bluuebunny/crossref_metadata_2025 huggingface dataset:
Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition
Authors: Taugner Julian , Käsmann Lukas , Karin Monika , Eze Chukwuka , Flörsch Benedikt , Guggenberger Julian , Li Minglun , Tufman Amanda , Reinmuth Niels , Duell Thomas , Belka Claus , Manapov Farkhad
Published: August 2021

Background. The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). Method and patients. Prospective data of thirty-three consecutive patients with inoperable stage III NSCLC treated with CRT and sequential durvalumab (67%, 22 patients) or concurrent and sequential nivolumab (33%, 11 patients) were analyzed. Different PTV cut offs and PTV as a continuous variable were evaluated for their association with progression-free (PFS), local–regional progression-free (LRPFS), extracranial distant metastasis-free (eMFS) and brain-metastasis free-survival (BMFS). Results. All patients were treated with conventionally fractionated thoracic radiotherapy (TRT); 93% to a total dose of at least 60 Gy, 97% of patients received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 19.9 (range: 6.0–42.4) months; median overall survival (OS), LRFS, BMFS and eMFS were not reached. Median PFS was 22.8 (95% CI: 10.7–34.8) months. Patients with PTV ≥ 900ccm had a significantly shorter PFS (6.9 vs 22.8 months, p = 0.020) and eMFS (8.1 months vs. not reached, p = 0.003). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (UICC-TNM Classification 8th Edition) achieved a very poor outcome with a median PFS and eMFS of 3.6 vs 22.8 months (p < 0.001) and 3.6 months vs. not reached (p = 0.001), respectively. PTV as a continuous variable also had a significant impact on eMFS (p = 0.048). However, no significant association of different PTV cut-offs or PTV as a continuous variable with LRPFS and BMFS could be shown. The multivariate analysis that was performed for PTV ≥ 900ccm and age (≥ 65 years), gender (male), histology (non-ACC) as well as T- and N-stage (T4, N3) as covariates also revealed PTV ≥ 900ccm as the only factor that had a significant correlation with PFS (HR: 5.383 (95% CI:1.263–22.942, p = 0.023)). Conclusion. In this prospective analysis of inoperable stage III NSCLC patients treated with definitive CRT combined with concurrent and/or sequential CPI, significantly shorter PFS and eMFS were observed in patients with initial PTV ≥ 900ccm.
Bioaccumulation of polonium 210Po in cats’ hair, taking into account potential factors influencing changes in its concentration
Authors: Rudnicki-Velasquez Paweł Błażej , Boryło Alicja , Kaczor Marcin , Wieczorek Jarosław
Published: August 2021

The main aim of this study was to determine the bioaccumulation of 210Po in the hair of various cat breeds and an attempt to interpret whether the following factors, such as: breed, length of hair, gender, age, place of living or residence, weight, type of food consumed, taking medications, origin taking into account the structural division of Poland into voivodeships and physiological processes such as pregnancy and lactation have a significant influence on the concentration of this radionuclide. The obtained results show that the factors such as breed, length of hair, living of the cat in a given voivodeship and the type of food served influence the degree of 210Po bioaccumulation.
Tropes variations: the topic of particulars beyond Sellars’s myth of the given
Authors: Nunziante Antonio M.
Published: August 2021

The aim of this paper is twofold. First, I would like to bring into the light the almost unexplored Sellars’s theory of particulars. Second, I would like to show its surprising degree of compatibility with the thesis supported by some contemporary tropists (Lowe, Gozzano and Orilia (eds), Tropes, Universals and the Philosophy of Mind, Ontos Verlag, 2008; Moltmann, Mind 113:1–41, 2004 and Moltmann, Noûs 47:346–370, 2013). It is difficult to establish whether Sellars possessed an own theory of tropes, developed independently by the classical form it took in Williams 1953, but as a matter of fact the peculiar features of his “complex particulars” model it is very much like Williams’s theory. So much so that to all intents and purposes it represents a tropes variation. One of its strengths is that it is not part of a constituent ontology, since it is essentially developed from a linguistic and phenomenological point of view. It is for these reasons that this theory manages to avoid some of the classic objections to tropes and it shows to be compatible with the argument of Jonathan Lowe’s “proper visibility” as well as with Friederike Moltmann’s exquisitely linguistic interpretation of tropes.
The neural basis of Tetris gameplay: implicating the role of visuospatial processing
Authors: Agren Thomas , Hoppe Johanna M. , Singh Laura , Holmes Emily A. , Rosén Jörgen
Published: August 2021

Tetris is not only a widely used entertaining computer game, but has been used as a component in emerging psychological interventions targeting dysfunctional mental imagery, e.g., intrusive memories and imagery-based cravings. However, little is known about the neurobiological mechanisms underlying these interventions. Tetris gameplay has been hypothesized to disrupt dysfunctional mental imagery (e.g., imagery-based intrusive memories of adverse events) and cravings (e.g., substance use) by taxing visuospatial working memory. In line with this, the present study aimed to characterize brain areas involved in the visuospatial aspects of Tetris gameplay, by controlling for motor activity (button presses) and using gameplay instructions emphasizing mental rotation. Participants (N = 28) received mental rotation instructions and thereafter either played Tetris, or only pressed buttons as if playing Tetris (motor activity), while undergoing functional magnetic resonance imaging. Tetris gameplay (when using mental rotation instructions and controlling for motor activity) robustly activated brain areas located in the ventral and dorsal stream, with maximum peak activation in the inferior and mid temporal gyrus. To the best of our knowledge, this is the first study to characterize brain areas specifically associated with the visuospatial aspects of Tetris gameplay, by controlling for motor activity and when using mental rotation instructions. Results demonstrate that engaging in Tetris gameplay recruits an extensive brain circuitry previously tied to visuospatial processing. Thus, findings are consistent with the use of Tetris as an imagery-competing task as one of several components of emerging interventions targeting dysfunctional mental imagery.
Understanding technology in mining and its effect on the work environment
Authors: Lööw Joel
Published: August 2021

This paper takes its starting point in the fact that many mines have managed to improve its work environment, with regards to, for example, accident occurrence, while at the same time having stopped seeing improvements in these areas even in the wake of technology interventions. Technology projects in the mining industry continue to make claims on further improvements to the work environment, and make wider claims still, but have not addressed underlying causes that lead to underperformance of technology in terms of work environment improvements. This paper suggests that when we look closer at the situation, we find a complex situation in which negative and positive effects on the work environment follow the implementation of new technology. The analysis conducted in the paper further suggests that this has to do with mining environments having reached a level where historically major risks have been addressed; remaining risks, which are still significant, are of such a nature that their singular treatment — attempting to address these risks through isolated action such as new technology — engenders risks elsewhere. At the same time, the mining industry is of such a character that technological sophistications will fail to ultimately address the fundamental underlying causes of technology’s underperformance; technology by itself will never be enough. In part, this is due to constraints stemming from the characteristics of the mining industry, resulting in lower and slower technological progress for instance. The paper, thus, proposes a shift in focus with regards to technology, from technology itself to the processes surrounding the development, implementation, and use of technology in the mining industry. The paper, then, outlines some requirements for such a process.
Race, Ethnicity, and Neighborhood Food Environment Are Associated with Adolescent Sugary Drink Consumption During a 5-Year Community Campaign
Authors: Boehm Rebecca , Cooksey Stowers Kristen , Schneider Glenn E. , Schwartz Marlene B.
Published: August 2021

Background

A multi-level county-wide campaign to reduce sugary drink consumption was associated with significant decreases in retail sales of soda and fruit drinks. The aim of the current study was to examine changes in adolescent beverage consumption during the campaign by race/ethnicity and neighborhood food environment.

Methods

Beverage consumption among adolescents was evaluated at four time points in a repeated cross-sectional survey of a racially and ethnically diverse sample of sixth graders (N = 13,129) from public middle schools in the county. Each school’s surrounding attendance zone (i.e., neighborhoods where students live) was characterized as providing high or low exposure to unhealthy food retail (e.g., convenience stores, fast-food restaurants). Logistic and multiple linear regression models were used to evaluate changes in beverage consumption over time by student race/ethnicity and high versus low unhealthy food exposure.

Results

Over the 5 years, there were significant declines in the overall share of students who reported daily sugary drink consumption (49.4 to 36.9%) and their reported daily calories from these products (220 to 158 calories). However, disparities were observed, with higher levels of consumption among Black and Hispanic youth and among youth living in neighborhoods with more unhealthy food retail. Notably, Black students living in healthier neighborhood food environments reported significant decreases in daily consumption and calories after 5 years, while Black students living in neighborhoods with more convenience stores and fast-food outlets did not.

Conclusion

These findings suggest that both race/ethnicity and neighborhood food environments are important considerations when designing interventions to reduce sugary drink consumption among adolescents.
Necessity, Norm and Missing Knowledge
Authors: Müller Marcus
Published: August 2021

This study examines modal verbs in German press coverage of COVID-19 during the first phase of the pandemic. The data basis is an 18-million-word corpus of newspaper articles. For analysis, a sample is drawn from the total number of modal verbs in the corpus and these are categorised according to their discourse function. The corresponding annotated data are analysed quantitatively and qualitatively. For this purpose, the study draws back to Kratzer’s concept of conversational backgrounds. It turns out that in addition to normative speech backgrounds, goal formulations can be found above all. Normative backgrounds are evoked, on the one hand, to address official rules and their effects and, on the other hand in appeals and demands, to refer to social norms that are assumed as common ground. The fact that teleological backgrounds play a relatively large role indicates that the normalisation perspective is of great importance as a regulative in the crisis discourse. More positive than negative determining factors are indicated and uncertainty markings occur comparatively rarely. This points to successful crisis communication in this discourse phase.
Perineal Cyst in Transgender Men: A Rare Complication Following Gender Affirming Surgery – A Case Series and Literature Overview
Authors: Asseler Joyce D. , Ronkes Brechje L. , Groenman Freek A. , de Leeuw Robert , Pigot Gary L.S. , van Mello Norah M.
Published: August 2021

Introduction

Genital gender affirming surgery (gGAS) is usually the final stage in the medical transition for transgender men and consists of creating a neophallus and neo-scrotum, with or without urethral lengthening(UL). To reduce the complication risks of UL, a mandatory colpectomy is performed prior to UL. Colpectomy is considered a complex surgery, which may lead to various perioperative complications. There are few long-term complications reported.

Aim

To describe the clinical presentation and management of 3 consecutive transgender men presenting with a perineal cyst following gGAS.

Methods

After obtaining informed consent all clinical data was collected, including medical history, current symptoms, imaging, as well as surgery and histological outcomes. Furthermore, a literature search was performed.

Main outcome measure

To hypothesize the aetiology of the perineal cyst based on current published literature.

Results

Three otherwise healthy transgender men, ages 26–46 with a similar medical history, presented with a perineal cyst several months or years following colpectomy and gGAS with UL. All patients underwent surgery to remove the cyst. Several theories regarding aetiology of this perineal cyst are discussed in this report.

Conclusion

There remain several gaps in our knowledge regarding the aetiology and management of this perineal cyst. Therefore, further research is necessary.
Estimating incidence and attributable length of stay of healthcare-associated infections—Modeling the Swiss point-prevalence survey
Authors: Doerken Sam , Metsini Aliki , Buyet Sabina , Wolfensberger Aline , Zingg Walter , Wolkewitz Martin
Published: August 2021

Objectives:

In 2017, a point-prevalence survey was conducted with 12,931 patients in 96 hospitals across Switzerland as part of the national strategy to prevent healthcare-associated infections (HAIs). We present novel statistical methods to assess incidence proportions of HAI and attributable length-of-stay (LOS) in point-prevalence surveys.

Methods:

Follow-up data were collected for a subsample of patients and were used to impute follow-up data for all remaining patients. We used weights to correct length bias in logistic regression and multistate analyses. Methods were also tested in simulation studies.

Results:

The estimated incidence proportion of HAIs during hospital stay and not present at admission was 2.3% (95% confidence intervals [CI], 2.1–2.6), the most common type being lower respiratory tract infections (0.8%; 95% CI, 0.6–1.0). Incidence proportion was highest in patients with a rapidly fatal McCabe score (7.8%; 95% CI, 5.7–10.4). The attributable LOS for all HAI was 6.4 days (95% CI, 5.6–7.3) and highest for surgical site infections (7.1 days, 95% CI, 5.2–9.0). It was longest in the age group of 18–44 years (9.0 days; 95% CI, 5.4–12.6). Risk-factor analysis revealed that McCabe score had no effect on the discharge hazard after infection (hazard ratio [HR], 1.21; 95% CI, 0.89–1.63). Instead, it only influenced the infection hazard (HR, 1.84; 95% CI, 1.39–2.43) and the discharge hazard prior to infection (HR, 0.73; 95% CI, 0.66–0.82).

Conclusions:

In point-prevalence surveys with limited follow-up data, imputation and weighting can be used to estimate incidence proportions and attributable LOS that would otherwise require complete follow-up data.
Socioeconomic correlates of sedentary time during pregnancy among women at risk of gestational diabetes in the UK
Authors: Wagnild Janelle M. , Pollard Tessa M.
Published: August 2021

Little is known about the relationship between socioeconomic position (SEP) and duration and patterning of objectively measured sedentary time (ST) among adults, especially adults at high risk of diabetes. The aim of this study was to examine cross-sectional associations of SEP with ST (total, prolonged ST, breaks in ST) and self-reported TV time among pregnant women at risk of gestational diabetes in the UK. At 20 weeks’ gestation, pregnant women (n=174) wore an activPAL accelerometer and reported their usual TV time. Generalized linear mixed models were used to test associations of education, household income and area-level deprivation (separately and with mutual adjustment) with total ST, prolonged ST and breaks in ST. Logistic regression models were used to test associations between SEP indicators and high (≥2h/day) TV time. Those with the lowest education, lowest household income and highest area-level deprivation had the lowest ST and lowest prolonged ST. After mutual adjustment, area-level deprivation remained associated with total ST (β=0.10 [0.01, 0.20]). There was an inverse association between area-level deprivation and breaks in sedentary time (exp(b)=1.11 [1.01, 1.22]). Education was the only SEP correlate of high TV time, with more of those with least education reporting high TV time; this association persisted after adjustment for household income and area-level deprivation. The association between SEP and total and prolonged ST (positive) was the opposite of the association between education and high TV time (negative) in this sample of high-risk pregnant women. These findings should inform interventions to reduce sedentary time.
Outcome of two-week head and neck cancer pathway for the otolaryngology department in a tertiary centre
Authors: Mettias B , Charlton A , Ashokkumar S
Published: August 2021

Background

The two-week-wait head and neck cancer referral pathway was introduced by the Department of Health, and refined through National Institute for Health and Care Excellence guidelines which were updated in 2015.

Methods

A retrospective study was conducted of two-week-wait referrals to out-patient ENT from January to June 2018. The analysis included demographics, referral symptoms according to National Institute for Health and Care Excellence 2015 guidelines, cancer pick-up rates and positive predictive values.

Results

A total of 1107 patients were referred for suspected head and neck cancer over six months, with 6 per cent diagnosed with cancer. Neck lump, persistent hoarseness and throat pain were the most common presenting symptoms. Neck lump had the highest positive predictive value, followed by oral swelling. Oral bleeding and persistent unilateral sore throat showed significant positive predictive values. Investigation for metastatic head and neck cancer of an unknown primary or the involvement of other multidisciplinary teams could hinder the achievement of a 62-day treatment target.

Conclusion

The cancer pick-up rate from two-week-wait referrals is only 1.5 times higher than routine referrals. The ‘red flag’ symptoms given in the 2015 National Institute for Health and Care Excellence update would benefit from further review.
The accuracy of dry surgical field sublabial biopsy in the diagnosis of sicca syndrome
Authors: O’ Byrne L , Ramli R , Khoo S G
Published: August 2021

Background

Sublabial gland biopsy is the ‘gold standard’ in establishing the diagnosis of primary Sjögren's syndrome. Bleeding and nerve damage are complications. Our centre has adopted the use of the chalazion clamp to provide a dry surgical field to address these challenges. This study aimed to assess the accuracy of minor salivary gland harvest rate using this technique.

Method

A retrospective review of all minor salivary gland biopsies was carried out in a single tertiary referral centre over a five-year period.

Results

Forty-one biopsy patients were identified, with a mean age of 56.1 years. There was 100 per cent accuracy in harvest rate in our series. Twelve patients (29 per cent) were positive for primary Sjögren's syndrome. No patients had a complication immediately or at one month follow up.

Conclusion

Dry surgical field sublabial gland biopsy is a safe and highly effective technique in the diagnosis of primary Sjögren's syndrome. Initial results indicate it may provide a higher harvest rate with fewer complications than traditional non-ischaemic techniques.
Acute kidney injury after the arterial switch operation: incidence, risk factors, and outcomes
Authors: Schoenmaker Nikki J. , Weeda Jesse A. , van der Palen Roel L.F. , Hazekamp Mark G. , Bunker-Wiersma Heleen E.
Published: August 2021

Background:

The aim of this retrospective cohort study was to determine the incidence, potential risk factors, characteristics, and outcomes of acute kidney injury in children following the arterial switch operation for transposition of the great arteries.

Methods:

Retrospective review of children who underwent ASO between 2000 and 2020 in our tertiary children’s hospital in the Netherlands. Pre-and post-ASO serum creatinine levels were collected. Severe AKI was defined as 100% serum creatinine rise or estimated creatinine clearance <35 ml/min/1.73 m2according to pRIFLE criteria. Logistic regression was used to adjust for confounders.

Results:

A total of 242 children were included. Fifty-seven (24%) children developed severe AKI after ASO. Four patients with severe AKI were treated with renal replacement therapy. Children with severe AKI had a longer duration of mechanical ventilation 4.5 (1.0–29) versus 3 (1.0–12) days (p = 0.001), longer PICU stay 7 (2–76) versus 5 (1–70) days, (p = 0.001), higher rate of myocardial infarction 5% versus 0.5% (p = 0.001), sepsis 24% versus 9% (p = 0.002), post-operative pulmonary hypertension 19% versus 6% (p = 0.002), post-operative bleeding 9% versus 3% (p = 0.044), longer time to sternal closure 3 (1–19) versus 2 (1–6) days, (p = 0.009), and a higher mortality rate 9.0% versus 0.5% (p = 0.001) compared to children without severe AKI. Sepsis was a risk factor for developing severe AKI.

Conclusions:

In this single-centre cohort, 24% of our patients developed severe AKI after ASO, which is associated with increased morbidity, longer PICU stay, and higher mortality.
Lower Thermospheric Material Transport via Lagrangian Coherent Structures
Authors: Datta‐Barua Seebany , Pedatella Nicholas , Greer Katelynn , Wang Ningchao , Nutter Leanne , Harvey V. Lynn
Published: August 2021

We show that inter‐model variation due to under‐constraint by observations impacts the ability to predict material transport in the lower thermosphere. Lagrangian coherent structures (LCSs), indicating regions of maximal separation (or convergence) in a time‐varying flow, are derived in the lower thermosphere from models for several space shuttle water vapor plume events. We find that inter‐model differences in thermospheric transport manifest in LCSs in a way that is more stringent than mean wind analyses. LCSs defined using horizontal flow fields from the Specified Dynamics version of the Whole Atmosphere Community Climate Model with thermosphere‐ionosphere eXtension (SD‐WACCMX) at 109 km altitude are compared to Global Ultraviolet Imager (GUVI) observations of the space shuttle main engine plume. In one case, SD‐WACCMX predicts an LCS ridge to produce spreading not found in the observations. LCSs and tracer transport from SD‐WACCMX and from data assimilative WACCMX (WACCMX + DART) are compared to each other and to GUVI observations. Differences in the modeled LCSs and tracer positions appear between SD‐WACCMX and WACCMX + DART despite the similarity of mean winds. WACCMX + DART produces better tracer transport results for a July 2006 event, but it is unclear which model performs better in terms of LCS ridges. For a February 2010 event, when mean winds differ by up to 50 m/s between the models, differences in LCSs and tracer trajectories are even more severe. Low‐pass filtering the winds up to zonal wavenumber 6 reduces but does not eliminate inter‐model LCS differences. Inter‐model alignment of LCSs improves at a lower 60 km altitude.
The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11)
Authors: Kundu Arpita , Kowarz Eric , Marschalek Rolf
Published: August 2021

Leukemia patients bearing t(6;11)(q27;q23) translocations can be divided in two subgroups: those with breakpoints in the major breakpoint cluster region of MLL (introns 9–10; associated mainly with AML M1/4/5), and others with breakpoints in the minor breakpoint cluster region (introns 21–23), associated with T-ALL. We cloned all four of the resulting fusion genes (MLL-AF6, AF6-MLL, exMLL-AF6, AF6-shMLL) and subsequently transfected them to generate stable cell culture models. Their molecular function was tested by inducing gene expression for 48 h in a Doxycycline-dependent fashion. Here, we present our results upon differential gene expression (DGE) that were obtained by the “Massive Analyses of cDNA Ends” (MACE-Seq) technology, an established 3′-end based RNA-Seq method. Our results indicate that the PHD/BD domain, present in the AF6-MLL and the exMLL-AF6 fusion protein, is responsible for chromatin activation in a genome-wide fashion. This led to strong deregulation of transcriptional processes involving protein-coding genes, pseudogenes, non-annotated genes, and RNA genes, e.g., LincRNAs and microRNAs, respectively. While cooperation between the MLL-AF6 and AF6-MLL fusion proteins appears to be required for the above-mentioned effects, exMLL-AF6 is able to cause similar effects on its own. The exMLL-AF6/AF6-shMLL co-expressing cell line displayed the induction of a myeloid-specific and a T-cell specific gene signature, which may explain the T-ALL disease phenotype observed in patients with such breakpoints. This again demonstrated that MLL fusion proteins are instructive and allow to study their pathomolecular mechanisms.
BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
Authors: Zhang Lu , Fang Yu , Zhao Xinyu , Zheng Yake , Ma Yunqing , Li Shuang , Huang Zhi , Li Lihao
Published: August 2021

Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome–lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome–lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD.
Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder
Authors: Kantrowitz Joshua T. , Dong Zhengchao , Milak Matthew S. , Rashid Rain , Kegeles Lawrence S. , Javitt Daniel C. , Lieberman Jeffrey A. , John Mann J.
Published: August 2021

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.
Tumor suppressor immune gene therapy to reverse immunotherapy resistance
Authors: Chada Sunil , Wiederhold Dora , Menander Kerstin B. , Sellman Beatha , Talbott Max , Nemunaitis John J. , Ahn Hyo Min , Jung Bo-Kyeong , Yun Chae-Ok , Sobol Robert E.
Published: August 2021

Background

While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies.

Methods

We investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays.

Results

The substantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with the complete tumor remissions of both the primary and contralateral tumors. Interestingly, contralateral tumors, which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p < 0.001). None of the monotherapies or doublet treatments induced the complete tumor regressions. Ad-p53 treatment increased interferon, CD8+ T cell, immuno-proteosome antigen presentation, and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune-suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 downregulated genes associated with stromal pathways and IL10 expression identified novel anticancer therapeutic applications.

Conclusions

These results imply the ability of Ad-p53 to induce efficacious local and systemic antitumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complementary immune mechanisms of action, which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist, and immune checkpoint inhibitor combination treatment.
High-density linkage map construction and identification of loci regulating fruit quality traits in blueberry
Authors: Mengist Molla F. , Bostan Hamed , Young Elisheba , Kay Kristine L. , Gillitt Nicholas , Ballington James , Kay Colin D. , Ferruzzi Mario G. , Ashrafi Hamid , Lila Mary Ann , Iorizzo Massimo
Published: August 2021

Fruit quality traits play a significant role in consumer preferences and consumption in blueberry (Vaccinium corymbosumL). The objectives of this study were to construct a high-density linkage map and to identify the underlying genetic basis of fruit quality traits in blueberry. A total of 287 F1individuals derived from a cross between two southern highbush blueberry cultivars, ‘Reveille’ and ‘Arlen’, were phenotyped over three years (2016–2018) for fruit quality-related traits, including titratable acidity, pH, total soluble solids, and fruit weight. A high-density linkage map was constructed using 17k single nucleotide polymorphisms markers. The linkage map spanned a total of 1397 cM with an average inter-loci distance of 0.08 cM. The quantitative trait loci interval mapping based on the hidden Markov model identified 18 loci for fruit quality traits, including seven loci for fruit weight, three loci for titratable acidity, five loci for pH, and three loci for total soluble solids. Ten of these loci were detected in more than one year. These loci explained phenotypic variance ranging from 7 to 28% for titratable acidity and total soluble solid, and 8–13% for pH. However, the loci identified for fruit weight did not explain more than 10% of the phenotypic variance. We also reported the association between fruit quality traits and metabolites detected by Proton nuclear magnetic resonance analysis directly responsible for these fruit quality traits. Organic acids, citric acid, and quinic acid were significantly (P < 0.05) and positively correlated with titratable acidity. Sugar molecules showed a strong and positive correlation with total soluble solids. Overall, the study dissected the genetic basis of fruit quality traits and established an association between these fruit quality traits and metabolites.
Brown adipose tissue is the key depot for glucose clearance in microbiota depleted mice
Authors: Li Min , Li Li , Li Baoguo , Hambly Catherine , Wang Guanlin , Wu Yingga , Jin Zengguang , Wang Anyongqi , Niu Chaoqun , Wolfrum Christian , Speakman John R.
Published: August 2021

Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.
Landscape heterogeneity buffers biodiversity of simulated meta-food-webs under global change through rescue and drainage effects
Authors: Ryser Remo , Hirt Myriam R. , Häussler Johanna , Gravel Dominique , Brose Ulrich
Published: August 2021

Habitat fragmentation and eutrophication have strong impacts on biodiversity. Metacommunity research demonstrated that reduction in landscape connectivity may cause biodiversity loss in fragmented landscapes. Food-web research addressed how eutrophication can cause local biodiversity declines. However, there is very limited understanding of their cumulative impacts as they could amplify or cancel each other. Our simulations of meta-food-webs show that dispersal and trophic processes interact through two complementary mechanisms. First, the ‘rescue effect’ maintains local biodiversity by rapid recolonization after a local crash in population densities. Second, the ‘drainage effect’ stabilizes biodiversity by preventing overshooting of population densities on eutrophic patches. In complex food webs on large spatial networks of habitat patches, these effects yield systematically higher biodiversity in heterogeneous than in homogeneous landscapes. Our meta-food-web approach reveals a strong interaction between habitat fragmentation and eutrophication and provides a mechanistic explanation of how landscape heterogeneity promotes biodiversity.
Skin-electrode iontronic interface for mechanosensing
Authors: Zhu Pang , Du Huifeng , Hou Xingyu , Lu Peng , Wang Liu , Huang Jun , Bai Ningning , Wu Zhigang , Fang Nicholas X. , Guo Chuan Fei
Published: August 2021

Electrodermal devices that capture the physiological response of skin are crucial for monitoring vital signals, but they often require convoluted layered designs with either electronic or ionic active materials relying on complicated synthesis procedures, encapsulation, and packaging techniques. Here, we report that the ionic transport in living systems can provide a simple mode of iontronic sensing and bypass the need of artificial ionic materials. A simple skin-electrode mechanosensing structure (SEMS) is constructed, exhibiting high pressure-resolution and spatial-resolution, being capable of feeling touch and detecting weak physiological signals such as fingertip pulse under different skin humidity. Our mechanical analysis reveals the critical role of instability in high-aspect-ratio microstructures on sensing. We further demonstrate pressure mapping with millimeter-spatial-resolution using a fully textile SEMS-based glove. The simplicity and reliability of SEMS hold great promise of diverse healthcare applications, such as pulse detection and recovering the sensory capability in patients with tactile dysfunction.
Photopatterned microswimmers with programmable motion without external stimuli
Authors: Choi Yeongjae , Park Cheolheon , Lee Amos C. , Bae Junghyun , Kim Hyeli , Choi Hansol , Song Seo woo , Jeong Yunjin , Choi Jaewon , Lee Howon , Kwon Sunghoon , Park Wook
Published: August 2021

We introduce highly programmable microscale swimmers driven by the Marangoni effect (Marangoni microswimmers) that can self-propel on the surface of water. Previous studies on Marangoni swimmers have shown the advantage of self-propulsion without external energy source or mechanical systems, by taking advantage of direct conversion from power source materials to mechanical energy. However, current developments on Marangoni microswimmers have limitations in their fabrication, thereby hindering their programmability and precise mass production. By introducing a photopatterning method, we generated Marangoni microswimmers with multiple functional parts with distinct material properties in high throughput. Furthermore, various motions such as time-dependent direction change and disassembly of swimmers without external stimuli are programmed into the Marangoni microswimmers.
Natural variation in a type-A response regulator confers maize chilling tolerance
Authors: Zeng Rong , Li Zhuoyang , Shi Yiting , Fu Diyi , Yin Pan , Cheng Jinkui , Jiang Caifu , Yang Shuhua
Published: August 2021

Maize (Zea maysL.) is a cold-sensitive species that often faces chilling stress, which adversely affects growth and reproduction. However, the genetic basis of low-temperature adaptation in maize remains unclear. Here, we demonstrate that natural variation in the type-AResponse Regulator 1(ZmRR1) gene leads to differences in chilling tolerance among maize inbred lines. Association analysis reveals that InDel-35 ofZmRR1, encoding a protein harboring a mitogen-activated protein kinase (MPK) phosphorylation residue, is strongly associated with chilling tolerance. ZmMPK8, a negative regulator of chilling tolerance, interacts with and phosphorylates ZmRR1 at Ser15. The deletion of a 45-bp region of ZmRR1 harboring Ser15 inhibits its degradation via the 26 S proteasome pathway by preventing its phosphorylation by ZmMPK8. Transcriptome analysis indicates that ZmRR1 positively regulates the expression ofZmDREB1andCellulose synthase(CesA) genes to enhance chilling tolerance. Our findings thus provide a potential genetic resource for improving chilling tolerance in maize.
Switching at the ribosome: riboswitches need rProteins as modulators to regulate translation
Authors: de Jesus Vanessa , Qureshi Nusrat S. , Warhaut Sven , Bains Jasleen K. , Dietz Marina S. , Heilemann Mike , Schwalbe Harald , Fürtig Boris
Published: August 2021

Translational riboswitches are cis-acting RNA regulators that modulate the expression of genes during translation initiation. Their mechanism is considered as an RNA-only gene-regulatory system inducing a ligand-dependent shift of the population of functional ON- and OFF-states. The interaction of riboswitches with the translation machinery remained unexplored. For the adenine-sensing riboswitch from Vibrio vulnificus we show that ligand binding alone is not sufficient for switching to a translational ON-state but the interaction of the riboswitch with the 30S ribosome is indispensable. Only the synergy of binding of adenine and of 30S ribosome, in particular protein rS1, induces complete opening of the translation initiation region. Our investigation thus unravels the intricate dynamic network involving RNA regulator, ligand inducer and ribosome protein modulator during translation initiation.
Competing correlated states and abundant orbital magnetism in twisted monolayer-bilayer graphene
Authors: He Minhao , Zhang Ya-Hui , Li Yuhao , Fei Zaiyao , Watanabe Kenji , Taniguchi Takashi , Xu Xiaodong , Yankowitz Matthew
Published: August 2021

Flat band moiré superlattices have recently emerged as unique platforms for investigating the interplay between strong electronic correlations, nontrivial band topology, and multiple isospin ‘flavor’ symmetries. Twisted monolayer-bilayer graphene (tMBG) is an especially rich system owing to its low crystal symmetry and the tunability of its bandwidth and topology with an external electric field. Here, we find that orbital magnetism is abundant within the correlated phase diagram of tMBG, giving rise to the anomalous Hall effect in correlated metallic states nearby most odd integer fillings of the flat conduction band, as well as correlated Chern insulator states stabilized in an external magnetic field. The behavior of the states at zero field appears to be inconsistent with simple spin and valley polarization for the specific range of twist angles we investigate, and instead may plausibly result from an intervalley coherent (IVC) state with an order parameter that breaks time reversal symmetry. The application of a magnetic field further tunes the competition between correlated states, in some cases driving first-order topological phase transitions. Our results underscore the rich interplay between closely competing correlated ground states in tMBG, with possible implications for probing exotic IVC ordering.
Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment
Authors: Ring Sandra S. , Cupovic Jovana , Onder Lucas , Lütge Mechthild , Perez-Shibayama Christian , Gil-Cruz Cristina , Scandella Elke , De Martin Angelina , Mörbe Urs , Hartmann Fabienne , Wenger Robert , Spiegl Matthias , Besse Andrej , Bonilla Weldy V. , Stemeseder Felix , Schmidt Sarah , Orlinger Klaus K. , Krebs Philippe , Ludewig Burkhard , Flatz Lukas
Published: August 2021

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated aCxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation ofIl33gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.
GluN2A and GluN2B NMDA receptors use distinct allosteric routes
Authors: Tian Meilin , Stroebel David , Piot Laura , David Mélissa , Ye Shixin , Paoletti Pierre
Published: August 2021

Allostery represents a fundamental mechanism of biological regulation that involves long-range communication between distant protein sites. It also provides a powerful framework for novel therapeutics. NMDA receptors (NMDARs), glutamate-gated ionotropic receptors that play central roles in synapse maturation and plasticity, are prototypical allosteric machines harboring large extracellular N-terminal domains (NTDs) that provide allosteric control of key receptor properties with impact on cognition and behavior. It is commonly thought that GluN2A and GluN2B receptors, the two predominant NMDAR subtypes in the adult brain, share similar allosteric transitions. Here, combining functional and structural interrogation, we reveal that GluN2A and GluN2B receptors utilize different long-distance allosteric mechanisms involving distinct subunit-subunit interfaces and molecular rearrangements. NMDARs have thus evolved multiple levels of subunit-specific allosteric control over their transmembrane ion channel pore. Our results uncover an unsuspected diversity in NMDAR molecular mechanisms with important implications for receptor physiology and precision drug development.
Reference in-vitro dataset for inertial-sensor-to-bone alignment applied to the tibiofemoral joint
Authors: Weygers Ive , Kok Manon , Seel Thomas , Shah Darshan , Taylan Orçun , Scheys Lennart , Hallez Hans , Claeys Kurt
Published: August 2021

Skin-attached inertial sensors are increasingly used for kinematic analysis. However, their ability to measure outside-lab can only be exploited after correctly aligning the sensor axes with the underlying anatomical axes. Emerging model-based inertial-sensor-to-bone alignment methods relate inertial measurements with a model of the joint to overcome calibration movements and sensor placement assumptions. It is unclear how good such alignment methods can identify the anatomical axes. Any misalignment results in kinematic cross-talk errors, which makes model validation and the interpretation of the resulting kinematics measurements challenging. This study provides an anatomically correct ground-truth reference dataset from dynamic motions on a cadaver. In contrast with existing references, this enables a true model evaluation that overcomes influences from soft-tissue artifacts, orientation and manual palpation errors. This dataset comprises extensive dynamic movements that are recorded with multimodal measurements including trajectories of optical and virtual (via computed tomography) anatomical markers, reference kinematics, inertial measurements, transformation matrices and visualization tools. The dataset can be used either as a ground-truth reference or to advance research in inertial-sensor-to-bone-alignment.