bluuebunny/crossref_metadata_2025 huggingface dataset:
N6-isopentenyladenosine induces cell death through necroptosis in human glioblastoma cells
Authors: Pagano Cristina , Navarra Giovanna , Coppola Laura , Avilia Giorgio , Pastorino Olga , Della Monica Rosa , Buonaiuto Michela , Torelli Giovanni , Caiazzo Pasquale , Bifulco Maurizio , Laezza Chiara
Published: April 2022

Targeting necroptosis is considered a promising therapeutic strategy in cancer, including Glioblastoma Multiforme (GBM), one of the most lethal brain tumors. Necroptosis is a mechanism of programmed cell death overcoming the apoptosis resistance mechanism underlying GBM tumorigenesis and malignant progression. N6-isopentenyladenosine (iPA), adenosine modified with isoprenoid derivative, displays antitumor activity in different cancer models. In previous studies, we demonstrated that iPA interferes with EGFR signaling reducing glioma cell viability. Here, we show that iPA induces necroptosis in glioblastoma cell lines and in primary cells established from tumor explants, without affecting the viability of non-cancerous brain cell lines, (Normal Human Astrocyte). The activation of RIP1, RIP3, and MLKL and the upregulation of necrosome formation were increased upon iPA treatment while caspase-3, caspase-8, and PARP were not activated in GBM cells. Co-treatment with specific necroptosis inhibitor necrostatin-1 (Nec-1) or Necrosulfonamide (NSA) prevented cell death caused by iPA treatment while the general caspase inhibitor Z-VAD-fluoromethylketone (z-VAD-fmk) did not elicit any effect, suggesting that this molecule induces caspase-independent necroptosis. These results suggest that iPA treatment can be able to bypass the apoptosis resistance mechanism in glioblastoma thereby offering higher therapeutic efficacy.
Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury
Authors: Sanghvi Shridhar , Szteyn Kalina , Ponnalagu Devasena , Sridharan Divya , Lam Alexander , Hansra Inderjot , Chaudhury Ankur , Majumdar Uddalak , Kohut Andrew R. , Gururaja Rao Shubha , Khan Mahmood , Garg Vidu , Singh Harpreet
Published: April 2022

BKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BKCa channel’s activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BKCa channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes, which protects the heart on inhibition but not activation. Furthermore, K+ currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BKCa channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL-positive cells. In NCMs, activation of BKCa channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BKCa channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BKCa channels in adults compared to neonatal heart could be attributed to their differential localization.
CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Authors: Bernareggi Davide , Xie Qi , Prager Briana C. , Yun Jiyoung , Cruz Luisjesus S. , Pham Timothy V. , Kim William , Lee Xiqing , Coffey Michael , Zalfa Cristina , Azmoon Pardis , Zhu Huang , Tamayo Pablo , Rich Jeremy N. , Kaufman Dan S.
Published: April 2022

Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a “two cell type” whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.
Host-guest liquid gating mechanism with specific recognition interface behavior for universal quantitative chemical detection
Authors: Wang Huimeng , Fan Yi , Hou Yaqi , Chen Baiyi , Lei Jinmei , Yu Shijie , Chen Xinyu , Hou Xu
Published: April 2022

Universal visual quantitative chemical detection technology has emerged as an increasingly crucial tool for convenient testing with immediate results in the fields of environmental assessment, homeland security, clinical drug testing and health care, particularly in resource-limited settings. Here, we show a host-guest liquid gating mechanism to translate molecular interface recognition behavior into visually quantifiable detection signals. Quantitative chemical detection is achieved, which has obvious advantages for constructing a portable, affordable, on-site sensing platform to enable the visual quantitative testing of target molecules without optical/electrical equipment. Experiments and theoretical calculations confirm the specificity and scalability of the system. This mechanism can also be tailored by the rational design of host-guest complexes to quantitatively and visually detect various molecules. With the advantages of versatility and freedom from additional equipment, this detection mechanism has the potential to revolutionize environmental monitoring, food safety analysis, clinical drug testing, and more.
A genetic toolkit and gene switches to limit Mycoplasma growth for biosafety applications
Authors: Broto Alicia , Gaspari Erika , Miravet-Verde Samuel , dos Santos Vitor A. P. Martins , Isalan Mark
Published: April 2022

Mycoplasmas have exceptionally streamlined genomes and are strongly adapted to their many hosts, which provide them with essential nutrients. Owing to their relative genomic simplicity, Mycoplasmas have been used to develop chassis for biotechnological applications. However, the dearth of robust and precise toolkits for genomic manipulation and tight regulation has hindered any substantial advance. Herein we describe the construction of a robust genetic toolkit for M. pneumoniae, and its successful deployment to engineer synthetic gene switches that control and limit Mycoplasma growth, for biosafety containment applications. We found these synthetic gene circuits to be stable and robust in the long-term, in the context of a minimal cell. With this work, we lay a foundation to develop viable and robust biosafety systems to exploit a synthetic Mycoplasma chassis for live attenuated vectors for therapeutic applications.
Emergence and intensification of dairying in the Caucasus and Eurasian steppes
Authors: Scott Ashley , Reinhold Sabine , Hermes Taylor , Kalmykov Alexey A. , Belinskiy Andrey , Buzhilova Alexandra , Berezina Natalia , Kantorovich Anatoliy R. , Maslov Vladimir E. , Guliyev Farhad , Lyonnet Bertille , Gasimov Parviz , Jalilov Bakhtiyar , Eminli Jeyhun , Iskandarov Emil , Hammer Emily , Nugent Selin E. , Hagan Richard , Majander Kerttu , Onkamo Päivi , Nordqvist Kerkko , Shishlina Natalia , Kaverzneva Elena , Korolev Arkadiy I. , Khokhlov Aleksandr A. , Smolyaninov Roman V. , Sharapova Svetlana V. , Krause Rüdiger , Karapetian Marina , Stolarczyk Eliza , Krause Johannes , Hansen Svend , Haak Wolfgang , Warinner Christina
Published: April 2022

Archaeological and archaeogenetic evidence points to the Pontic–Caspian steppe zone between the Caucasus and the Black Sea as the crucible from which the earliest steppe pastoralist societies arose and spread, ultimately influencing populations from Europe to Inner Asia. However, little is known about their economic foundations and the factors that may have contributed to their extensive mobility. Here, we investigate dietary proteins within the dental calculus proteomes of 45 individuals spanning the Neolithic to Greco-Roman periods in the Pontic–Caspian Steppe and neighbouring South Caucasus, Oka–Volga–Don and East Urals regions. We find that sheep dairying accompanies the earliest forms of Eneolithic pastoralism in the North Caucasus. During the fourth millennium bc, Maykop and early Yamnaya populations also focused dairying exclusively on sheep while reserving cattle for traction and other purposes. We observe a breakdown in livestock specialization and an economic diversification of dairy herds coinciding with aridification during the subsequent late Yamnaya and North Caucasus Culture phases, followed by severe climate deterioration during the Catacomb and Lola periods. The need for additional pastures to support these herds may have driven the heightened mobility of the Middle and Late Bronze Age periods. Following a hiatus of more than 500 years, the North Caucasian steppe was repopulated by Early Iron Age societies with a broad mobile dairy economy, including a new focus on horse milking.
EEG-based measurement system for monitoring student engagement in learning 4.0
Authors: Apicella Andrea , Arpaia Pasquale , Frosolone Mirco , Improta Giovanni , Moccaldi Nicola , Pollastro Andrea
Published: April 2022

A wearable system for the personalized EEG-based detection of engagement in learning 4.0 is proposed. In particular, the effectiveness of the proposed solution is assessed by means of the classification accuracy in predicting engagement. The system can be used to make an automated teaching platform adaptable to the user, by managing eventual drops in the cognitive and emotional engagement. The effectiveness of the learning process mainly depends on the engagement level of the learner. In case of distraction, lack of interest or superficial participation, the teaching strategy could be personalized by an automatic modulation of contents and communication strategies. The system is validated by an experimental case study on twenty-one students. The experimental task was to learn how a specific human-machine interface works. Both the cognitive and motor skills of participants were involved. De facto standard stimuli, namely (1) cognitive task (Continuous Performance Test), (2) music background (Music Emotion Recognition—MER database), and (3) social feedback (Hermans and De Houwer database), were employed to guarantee a metrologically founded reference. In within-subject approach, the proposed signal processing pipeline (Filter bank, Common Spatial Pattern, and Support Vector Machine), reaches almost 77% average accuracy, in detecting both cognitive and emotional engagement.
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Authors: Brian Ben F. , Sjaastad Frances V. , Freedman Tanya S.
Published: April 2022

The kinase Csk is the primary negative regulator of the Src-family kinases (SFKs, e.g., Lck, Fyn, Lyn, Hck, Fgr, Blk, Yes), phosphorylating a tyrosine on the SFK C-terminal tail that mediates autoinhibition. Csk also binds phosphatases, including PTPN12 (PTP-PEST) and immune-cell PTPN22 (LYP/Pep), which dephosphorylate the SFK activation loop to promote autoinhibition. Csk-binding proteins (e.g., CBP/PAG1) oligomerize within membrane microdomains, and high local concentration promotes Csk function. Purified Csk homodimerizes in solution through an interface that overlaps the phosphatase binding footprint. Here we demonstrate that Csk can homodimerize in Jurkat T cells, in competition with PTPN22 binding. We designed SH3-domain mutations in Csk that selectively impair homodimerization (H21I) or PTPN22 binding (K43D) and verified their kinase activity in solution. Disruption of either interaction in cells, however, decreased the negative-regulatory function of Csk. Csk W47A, a substitution previously reported to block PTPN22 binding, had a secondary effect of impairing homodimerization. Csk H21I and K43D will be useful tools for dissecting the protein-specific drivers of autoimmunity mediated by the human polymorphism PTPN22 R620W, which impairs interaction with Csk and with the E3 ubiquitin ligase TRAF3. Future investigations of Csk homodimer activity and phosphatase interactions may reveal new facets of SFK regulation in hematopoietic and non-hematopoietic cells.
Rare species disproportionally contribute to functional diversity in managed forests
Authors: Basile Marco
Published: April 2022

Functional diversity is linked with critical ecosystem functions, yet its relationship with numerical diversity, e.g. species richness, is not fully understood. The mechanisms linking changes of species richness, e.g. random and non-random species losses and gains, with changes of functional diversity become more relevant in the face of rapid environmental changes. In particular, non-random species changes including rare species may affect functional diversity, and the overall ecosystem function, disproportionately compared to random species changes including common species. In this study, I investigated how changes in numerical diversity of bird assemblages are related to functional diversity, and how the environment, and in particular forest management, influences such a relationship. I collected bird count data in the extensively-managed forest landscape of the Black Forest (Germany), at 82 sampling sites over three years. Data included species richness and abundance per site, and functional traits related to diet and habitat type for each species to compute functional diversity. By partitioning numerical diversity changes into five components using Price Equations, I calculated the contribution of random and non-random species losses and gains, and the abundance of common species, to functional diversity. Then I modelled these contributions as a function of several environmental variables describing broad forest conditions, and including forest management intensity. I found that, beside the major contribution of random species losses to functional diversity, non-random species losses also play a role, indicating that rare species that contribute more to functional diversity are often lost earlier than common species. The overall contribution to functional diversity of species losses is larger than that of species gains, pointing toward an ongoing simplification of the forest bird assemblage. Among all Price components, random species gains were influenced by management intensity, while other components were not influenced by any management variable. This highlight that potential conservation actions may not be effective in halting ecosystem functioning decline, as species gains do not result in increased functional diversity.
Quantum spinning photonic circulator
Authors: Jing Yu-Wei
Published: April 2022

We propose a scheme to realize a four-port quantum optical circulator for critical coupling of a spinning Kerr resonator to two tapered fibers. Its nonreciprocal effect arises from the Fizeau drag induced splitting of the resonance frequencies of the two counter-travelling optical modes. The transmitted photons exhibit direction dependent quantum correlations and nonreciprocal photon blockade occurs for photons transferred between the two fibers. Moreover, the quantum optical circulator is robust against the back scattering induced by intermodal coupling between counter-travelling optical modes. The present quantum optical circulator has significant potential as an elementary cell in chiral quantum information processing without magnetic field.
The CMS19 disease model specifies a pivotal role for collagen XIII in bone homeostasis
Authors: Kemppainen A. V. , Finnilä M. A. , Heikkinen A. , Härönen H. , Izzi V. , Kauppinen S. , Saarakkala S. , Pihlajaniemi T. , Koivunen J.
Published: April 2022

Mutations in theCOL13A1gene result in congenital myasthenic syndrome type 19 (CMS19), a disease of neuromuscular synapses and including various skeletal manifestations, particularly facial dysmorphisms. The phenotypic consequences inCol13a1null mice (Col13a1−/−) recapitulate the muscle findings of the CMS19 patients. Collagen XIII (ColXIII) is exists as two forms, a transmembrane protein and a soluble molecule. While theCol13a1−/−mice have poorly formed neuromuscular junctions, the prevention of shedding of the ColXIII ectodomain in theCol13a1tm/tmmice results in acetylcholine receptor clusters of increased size and complexity. In view of the bone abnormalities in CMS19, we here studied the tubular and calvarial bone morphology of theCol13a1−/−mice. We discovered several craniofacial malformations, albeit less pronounced ones than in the human disease, and a reduction of cortical bone mass in aged mice. In theCol13a1tm/tmmice, where ColXIII is synthesized but the ectodomain shedding is prevented due to a mutation in a protease recognition sequence, the cortical bone mass decreased as well with age and the cephalometric analyses revealed significant craniofacial abnormalities but no clear phenotypical pattern. To conclude, our data indicates an intrinsic role for ColXIII, particularly the soluble form, in the upkeep of bone with aging and suggests the possibility of previously undiscovered bone pathologies in patients with CMS19.
Affective response to physical activity as a deep phenotype in a non-randomized pilot study
Authors: Lee Harold H. , McGeary John E. , Dunsiger Shira , Emerson Jessica A. , Bock Beth , McCaffery Jeanne , Dwyer Kayla , Bryan Angela D. , Williams David M.
Published: April 2022

Large-scale genomic studies are beginning to identify genetic predictors of physical activity (PA). For those genetically predisposed to engage in low PA, a behavioral intervention may target a malleable factor that mediates genetic predisposition to low PA (i.e., intermediate phenotype) to mitigate the genetic influences. In a non-randomized exercise promotion pilot study, we test the feasibility of examining affective response to PA (how one feels during PA) as an intermediate phenotype between genetic variation and PA adherence. We hypothesized that three single nucleotide polymorphisms (SNPs; rs8044769 and rs3751812 in FTO; rs6265 in BDNF), identified from a prior systematic review, would be predictive of affective response to PA, and that affective response to PA would mediate the SNP-PA link. Forty five healthy, low-active adults received a 12-week print-based PA promotion program. Baseline affective response to PA was assessed using the Feeling Scale, a single-item measure of affective valence. Moderate to vigorous PA (MVPA) was assessed using accelerometers pre- and post-intervention. We examined the three SNPs in a weighted genetic score. Age, sex, body mass index, race, and neighborhood walkability were potential covariates. Affective response to PA and MVPA at follow-up (minutes/day over 4–7 days) were regressed on variation in SNPs, controlling for covariates. One unit increase in genetic score was associated with a 0.14 higher mean Feeling Scale, though was not statistically significant (p = 0.13). Among individual SNPs, having an additional FTO rs8044769 C allele was associated with a mean Feeling Scale score of 0.53 units higher (p = 0.015), which was statistically significant after applying the corrected p-value of 0.016. The genetic score or individual SNPs were not predictive of MVPA 12 weeks later, thereby mediation analyses were not performed. The preliminary findings demonstrate the promise of the intermediate phenotype approach.
Spatial frequency domain imaging for monitoring immune-mediated chemotherapy treatment response and resistance in a murine breast cancer model
Authors: Tank Anup , Vergato Cameron , Waxman David J. , Roblyer Darren
Published: April 2022

Spatial Frequency Domain Imaging (SFDI) can provide longitudinal, label-free, and widefield hemodynamic and scattering measurements of murine tumors in vivo. Our previous work has shown that the reduced scattering coefficient (μ′s) at 800 nm, as well as the wavelength dependence of scattering, both have prognostic value in tracking apoptosis and proliferation during treatment with anti-cancer therapies. However, there is limited work in validating these optical biomarkers in clinically relevant tumor models that manifest specific treatment resistance mechanisms that mimic the clinical setting. It was recently demonstrated that metronomic dosing of cyclophosphamide induces a strong anti-tumor immune response and tumor volume reduction in the E0771 murine breast cancer model. This immune activation mechanism can be blocked with an IFNAR-1 antibody, leading to treatment resistance. Here we present a longitudinal study utilizing SFDI to monitor this paired responsive-resistant model for up to 30 days of drug treatment. Mice receiving the immune modulatory metronomic cyclophosphamide schedule had a significant increase in tumor optical scattering compared to mice receiving cyclophosphamide in combination with the IFNAR-1 antibody (9% increase vs 10% decrease on day 5 of treatment, p < 0.001). The magnitude of these differences increased throughout the duration of treatment. Additionally, scattering changes on day 4 of treatment could discriminate responsive versus resistant tumors with an accuracy of 78%, while tumor volume had an accuracy of only 52%. These results validate optical scattering as a promising prognostic biomarker that can discriminate between treatment responsive and resistant tumor models.
Usp5, Usp34, and Otu1 deubiquitylases mediate DNA repair in Drosophila melanogaster
Authors: Páhi Zoltán G. , Kovács Levente , Szűcs Diána , Borsos Barbara N. , Deák Péter , Pankotai Tibor
Published: April 2022

Ubiquitylation is critical for preventing aberrant DNA repair and for efficient maintenance of genome stability. As deubiquitylases (DUBs) counteract ubiquitylation, they must have a great influence on many biological processes, including DNA damage response. To elucidate the role of DUBs in DNA repair in Drosophila melanogaster, systematic siRNA screening was applied to identify DUBs with a reduced survival rate following exposure to ultraviolet and X-ray radiations. As a secondary validation, we applied the direct repeat (DR)-white reporter system with which we induced site-specific DSBs and affirmed the importance of the DUBs Ovarian tumor domain-containing deubiquitinating enzyme 1 (Otu1), Ubiquitin carboxyl-terminal hydrolase 5 (Usp5), and Ubiquitin carboxyl-terminal hydrolase 34 (Usp34) in DSB repair pathways using Drosophila. Our results indicate that the loss of Otu1 and Usp5 induces strong position effect variegation in Drosophila eye following I-SceI-induced DSB deployment. Otu1 and Usp5 are essential in DNA damage-induced cellular response, and both DUBs are required for the fine-tuned regulation of the non-homologous end joining pathway. Furthermore, the Drosophila DR-white assay demonstrated that homologous recombination does not occur in the absence of Usp34, indicating an indispensable role of Usp34 in this process.
Better, worse, or different than expected: on the role of value and identity prediction errors in fear memory reactivation
Authors: Gerlicher A. M. V. , Verweij S. A. , Kindt M.
Published: April 2022

Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.
Spontaneous regression rates of actinic keratosis: a systematic review and pooled analysis of randomized controlled trials
Authors: Steeb Theresa , Petzold Anne , Hornung Annkathrin , Wessely Anja , Berking Carola , Heppt Markus V.
Published: April 2022

Actinic keratosis (AK) are precancerous lesions of the skin which may progress to invasive squamous cell carcinoma. However, single lesions may also persist or even regress and heal spontaneously. Until now, evidence on the natural course of AK including spontaneous regression is limited. We aimed to synthesize regression rates of AK. We performed a systematic literature research in Medline, Embase, and CENTRAL for eligible trials until 3rd March 2020. Spontaneous regression rates were pooled using a random-effects model to calculate pooled proportions of participant-specific and lesion-specific complete clearance rates reported for the placebo arms of randomized controlled trials. Subgroup analyses were performed to dissect differences according to the type of placebo, immunocompetence of the participants, and localization of the lesions. Data from 38 records was included. The pooled participant-specific clearance rate was 8% (95% CI 6–10%, I2 = 71%) while the lesion-specific clearance rate was 23% (95% CI 16–31%, I2 = 97%). The highest participant- and lesion-specific clearance rates were achieved 12 weeks after the end of treatment (12% and 33%, respectively). Subgroup analysis revealed participant- as well as lesion-specific clearance rates of 0% for organ transplant recipients (OTR). We conclude that only a few participants achieve complete regression of their AK without any active treatment. Besides, the results underline that lesion clearance without active treatment is unlikely in OTR. Thus, early and consequent treatment of AK is recommended. Special attention should be paid when treating AK of OTR.
Adherence to a western dietary pattern and risk of invasive ductal and lobular breast carcinomas: a case–control study
Authors: Foroozani Elahe , Akbari Ali , Amanat Sasan , Rashidi Nastaran , Bastam Dariush , Ataee Shima , Sharifnia Golnaz , Faraouei Mohammad , Dianatinasab Mostafa , Safdari Hassan
Published: April 2022

Little is known about the role of diet in the risk of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of the breast, the most common histological subtypes of breast cancer (BC). This is because, the majority of studies on the association of diet and the risk of BC are focused on single food items, and studies considering the overall diet in terms of dietary patterns are limited. Also, the potential heterogeneity in the impact of Western diet (WD) on histological subtypes of BC is not established. This, the age-frequency-matched case–control study included 1009 incident BC cases and 1009 healthy controls. The required data was obtained from the patients’ medical files and interviews using a previously validated researcher-designed questionnaire for collecting data on socio-economic and anthropometric statuses and a valid food frequency questionnaire (FFQ) to measure the participants’ dietary intake. We used multinomial logistic regression, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A positive and significant association was observed between higher adherence to a WD and risk of IDC (OR comparing highest with the lowest tertile: 2.45, 95% CI 1.88, 3.17; p-trend < 0.001), whereas no significant association was observed between adherence to the WD and the risk of ILC (OR comparing highest with the lowest tertile: 1.63, 95% CI 0.63, 3.25) (p for heterogeneity = 0.03). The results of an analysis stratified by menopausal status suggested a similar pattern. We provided evidence that adherence to a WD raises the risk of IDC, but not ILC, suggesting different etiological mechanisms for IDC and ILC.
Altered hypoxia inducible factor regulation in hereditary haemorrhagic telangiectasia
Authors: Wrobeln Anna , Leu Tristan , Jablonska Jadwiga , Geisthoff Urban , Lang Stephan , Fandrey Joachim , Droege Freya
Published: April 2022

Patients with hereditary haemorrhagic telangiectasia (HHT), also known as Rendu–Osler–Weber syndrome, suffer from the consequences of abnormal vessel structures. These structures can lead to haemorrhages or shunt effects in liver, lungs and brain. This inherited and rare disease is characterized by mutations affecting the transforming growth factor-β (TGF-β)/Bone Morphogenetic Protein (BMP) pathway that results in arteriovenous malformations and studies indicate an impaired immune response. The mechanism underlying this altered immune response in HHT patients is still unknown. TGF-β interacts with hypoxia inducible factors (HIF), which both orchestrate inflammatory and angiogenic processes. Therefore, we analysed the expression of HIF and related genes in whole blood samples from HHT patients. We could show significantly decreased expression of HIF-1α on the mRNA and protein level. However, commonly known upstream regulators of HIF-1α in inflammatory responses were not affected, whereas HIF-1α target genes were significantly downregulated. There was no correlation between HIF1A or HIF2A gene expression and the severity of HHT detected. Our results represent a rare case of HIF-1α downregulation in a human disease, which underlines the relevance of HIFs in HHT. The study indicates an interaction of the known mutation in HHT and the dysregulation of HIF-1α in HHT patients, which might contribute to the clinical phenotype.
Hypothermia differentially modulates the formation and decay of NBS1, γH2AX and 53BP1 foci in U2OS cells exposed to gamma radiation
Authors: Płódowska Magdalena , Krakowiak Wiktoria , Węgierek-Ciuk Aneta , Lankoff Anna , Szary Karol , Lis Krzysztof , Wojcik Andrzej , Lisowska Halina
Published: April 2022

In studies on the mechanism of DNA damage response where ionizing radiation is used as the DNA damaging agent, cells are often exposed to ionizing radiation on melting ice (corresponding to 0.8 °C). The purpose of this procedure is to inhibit cellular processes i.e. DNA repair. Low temperature at exposure has been shown to act in a radioprotective manner at the level of cytogenetic damage, but its mechanisms of action are poorly understood. The aim of the study was to analyze the effect of hypothermia at the level of formation and decay of NBS1, γH2AX, and 53BP1 foci, micronuclei, survival, cell cycle progression and oxidative stress in U2OS cells. The results show that hypothermia alone induced oxidative stress and foci. When applied in combination with radiation but only during the exposure time, it potentiated the formation of γH2AX and 53BP1 but not of NBS1 foci. When applied during irradiation and subsequent repair time, 53BP1 and NBS1 foci formed and decayed, but the levels were markedly lower than when repair was carried out at 37 °C. The frequency of micronuclei was elevated in cells irradiated at 0.8 °C, but only when analysed 20 h after irradiation which is likely due to a reduced G2 cell cycle block. Hypothermia reduced cell survival, both with and without radiation exposure. The temperature effect should be considered when cooling cells on melting ice to inhibit DNA repair in the induction of DNA damage.
Prediction of global marginal land resources for Pistacia chinensis Bunge by a machine learning method
Authors: Chen Shuai , Hao Mengmeng , Qian Yushu , Ding Fangyu , Xie Xiaolan , Ma Tian
Published: April 2022

Biofuel has attracted worldwide attention due to its potential to combat climate change and meet emission reduction targets. Pistacia chinensis Bunge (P. chinensis) is a prospective plant for producing biodiesel. Estimating the global potential marginal land resources for cultivating this species would be conducive to exploiting bioenergy yielded from it. In this study, we applied a machine learning method, boosted regression tree, to estimate the suitable marginal land for growing P. chinensis worldwide. The result indicated that most of the qualified marginal land is found in Southern Africa, the southern part of North America, the western part of South America, Southeast Asia, Southern Europe, and eastern and southwest coasts of Oceania, for a grand total of 1311.85 million hectares. Besides, we evaluated the relative importance of the environmental variables, revealing the major environmental factors that determine the suitability for growing P. chinensis, which include mean annual water vapor pressure, mean annual temperature, mean solar radiation, and annual cumulative precipitation. The potential global distribution of P. chinensis could provide a valuable basis to guide the formulation of P. chinensis-based biodiesel policies.
Loss of β4-spectrin impairs Nav channel clustering at the heminode and temporal fidelity of presynaptic spikes in developing auditory brain
Authors: Nip Kaila , Kashiwagura Sean , Kim Jun Hee
Published: April 2022

Beta-4 (β4)-spectrin, encoded by the gene Sptbn4, is a cytoskeleton protein found at nodes and the axon initial segments (AIS). Sptbn4 mutations are associated with myopathy, neuropathy, and auditory deficits in humans. Related to auditory dysfunction, however, the expression and roles of β4-spectrin at axon segments along the myelinated axon in the developing auditory brain are not well explored. We found during postnatal development, β4-spectrin is critical for voltage-gated sodium channel (Nav) clustering at the heminode along the nerve terminal, but not for the formation of nodal and AIS structures in the auditory brainstem. Presynaptic terminal recordings in Sptbn4geo mice, β4-spectrin null mice, showed an elevated threshold of action potential and increased failures during action potential train at high-frequency. Sptbn4geo mice exhibited a slower central conduction and showed no startle responses, but had normal cochlear function. Taken together, the lack of β4-spectrin impairs Nav clustering at the heminode along the nerve terminal and the temporal fidelity and reliability of presynaptic spikes, leading to central auditory processing deficits during postnatal development.
Graphene–oxide interface for optoelectronic synapse application
Authors: Martinez-Martinez Ricardo , Islam Molla Manjurul , Krishnaprasad Adithi , Roy Tania
Published: April 2022

Optoelectronic synapses combine the functionalities of a non-volatile memory and photodetection in the same device, paving the path for the realization of artificial retina systems which can capture, pre-process, and identify images on the same platform. Graphene/Ta2O5/graphene phototransistor exhibits synapse characteristics when visible electromagnetic radiation of wavelength 405 nm illuminates the device. The photocurrent is retained after light withdrawal when positive gate voltage is applied to the device. The device exhibits distinct conductance states, modulated by different parameters of incident light, such as pulse width and number of pulses. The conductance state can be retained for 104 s, indicating long term potentiation (LTP), similar to biological synapses. By using optical and electrical pulses, the device shows optical potentiation and electrical LTD repeatably, implying their applicability in neural networks for pattern recognition.
Modulation of thermometric performance of single-band-ratiometric luminescent thermometers based on luminescence of Nd3+ activated tetrafluorides by size modification
Authors: Trejgis K. , Ledwa K. , Maciejewska K. , Li L. , Marciniak L.
Published: April 2022

Due to a number of its advantages, luminescence thermometry has been a strongly developed strand of temperature metrology over a period of time. Although there are several different types of luminescent thermometers, recently attention has been focused on a new single-band ratiometric approach, which is based on the excited state absorption phenomenon. Nevertheless, since this process is nontrivial and has not been studied extensively in the context of thermometry to date, a number of studies are necessary to enable the intentional development of highly sensitive thermometers based on this method. One of the important aspects is to investigate the influence of material size and the associated occurrence of surface effects, which is considered in this work. In addition, the research in this paper has been extended to explore the aspect of host material composition. Accordingly, nanocrystals and microcrystals of β-NaYF4:2%Nd3+, β-NaGdF4:2%Nd3+, and LiGdF4:2%Nd3+ were investigated in this work. The influence of surface effects on thermometric parameters was proved, with special emphasis on the useful temperature range. Thus, by increasing the particle size, it was possible to intentionally extend the useful range by even more than 100 K.
Behavioral intentions of rural farmers to recycle human excreta in agriculture
Authors: Gwara Simon , Wale Edilegnaw , Odindo Alfred
Published: April 2022

Considerable progress has been made in developing human excreta recovery pathways and processes for maximum nutrient recovery and contaminant elimination. The demand segment has often been ignored as an area for future research, especially during the technology development. The findings from the few published articles on social acceptance show missing and inconclusive influence of demographic, sociological, and economic farmer-characteristics. This study endeavours to close this gap by using the social psychological theories, technology adoption theories and the new ecological paradigm to investigate the factors that influence the behavioral intentions of rural farmers to recycle human excreta in agriculture. Study findings show that social acceptance was driven by awareness, religiosity, income, source of income, and environmental dispositions. Perceived behavioral control represents a potential barrier to human excreta reuse. The study recommends the demographic, cultural, sociological, and economic mainstreaming of dissemination strategies of circular bioeconomy approaches within the context of agricultural innovation systems.
3D-SLIP model based dynamic stability strategy for legged robots with impact disturbance rejection
Authors: Han Bin , Yi Haoyuan , Xu Zhenyu , Yang Xin , Luo Xin
Published: April 2022

Inspired by biomechanical studies, the spring-loaded inverted pendulum model is an effective behavior model to describe the running movement of animals and legged robots in the sagittal plane. However, when confronted with external lateral disturbances, the model has to move out of the 2-D plane and be extended to 3-D locomotion. With the degree of freedom increasing, the computational complexity is higher and the real-time control is more and more difficult, especially when considering the complex legged model. Here, we construct a control strategy based on the classical Raibert controller for legged locomotion under lateral impact disturbances. This strategy, named 3D-HFC, is composed of three core modules: touchdown angle control, body attitude angle control and energy compensation. The energy loss in each step is taken into consideration, and the real-time measured energy loss of the current step is adopted to predict that of the next step. We demonstrate the efficiency of the proposed control strategy on a simulated 3D-SLIP lower order model and a simulated running quadruped, which are perturbed by different impact forces. Furthermore, a quadruped bionic prototype named MBBOT was set up, on which lateral impact experiments were designed and implemented. Both simulation and experimental results show that the proposed approach can realize the impact disturbance rejection.
Artificial shelters provide suitable thermal habitat for a cold-blooded animal
Authors: Yu Xin , Wu Nicholas. C. , Ge Luyuan , Li Lianshan , Zhang Zhengwang , Lei Juan
Published: April 2022

Human activities such as urbanization often has negative affects wildlife. However, urbanization can also be beneficial to some animals by providing suitable microhabitats. To test the impact of urbanization on cold-blooded animals, we first conducted a snake survey at a national nature reserve (Xianghai natural reserve) and an adjacent tourist bird park (Red-crowned Crane Park). We show high presence ofElaphe dionein the tourist park even with high human activities and predator population (the endangered, red-crowned crane,Grus japonensis). We then radio-tracked 20 individuals ofE. dione, set seven camera traps, and recorded the temperature of the snakes and artificial structures in Crane Park to document their space use, activity, and thermal preference, respectively. Our results showE. dionepreferred to use artificial facilities to shelter from their predators and for thermoregulation. The high number of rats from the camera traps indicate abundant prey items. Overall,E. dioneappears to be adapted to modified habitats and may expand population size at the current study site.
Relevance to the higher order structure may govern auditory statistical learning in neonates
Authors: Todd Juanita , Háden Gábor P. , Winkler István
Published: April 2022

Hearing is one of the earliest senses to develop and is quite mature by birth. Contemporary theories assume that regularities in sound are exploited by the brain to create internal models of the environment. Through statistical learning, internal models extrapolate from patterns to predictions about subsequent experience. In adults, altered brain responses to sound enable us to infer the existence and properties of these models. In this study, brain potentials were used to determine whether newborns exhibit context-dependent modulations of a brain response that can be used to infer the existence and properties of internal models. Results are indicative of significant context-dependence in the responsivity to sound in newborns. When common and rare sounds continue in stable probabilities over a very long period, neonates respond to all sounds equivalently (no differentiation). However, when the same common and rare sounds at the same probabilities alternate over time, the neonate responses show clear differentiations. The context-dependence is consistent with the possibility that the neonate brain produces more precise internal models that discriminate between contexts when there is an emergent structure to be discovered but appears to adopt broader models when discrimination delivers little or no additional information about the environment.
Imaging immunity in patients with cancer using positron emission tomography
Authors: Hegi-Johnson Fiona , Rudd Stacey , Hicks Rodney J. , De Ruysscher Dirk , Trapani Joseph A. , John Thomas , Donnelly Paul , Blyth Benjamin , Hanna Gerard , Everitt Sarah , Roselt Peter , MacManus Michael P.
Published: April 2022

Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.
Identification of genetic effects underlying type 2 diabetes in South Asian and European populations
Authors: Loh Marie , Zhang Weihua , Ng Hong Kiat , Schmid Katharina , Lamri Amel , Tong Lin , Ahmad Meraj , Lee Jung-Jin , Ng Maggie C. Y. , Petty Lauren E. , Spracklen Cassandra N. , Takeuchi Fumihiko , Islam Md. Tariqul , Jasmine Farzana , Kasturiratne Anuradhani , Kibriya Muhammad , Mohlke Karen L. , Paré Guillaume , Prasad Gauri , Shahriar Mohammad , Chee Miao Ling , de Silva H. Janaka , Engert James C. , Gerstein Hertzel C. , Mani K. Radha , Sabanayagam Charumathi , Vujkovic Marijana , Wickremasinghe Ananda R. , Wong Tien Yin , Yajnik Chittaranjan S. , Yusuf Salim , Ahsan Habibul , Bharadwaj Dwaipayan , Anand Sonia S. , Below Jennifer E. , Boehnke Michael , Bowden Donald W. , Chandak Giriraj R. , Cheng Ching-Yu , Kato Norihiro , Mahajan Anubha , Sim Xueling , McCarthy Mark I. , Morris Andrew P. , Kooner Jaspal S. , Saleheen Danish , Chambers John C.
Published: April 2022

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10−8 to 5.2 × 10−12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.