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Background: Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood., Methods: To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses., Results: Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor., Conclusions: Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy., (© 2024. The Author(s).)

We investigated which parts of the cerebellum are involved in formulating and articulating sentences using (i) a sentence production task that involved describing simple events in pictures; (ii) an auditory sentence repetition task involving the same sentence articulation but not sentence formulation; and (iii) an auditory sentence-to-picture matching task that involved the same pictorial events and no overt articulation. Activation for each of these tasks was compared to the equivalent word processing tasks: noun production, verb production, auditory noun repetition, and auditory noun-to-picture matching. We associate activation in bilateral cerebellum lobule VIIb with sequencing words into sentences because it increased for sentence production compared to all other conditions and was also activated by word production compared to word matching. We associate a paravermal part of right cerebellar lobule VIIIb with overt motor execution of speech, because activation was higher during (i) production and repetition of sentences compared to the corresponding noun conditions and (ii) noun and verb production compared to all matching tasks, with no activation relative to fixation during any silent (nonspeaking) matching task. We associate activation within right cerebellar Crus II with covert articulatory activity because it activated for (i) all speech production more than matching tasks and (ii) sentences compared to nouns during silent (nonspeaking) matching as well as sentence production and sentence repetition. Our study serendipitously segregated, for the first time, three distinct functional roles for the cerebellum in generic speech production, and it demonstrated how sentence production enhanced the demands on these cerebellar regions., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2024 Massachusetts Institute of Technology.)

Background: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood., Methods: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment., Results: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth., Conclusions: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes., (© 2024. The Author(s).)

Cyclopropane fatty acids (CPFAs) serve as indicators of silage feeding, verifying the authenticity of hay milk where silage feeding is forbidden. In this study, the authenticity of hay milk was determined by detecting CPFAs using proton nuclear magnetic resonance ( 1 H NMR) spectroscopy. 245 milk samples were collected in South Tyrol (Italy), categorized as follows: 98 from grass silage-fed cows, 98 from maize silage-fed cows, and 49 authentic hay milk. The limit of detection of CPFAs was 12 µM, corresponding to 70 mg/kg of freeze-dried milk. The CPFAs were absent in all of the hay milk samples, verifying their authenticity. In contrast, 97 % of maize silage and 77 % of grass silage samples exhibited distinct CPFAs signals. These findings were further corroborated by gas chromatography-mass detector (GC-MS) analysis. The study highlights 1 H NMR as a robust, and rapid technique for hay milk authentication, supporting alpine dairy production and increasing consumer trust in food authenticity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Over the years, NMR spectroscopy has become a powerful analytical tool for the identification and quantification of a variety of natural compounds in a broad range of food matrices. Furthermore, NMR can be useful for characterizing food matrices in terms of quality and authenticity, also allowing for the identification of counterfeits. Although NMR requires minimal sample preparation, this technique suffers from low intrinsic sensitivity relative to complementary techniques; thus, the detection of adulterants or markers for authenticity at low concentrations remains challenging. Here, we present a strategy to overcome this limitation by the introduction of a simple band-selective homonuclear decoupling sequence that consists of double irradiation on 1 H during NMR signal acquisition. The utility of the proposed method is tested on dihydrosterculic acid (DHSA), one of the cyclopropane fatty acids (CPFAs) shown to be a powerful molecular marker for authentication of milk products. A quantitative description of how the proposed NMR scheme allows sensitivity enhancement yet accurate quantification of DHSA is provided., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Nuclear magnetic resonance (NMR) spectroscopy is emerging as a promising technique for the analysis of bovine milk, primarily due to its non-destructive nature, minimal sample preparation requirements, and comprehensive approach to untargeted milk analysis. These inherent strengths of NMR make it a formidable complementary tool to mass spectrometry-based techniques in milk metabolomic studies. This review aims to provide a comprehensive overview of the applications of NMR techniques in the quality assessment and authentication of bovine milk. It will focus on the experimental setup and data processing techniques that contribute to achieving accurate and highly reproducible results. The review will also highlight key studies that have utilized commonly used NMR methodologies in milk analysis, covering a wide range of application fields. These applications include determining milk animal species and feeding regimes, as well as assessing milk nutritional quality and authenticity. By providing an overview of the diverse applications of NMR in milk analysis, this review aims to demonstrate the versatility and significance of NMR spectroscopy as an invaluable tool for milk and dairy metabolomics research and hence, for assessing the quality and authenticity of bovine milk.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa., (© 2023. BioMed Central Ltd., part of Springer Nature.)

During senescence and ripening, higher plants degrade the green pigment chlorophyll to linear tetrapyrrols, referred to as phyllobilins (PBs). This dataset provides chromatograms and mass spectral data of PBs acquired from methanolic extracts of cv. Gala apple peels at five different shelf life (SL) stages. Data were obtained using a (ultra-high) pressure liquid chromatograph (UHPLC) coupled to high resolution quadrupole-time of flight-mass spectrometer (HRMS-Q-TOF). A data-dependent inclusion list (IL) ex professo containing all known masses of PBs was applied to address PBs, and fragmentation patterns were studied to confirm their identity operating a MS 2 method. Mass accuracy was set to 5 ppm for parent ion peaks, this parameter was adopted as inclusion criterium. The detection of PBs' appearance during ripening can be helpful for assessing the quality and maturity of the apples., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

The ascomycete Erysiphe necator is a serious pathogen in viticulture. Despite the fact that some grapevine genotypes exhibit mono-locus or pyramided resistance to this fungus, the lipidomics basis of these genotypes' defense mechanisms remains unknown. Lipid molecules have critical functions in plant defenses, acting as structural barriers in the cell wall that limit pathogen access or as signaling molecules after stress responses that may regulate innate plant immunity. To unravel and better understand their involvement in plant defense, we used a novel approach of ultra-high performance liquid chromatography (UHPLC)-MS/MS to study how E. necator infection changes the lipid profile of genotypes with different sources of resistance, including BC4 ( Run1 ), "Kishmish vatkhana" ( Ren1 ), F26P92 ( Ren3 ; Ren9 ), and "Teroldego" (a susceptible genotype), at 0, 24, and 48 hpi. The lipidome alterations were most visible at 24 hpi for BC4 and F26P92, and at 48 hpi for "Kishmish vatkhana". Among the most abundant lipids in grapevine leaves were the extra-plastidial lipids: glycerophosphocholine (PCs), glycerophosphoethanolamine (PEs) and the signaling lipids: glycerophosphates (Pas) and glycerophosphoinositols (PIs), followed by the plastid lipids: glycerophosphoglycerols (PGs), monogalactosyldiacylglycerols (MGDGs), and digalactosyldiacylglycerols (DGDGs) and, in lower amounts lyso-glycerophosphocholines (LPCs), lyso-glycerophosphoglycerols (LPGs), lyso-glycerophosphoinositols (LPIs), and lyso-glycerophosphoethanolamine (LPEs). Furthermore, the three resistant genotypes had the most prevalent down-accumulated lipid classes, while the susceptible genotype had the most prevalent up-accumulated lipid classes.

Numerous fungicide applications are required to control Erysiphe necator , the causative agent of powdery mildew. This increased demand for cultivars with strong and long-lasting field resistance to diseases and pests. In comparison to the susceptible cultivar 'Teroldego', the current study provides information on some promising disease-resistant varieties (mono-locus) carrying one E. necator- resistant locus: BC4 and 'Kishmish vatkana', as well as resistant genotypes carrying several E. necator resistant loci (pyramided): 'Bianca', F26P92, F13P71, and NY42. A clear picture of the metabolites' alterations in response to the pathogen is shown by profiling the main and secondary metabolism: primary compounds and lipids; volatile organic compounds and phenolic compounds at 0, 12, and 48 hours after pathogen inoculation. We identified several compounds whose metabolic modulation indicated that resistant plants initiate defense upon pathogen inoculation, which, while similar to the susceptible genotype in some cases, did not imply that the plants were not resistant, but rather that their resistance was modulated at different percentages of metabolite accumulation and with different effect sizes. As a result, we discovered ten up-accumulated metabolites that distinguished resistant from susceptible varieties in response to powdery mildew inoculation, three of which have already been proposed as resistance biomarkers due to their role in activating the plant defense response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ciubotaru, Franceschi, Vezzulli, Zulini, Stefanini, Oberhuber, Robatscher, Chitarrini and Vrhovsek.)

Chlorophyll (Chl) degradation is an important process of fruit ripening, mediated by the pheophorbide a oxygenase/phyllobilin (PaO/PB) pathway. Chl is catabolized to linear tetrapyrrolic phyllobilins that resemble the bile pigments. Determining the optimal harvest date is of pivotal importance for the fruit industry. Among the physiological changes at the onset of ripening and during shelf life, the breakdown of Chl appears as a promising indicator for fruit maturity. In addition, PBs are a frequently overlooked component of the human diet with antioxidant and antiproliferative activities. However, their relevance for a healthy diet and their potential as ripening indicator in fruit cannot be evaluated yet, as details on emergence and composition of PBs in fruit are yet elusive. Using apple (Malus × domestica Borkh.) cv. 'Gala' as a model fruit, the Chl content and the emergence and identity of PBs were analyzed during a controlled shelf life period using UV/Vis spectroscopy and ultra-high pressure liquid chromatography coupled to high resolution quadrupole-time of flight-mass spectrometry (UHPLC-Q-TOF-MS). An in-house database with chromatographic and MS data from 51 PBs, revealed ten chlorophyll catabolites, including five NCCs, one YCC, and four DNCCs (including a previously unknown one). PBs were identified with increasing abundance and diversity from the onset of Chl degradation, suggesting a potential role as ripening indicators., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential COVID-19 biomarkers in end-stage kidney disease (CKD G5), we analyzed the plasma metabolites in different COVID-19 stages in patients with or without HD. We recruited 18 and 9 asymptomatic and mild, 11 and 11 moderate, 2 and 13 severely affected, and 10 and 6 uninfected HD and non-HD patients, respectively. Plasma samples were taken at the time of diagnosis and/or upon admission to the hospital and analyzed by targeted metabolomics and cytokine/chemokine profiling. Targeted metabolomics confirmed stage-dependent alterations of the metabolome in non-HD patients with COVID-19, which were less pronounced in HD patients. Elevated kynurenine levels and lipid dysregulation, shown by an increase in circulating free fatty acids and a decrease in lysophospholipids, could distinguish patients with moderate COVID-19 from non-infected individuals in both groups. Kynurenine and lipid alterations were also associated with ICAM-1 and IL-15 levels in HD and non-HD patients. Our findings support the kynurenine pathway and plasma lipids as universal biomarkers of moderate and severe COVID-19 independent of kidney function.

Potatoes ( Solanum tuberosum L.) are one of the most valuable agricultural crops, and the flesh of these tubers provides various classes of healthy compounds important for human nutrition. This work presents the results of a joint analysis of different chemical classes of compounds which provided insights on the metabolic characterization of pigmented and non-pigmented potato varieties collected from Italy. The identification of common or individual metabolic characteristics across the omic datasets (antioxidants, total polyphenolic content, polyphenols, and sugars) is conducted by Joint and Individual Variation Explained (JIVE), a data fusion multivariate approach. The common part of the multivariate model allowed the separation between non-pigmented and pigmented samples. Polyphenolic compounds were mainly responsible for the separation between purple-fleshed and red-skinned potatoes. An additional detailed analysis of the anthocyanin composition, including the acylated anthocyanins, allowed to pinpoint the diversities between the pigmented potato groups. Furthermore, the presence of an appreciable amount of hydroxycinnamic acids and anthocyanins in the purple-fleshed varieties, which are also characterized by a lower content of sugars, is found. Our results provide scientific evidence for the promotion of promising potato cultivars, which are characterized by a remarkable amount of various health benefit compounds.

Using fMRI, we investigated how right temporal lobe gliomas affecting the posterior superior temporal sulcus alter neural processing observed during speech perception and production tasks. Behavioural language testing showed that three pre-operative neurosurgical patients with grade 2, grade 3 or grade 4 tumours had the same pattern of mild language impairment in the domains of object naming and written word comprehension. When matching heard words for semantic relatedness (a speech perception task), these patients showed under-activation in the tumour infiltrated right superior temporal lobe compared to 61 neurotypical participants and 16 patients with tumours that preserved the right postero-superior temporal lobe, with enhanced activation within the (tumour-free) contralateral left superior temporal lobe. In contrast, when correctly naming objects (a speech production task), the patients with right postero-superior temporal lobe tumours showed higher activation than both control groups in the same right postero-superior temporal lobe region that was under-activated during auditory semantic matching. The task dependent pattern of under-activation during the auditory speech task and over-activation during object naming was also observed in eight stroke patients with right hemisphere infarcts that affected the right postero-superior temporal lobe compared to eight stroke patients with right hemisphere infarcts that spared it. These task-specific and site-specific cross-pathology effects highlight the importance of the right temporal lobe for language processing and motivate further study of how right temporal lobe tumours affect language performance and neural reorganisation. These findings may have important implications for surgical management of these patients, as knowledge of the regions showing functional reorganisation may help to avoid their inadvertent damage during neurosurgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yamamoto, Sanjuán, Pope, Parker Jones, Hope, Prejawa, Oberhuber, Mancini, Ekert, Garjardo-Vidal, Creasey, Yousry, Green and Price.)

Background: Frequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated., Methods: To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients., Results: We show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16 INK4A . In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer., Conclusions: We identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis., (© 2022. The Author(s).)

The synthesis of volatile organic compounds (VOCs) in plants is triggered in response to external stimuli, and these compounds can migrate to distal tissues and neighbouring receivers. Although grapevine VOCs responsible for wine aroma and plant-insect communications are well characterized, functional properties of VOCs produced in response to phytopathogens, beneficial microorganisms, resistance inducers, and abiotic factors have been less studied. In this review, we focused on the emission patterns and potential biological functions of VOCs produced by grapevines in response to stimuli. Specific grapevine VOCs are emitted in response to the exogenous stimulus, suggesting their precise involvement in plant defence response. VOCs with inhibitory activities against pathogens and responsible for plant resistance induction are reported, and some of them can also be used as biomarkers of grapevine resistance. Likewise, VOCs produced in response to beneficial microorganisms and environmental factors are possible mediators of grapevine-microbe communications and abiotic stress tolerance. Although further functional studies may improve our knowledge, the existing literature suggests that VOCs have an underestimated potential application as pathogen inhibitors, resistance inducers against biotic or abiotic stresses, signalling molecules, membrane stabilizers, and modulators of reactive oxygen species. VOC patterns could also be used to screen for resistant traits or to monitor the plant physiological status., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Alternaria sp. infections on apple ( Malus × domestica Borkh.) lead to impaired fruit quality and yield losses by leaf blotches and fruit spots, caused by host-specific toxins (HSTs) of the Alternaria apple pathotype like AM-toxins. Fungal isolates were obtained during severe outbreaks on cv. Gala, Golden Delicious, and Cripps Pink (cov) /Rosy Glow (cov) in South Tyrol and other regions in northern Italy. The isolates were tested for pathogenicity using in vitro assays with detached apple leaves. Conidial suspensions of pathogenic isolates were shown to provoke necrotic lesions also in apple seedlings and on fruits. Detached-leaf assay-guided fractionation of the isolates' culture supernatant and a high-resolution liquid chromatography-mass spectrometry (LC-MS) analysis tentatively identified 27 known Alternaria phytotoxins and a new putative toxin, (3ξ,4ξ,5ξ,6ξ,7ξ,11ξ)-3,6-dihydroxy-8-oxo-9-eremophilene-12-oic acid ( 1 ). The constitution and the relative configuration of the ring stereocenters of 1 were elucidated by NMR spectroscopy, revealing unique structural features among Alternaria phytotoxins. Indeed, molecular analysis revealed the lack of the toxin-related genes AMT1 , AMT4 , and AMT14 in all isolates from the region, suggesting that Alternaria apple blotch in the area was associated with another metabolite ( 1) .

Broca's area in the posterior half of the left inferior frontal gyrus has traditionally been considered an important node in the speech production network. Nevertheless, recovery of speech production has been reported, to different degrees, within a few months of damage to Broca's area. Importantly, contemporary evidence suggests that, within Broca's area, its posterior part (i.e. pars opercularis) plays a more prominent role in speech production than its anterior part (i.e. pars triangularis). In this study, we therefore investigated the brain activation patterns that underlie accurate speech production following stroke damage to the opercular part of Broca's area. By combining functional MRI and 13 tasks that place varying demands on speech production, brain activation was compared in (i) seven patients of interest with damage to the opercular part of Broca's area; (ii) 55 neurologically intact controls; and (iii) 28 patient controls with left-hemisphere damage that spared Broca's area. When producing accurate overt speech responses, the patients with damage to the left pars opercularis activated a substantial portion of the normal bilaterally distributed system. Within this system, there was a lesion-site-dependent effect in a specific part of the right cerebellar Crus I where activation was significantly higher in the patients with damage to the left pars opercularis compared to both neurologically intact and patient controls. In addition, activation in the right pars opercularis was significantly higher in the patients with damage to the left pars opercularis relative to neurologically intact controls but not patient controls (after adjusting for differences in lesion size). By further examining how right Crus I and right pars opercularis responded across a range of conditions in the neurologically intact controls, we suggest that these regions play distinct roles in domain-general cognitive control. Finally, we show that enhanced activation in the right pars opercularis cannot be explained by release from an inhibitory relationship with the left pars opercularis (i.e. dis-inhibition) because right pars opercularis activation was positively related to left pars opercularis activation in neurologically intact controls. Our findings motivate and guide future studies to investigate (i) how exactly right Crus I and right pars opercularis support accurate speech production after damage to the opercular part of Broca's area and (ii) whether non-invasive neurostimulation to one or both of these regions boosts speech production recovery after damage to the opercular part of Broca's area., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Lyssaviruses are neurotropic rhabdoviruses thought to be restricted to mammalian hosts, and to originate from bats. The identification of lyssavirus sequences from amphibians and reptiles by metatranscriptomics thus comes as a surprise and challenges the mammalian origin of lyssaviruses. The novel sequences of the proposed American tree frog lyssavirus (ATFLV) and anole lizard lyssavirus (ALLV) reveal substantial phylogenetic distances from each other and from bat lyssaviruses, with ATFLV being the most distant. As virus isolation has not been successful yet, we have here studied the functionality of the authentic ATFLV- and ALLV-encoded glycoproteins in the context of rabies virus pseudotype particles. Cryogenic electron microscopy uncovered the incorporation of the plasmid-encoded G proteins in viral envelopes. Infection experiments revealed the infectivity of ATFLV and ALLV G-coated RABV pp for a broad spectrum of cell lines from humans, bats, and reptiles, demonstrating membrane fusion activities. As presumed, ATFLV and ALLV G RABV pp escaped neutralization by human rabies immune sera. The present findings support the existence of contagious lyssaviruses in poikilothermic animals, and reveal a broad cell tropism in vitro, similar to that of the rabies virus.

One of the most economically important grapevine diseases is Downy mildew (DM) caused by the oomycete Plasmopara viticola . A strategy to reduce the use of fungicides to compensate for the high susceptibility of V. vinifera is the selection of grapevine varieties showing pathogen-specific resistance. We applied a metabolomics approach to evaluate the metabolic modulation in mono-locus resistant genotypes carrying one locus associated with P. viticola resistance ( Rpv ) (BC4- Rpv1 , Bianca- Rpv3-1 , F12P160- Rpv12 , Solaris- Rpv10 ), as well as in pyramided resistant genotypes carrying more than one Rpv (F12P60- Rpv3-1; Rpv12 and F12P127- Rpv3-1, Rpv3-3; Rpv10 ) taking as a reference the susceptible genotype Pinot Noir. In order to understand if different sources of resistance are associated with different degrees of resistance and, implicitly, with different responses to the pathogen, we considered the most important classes of plant metabolite primary compounds, lipids, phenols and volatile organic compounds at 0, 12, 48, and 96 h post-artificial inoculation (hpi). We identified 264 modulated compounds; among these, 22 metabolites were found accumulated in significant quantities in the resistant cultivars compared to Pinot Noir. In mono-locus genotypes, the highest modulation of the metabolites was noticed at 48 and 96 hpi, except for Solaris, that showed a behavior similar to the pyramided genotypes in which the changes started to occur as early as 12 hpi. Bianca, Solaris and F12P60 showed the highest number of interesting compounds accumulated after the artificial infection and with a putative effect against the pathogen. In contrast, Pinot Noir showed a less effective defense response in containing DM growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ciubotaru, Franceschi, Zulini, Stefanini, Škrab, Rossarolla, Robatscher, Oberhuber, Vrhovsek and Chitarrini.)

In this study, a metabolomic investigation was presented to correlate single polyphenolic compounds in apple pulp with quality characteristics such as antioxidant activity and content of phenolic compounds and anthocyanins in apple skin. Since the concentration of these compounds is influenced by environmental factors, the twenty-two apple cultivars originate from the same site. The polyphenolic compounds were analyzed by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS). The antioxidant activity, phenolic content, and anthocyanins were evaluated on the sunny and the shady sides of apple skin by spectrometric assays. In old apple varieties, the measured parameters were higher than in the commercial and red-fleshed varieties. By contrast, the profile of flavan-3-ols and anthocyanins was variable amongst commercial and red-fleshed varieties. The partial least square (PLS) method was applied to investigate the association between the skin proprieties and the metabolic profile of the pulp. The highest coefficients of determination in prediction (Q2) were obtained for compounds quantified in old cultivars. These results provided information to define the old apple varieties as a reliable group based on the pathway of the antioxidant compounds and anthocyanins content. Our results show the possibility to find cultivars with promising health features based on their content of polyphenols suitable for commercialization or breeding.

Vaccines of outstanding efficiency, safety, and public acceptance are needed to halt the current SARS-CoV-2 pandemic. Concerns include potential side effects caused by the antigen itself and safety of viral DNA and RNA delivery vectors. The large SARS-CoV-2 spike (S) protein is the main target of current COVID-19 vaccine candidates but can induce non-neutralizing antibodies, which might cause vaccination-induced complications or enhancement of COVID-19 disease. Besides, encoding of a functional S in replication-competent virus vector vaccines may result in the emergence of viruses with altered or expanded tropism. Here, we have developed a safe single round rhabdovirus replicon vaccine platform for enhanced presentation of the S receptor-binding domain (RBD). Structure-guided design was employed to build a chimeric minispike comprising the globular RBD linked to a transmembrane stem-anchor sequence derived from rabies virus (RABV) glycoprotein (G). Vesicular stomatitis virus (VSV) and RABV replicons encoding the minispike not only allowed expression of the antigen at the cell surface but also incorporation into the envelope of secreted non-infectious particles, thus combining classic vector-driven antigen expression and particulate virus-like particle (VLP) presentation. A single dose of a prototype replicon vaccine complemented with VSV G, VSVΔG-minispike-eGFP (G), stimulated high titers of SARS-CoV-2 neutralizing antibodies in mice, equivalent to those found in COVID-19 patients, and protected transgenic K18-hACE2 mice from COVID-19-like disease. Homologous boost immunization further enhanced virus neutralizing activity. The results demonstrate that non-spreading rhabdovirus RNA replicons expressing minispike proteins represent effective and safe alternatives to vaccination approaches using replication-competent viruses and/or the entire S antigen., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AAH and KKC are listed as inventors on a rhabdovirus minispike patent application.

A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis-known as the Warburg effect-is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1-3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed., Competing Interests: LK is a member of the scientific advisory board of CBmed-Center for Biomarker Research in Medicine GmbH. Author MO was employed by COMET centre (K1) CBmed—Center for Biomarker Research in Medicine GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Atas, Oberhuber and Kenner.)

Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons.