified a new W-shaped body stage and three distinct sub-stages of the well-known capillary loop stage. Chromatin organization, nuclear shape and location were used to describe tubule cell identity and maturity, indicating a specific order of tubular maturation. The greatest congruence with adult tissue was seen in proximal tubules and the least in distal tubules. Finally, cytoplasmic glycogen depositions in collecting duct cells, which are absent in adult tissue, were found to be an early feature distinguishing distal tubules from collecting ducts as well as differentiating cortical from medullary collecting ducts. The findings of this research provide new fundamental insights for researchers who aim to understand and recreate kidney development.
A model for the gradual evolution of dioecy and heterogametic sex determination
Authors: Lesaffre Thomas , Pannell John R. , Mullon Charles
Published: March 2023

In plants with separate sexes, the development of an individual as male or female is controlled by a dominant allele at a sex-determining locus - the fundamental basis of XY and ZW systems. The many independent transitions from hermaphroditism to dioecy that have taken place in flowering plants must therefore often have entailed the emergence of such a locus. One proposition is that this evolution occurs in two steps, with the initial invasion of a male-sterility mutation at one locus followed by mutations causing female sterility at a second closely linked locus. Here, we show how dioecy with heterogametic sex determination can also emerge in a gradual adaptive process, involving the co-evolution of resource allocation to different sexual functions jointly with its genetic architecture. Our model reveals that whether an XY or a ZW system evolves depends on the mating system of the ancestral hermaphrodites as well as the trade-off they face between allocation to male and female functions. In particular, the evolution of dioecy in response to selection to avoid selfing and inbreeding depression favours the emergence of XY systems, which characterise the vast majority of dioecious flowering plants. Selection favouring female specialisation also favours XY over ZW sex determination. Taken together, our results throw new light on the possible origins of dioecy from hermaphroditism by revealing a hitherto unrecognised link between the ecology and economics of sex allocation and the genetic basis of sex determination.
Massive genome reduction occurred prior to the origin of coral algal symbionts
Authors: Shah Sarah , Dougan Katherine E. , Chen Yibi , Lo Rosalyn , Laird Gemma , Fortuin Michael D. A. , Rai Subash K. , Murigneux Valentine , Bellantuono Anthony J. , Rodriguez-Lanetty Mauricio , Bhattacharya Debashish , Chan Cheong Xin
Published: March 2023

Dinoflagellates in the Family Symbiodiniaceae (Order Suessiales) are diverse, predominantly symbiotic lineages that associate with taxa such as corals and jellyfish. Their ancestor is believed to have been free-living, and the establishment of symbiosis (i.e., symbiogenesis) is hypothesised to have occurred multiple times during Symbiodiniaceae evolution. Among Symbiodiniaceae taxa, the genusEffreniumis an early diverging, free-living lineage that is phylogenetically positioned between two robustly supported groups of genera within which symbiotic taxa have emerged. The lack of symbiogenesis inEffreniumsuggests that the ancestral features of Symbiodiniaceae may have been retained in this lineage. Here we presentde novoassembled genomes and associated transcriptome data from three isolates ofEffrenium voratum. We compared theEffreniumgenomes (1.2-1.9 Gbp in size) and gene features with those of 16 Symbiodiniaceae taxa and other outgroup dinoflagellates. Surprisingly, we find that genome reduction, which is often associated with a symbiotic lifestyle, predates the origin of Symbiodiniaceae. We postulate that adaptation to an extreme habitat (e.g., as inPolarella glacialis) or life in oligotrophic conditions resulted in the Suessiales ancestor having a haploid genome size<2Gbp, which was retained (or reduced) among all extant algae in this lineage. Nonetheless, our data reveal that the free-living lifestyle distinguishesEffreniumfrom symbiotic Symbiodiniaceae vis-à-vis their longer introns, more-extensive mRNA editing, fewer (∼30%) lineage-specific gene families, and lower (∼10%) level of pseudogenisation. These results demonstrate how genome reduction and the adaptation to symbiotic versus free-living lifestyles intersect, and have driven the diversification and genome evolution of Symbiodiniaceae.
Mid-cell migration of the chromosomal terminus is coupled to origin segregation inEscherichia coli
Authors: Sadhir Ismath , Murray Seán M.
Published: March 2023

Bacterial chromosomes are dynamically and spatially organised within cells. In slow-growingEscherichia coli, the chromosomal terminus is initially located at the new pole and must therefore migrate to midcell during replication to reproduce the same pattern in the daughter cells. Here, we use high-throughput time-lapse microscopy to quantify this transition, its timing and its relationship to chromosome segregation. We find that terminus centralisation is a rapid discrete event that occurs ~25 min after initial separation of duplicated origins and ~50 min before the onset of bulk nucleoid segregation but with substantial variation between cells. Despite this variation, its movement is tightly coincident with the completion of origin segregation, even in the absence of its linkage to the divisome, suggesting a coupling between these two events. Indeed, we find that terminus centralisation does not occur if origin segregation away from mid-cell is disrupted, which results in daughter cells having an inverted chromosome organisation. Overall, our study quantifies the choreography of origin-terminus positioning and identifies an unexplored connection between these loci, furthering our understanding of chromosome segregation in this bacterium.