DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

Nucleus accumbens neurons dynamically respond to appetitive and aversive associative learning.

To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined. Here, we investigated the relevance of D1- and D2-neurons in associative learning, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks in mice. Sucrose was used as a positive valence unconditioned stimulus (US) and foot shock was used as a negative valence US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general increase in activity in response to the conditioned stimuli (CS). Interestingly, D1- and D2-neurons present distinct changes in activity after sucrose consumption that dynamically evolve throughout learning. During the aversive Pavlovian conditioning, D1- and D2-neurons present an increase in the activity in response to the CS and to the US (shock). Our data support a model in which D1- and D2-neurons are concurrently activated during appetitive and aversive conditioning.

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice.

[Figure: see text].

Involvement of nucleus accumbens D2-medium spiny neurons projecting to the ventral pallidum in anxiety-like behaviour.

BACKGROUND: The nucleus accumbens (NAcc) is a crucial brain region for emotionally relevant behaviours. The NAcc is mainly composed of medium spiny neurons (MSNs) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). The D1-MSNs project to the ventral tegmental area (VTA) and the ventral pallidum (VP), whereas the D2-MSNs project only to the VP. The D1- and D2-MSNs have been associated with depression-like behaviours, but their contribution to anxiety remains to be determined. METHODS: We used optogenetic tools to selectively manipulate D1-MSN projections from the NAcc core to the VP or VTA and D2-MSN projections to the VP during validated anxiety-producing behavioural procedures in naive mice. In addition, we assessed the effects of optical stimulation on neuronal activity using in vivo electrophysiologic recordings in anesthetized animals. RESULTS: Optogenetic activation of D1-MSN projections to the VTA or VP did not trigger anxiety-like behaviour. However, optical activation of D2-MSN projections to the VP significantly increased anxiety-like behaviour. This phenotype was associated with a decrease in the neuronal activity of putative GABAergic neurons in the VP. Importantly, pretreating D2-MSN-VP animals with the γ-aminobutyric acid modulator diazepam prevented the optically triggered anxiety-like behaviour. LIMITATIONS: The exclusive use of males in the behavioural tests limits broader interpretation of the findings. Although we used optogenetic conditions that trigger quasi-physiologic changes, there are caveats associated with the artificial manipulation of neuronal activity. CONCLUSION: The D2-MSN-VP projections contributed to the development of anxiety-like behaviour, through modulation of GABAergic activity in the VP.

Environmental performance measurement in arts and cultural organisations: Exploring factors influencing organisational changes.

Arts and Cultural Organisations (ACOs) have received significant attention over the last few years regarding their environmental performance. ACOs are often non-profit organisations, relying on government funding to implement various programmes to support societal development. Funding dependence can shift ACOs' focus from creating socio-cultural value to being more commercially driven. This paper explores factors influencing organisational changes in ACOs related to environmental performance measurement. Stakeholders in ACOs based in Nottingham, England, were interviewed and participated in a workshop to validate and collect additional data. Our research uncovered five interrelated factors that influence organisational change: the role of funding bodies; local policies and networks; organisational culture and leadership; lack of resources; and building proprietary-tenant relationships. This paper contributes to understanding ACOs responses to measuring environmental performance and the challenges they face as they move from measuring to implementation. Implications are explored for how funding is allocated and understood in terms of moving beyond merely measuring the carbon footprint of activities. ACOs' funding dependence indicates a focus on carbon measurement, omitting a more holistic approach towards the environment and sustainability.

Laterodorsal tegmentum-ventral tegmental area projections encode positive reinforcement signals.

The laterodorsal tegmentum (LDT) is a brainstem nucleus classically involved in REM sleep and attention, and that has recently been associated with reward-related behaviors, as it controls the activity of ventral tegmental area (VTA) dopaminergic neurons, modulating dopamine release in the nucleus accumbens. To further understand the role of LDT-VTA inputs in reinforcement, we optogenetically manipulated these inputs during different behavioral paradigms in male rats. We found that in a two-choice instrumental task, optical activation of LDT-VTA projections shifts and amplifies preference to the laser-paired reward in comparison to an otherwise equal reward; the opposite was observed with inhibition experiments. In a progressive ratio task, LDT-VTA activation boosts motivation, that is, enhances the willingness to work to get the reward associated with LDT-VTA stimulation; and the reverse occurs when inhibiting these inputs. Animals abolished preference if the reward was omitted, suggesting that LDT-VTA stimulation adds/decreases value to the stimulation-paired reward. In addition, we show that LDT-VTA optical activation induces robust preference in the conditioned and real-time place preference tests, while optical inhibition induces aversion. The behavioral findings are supported by electrophysiological recordings and c-fos immunofluorescence correlates in downstream target regions. In LDT-VTA ChR2 animals, we observed an increase in the recruitment of lateral VTA dopamine neurons and D1 neurons from nucleus accumbens core and shell; whereas in LDT-VTA NpHR animals, D2 neurons appear to be preferentially recruited. Collectively, these data show that the LDT-VTA inputs encode positive reinforcement signals and are important for different dimensions of reward-related behaviors.

Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.

Deficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1-expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2-MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions. We further show that blocking κ-opioid receptors in the VTA (but not in VP) abolishes the behavioral effects induced by D1-MSN prolonged stimulation. In turn, blocking δ-opioid receptors in the VP (but not in VTA) blocks the behavioral effects elicited by D2-MSN prolonged stimulation. Our findings demonstrate that D1- and D2-MSNs can bidirectionally control reward and aversion, explaining the existence of controversial studies in the field, and highlights that the proposed striatal functional opposition needs to be reconsidered.

Correction: Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Glial cells in Parkinson´s disease: protective or deleterious?

Glial cells have been identified more than 100 years ago, and are known to play a key role in the central nervous system (CNS) function. A recent piece of evidence is emerging showing that in addition to the capacity of CNS modulation and homeostasis, glial cells are also being looked like as a promising cell source not only to study CNS pathologies initiation and progression but also to the establishment and development of new therapeutic strategies. Thus, in the present review, we will discuss the current evidence regarding glial cells' contribution to neurodegenerative diseases as Parkinson's disease, providing cellular, molecular, functional, and behavioral data supporting its active role in disease initiation, progression, and treatment. As so, considering their functional relevance, glial cells may be important to the understanding of the underlying mechanisms regarding neuronal-glial networks in neurodegeneration/regeneration processes, which may open new research opportunities for their future use as a target or treatment in human clinical trials.

Spinal neuroschistosomiasis caused by Schistoma mansoni: cases reported in two brothers.

BACKGROUND: Spinal neuroschistosomiasis (SN) is one of the most severe clinical presentations of schistosomiasis infection and an ectopic form of the disease caused by any species of Schistosoma. In Brazil, all cases of this clinical manifestation are related to Schistosoma mansoni, the only species present in the country. Although many cases have been reported in various endemic areas in Brazil, this is the first time in the literature that SN is described in two brothers. CASE PRESENTATION: Two cases of SN were accidentally diagnosed during an epidemiological survey in an urban area endemic for schistosomiasis transmission. Both patients complained of low back pain and muscle weakness in the lower limbs. Sphincter dysfunction and various degrees of paresthesia were also reported. The patients' disease was classified as hepato-intestinal stage schistosomiasis mansoni at the onset of the chronic form. A positive parasitological stool test for S. mansoni, clinical evidence of myeloradicular damage and exclusion of other causes of damage were the basic criteria for diagnosis. After treatment with praziquantel and corticosteroid, the patients presented an improvement in symptoms, although some complaints persisted. CONCLUSIONS: It is important to consider SN when patients come from areas endemic for transmission of schistosomiasis mansoni. Clinical physicians and neurologists should consider this diagnostic hypothesis, because recovery from neurological injuries is directly related to early treatment. As, described here in two brothers, a genetic predisposition may be related to neurological involvement. Primary care physicians should thus try to evaluate family members and close relatives in order to arrive at prompt schistosomiasis diagnosis in asymptomatic individuals and propose treatment in an attempt to avoid progression to SN.

Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been developed not only to better understand the mechanisms underlying neurodegeneration but also to test the potential of emerging disease-modifying therapies. However, despite aging being the main risk factor for developing idiopathic PD, most of the studies do not use aged animals. Therefore, this study aimed at assessing the effect of aging in the unilateral 6-hydroxydopamine (6-OHDA)-induced animal model of PD. For this, female young adult and aged rats received a unilateral injection of 6-OHDA into the medial forebrain bundle. Subsequently, the impact of aging on 6-OHDA-induced effects on animal welfare, motor performance, and nigrostriatal integrity were assessed. The results showed that aging had a negative impact on animal welfare after surgery. Furthermore, 6-OHDA-induced impairments on skilled motor function were significantly higher in aged rats when compared with their younger counterparts. Nigrostriatal histological analysis further revealed an increased 6-OHDA-induced dopaminergic cell loss in the SNpc of aged animals when compared to young animals. Overall, our results demonstrate a higher susceptibility of aged animals to 6-OHDA toxic insult.

Histone Acetyltransferase KAT2A Stabilizes Pluripotency with Control of Transcriptional Heterogeneity.

Cell fate transitions in mammalian stem cell systems have often been associated with transcriptional heterogeneity; however, existing data have failed to establish a functional or mechanistic link between the two phenomena. Experiments in unicellular organisms support the notion that transcriptional heterogeneity can be used to facilitate adaptability to environmental changes and have identified conserved chromatin-associated factors that modulate levels of transcriptional noise. Herein, we show destabilization of pluripotency-associated gene regulatory networks through increased transcriptional heterogeneity of mouse embryonic stem cells in which paradigmatic histone acetyl-transferase, and candidate noise modulator, Kat2a (yeast orthologue Gcn5), have been inhibited. Functionally, network destabilization associates with reduced pluripotency and accelerated mesendodermal differentiation, with increased probability of transitions into lineage commitment. Thus, we show evidence of a relationship between transcriptional heterogeneity and cell fate transitions through manipulation of the histone acetylation landscape of mouse embryonic stem cells, suggesting a general principle that could be exploited in other normal and malignant stem cell fate transitions. Stem Cells 2018;36:1828-11.

The cost of a disease targeted for elimination in Brazil: the case of schistosomiasis mansoni.

BACKGROUND: Schistosomiasis mansoni is a poverty-related parasitic infection that has a variety of clinical manifestations. We consider the disability and deaths caused by schistosomiasis unacceptable for a tool-ready disease. Its condition in Brazil warrants an analysis that will enable better understanding of the local health losses and contribute to the complex decision-making process. OBJECTIVE: This study estimates the cost of schistosomiasis in Brazil in 2015. METHODS: We conducted a cost of illness study of schistosomiasis mansoni in Brazil in 2015 based on a prevalence approach and from a societal perspective. The study included 26,499 schistosomiasis carriers, 397 hepatosplenic cases, 48 cases with the neurological form, 284 hospitalisations, and 11,368.26 years of life lost (YLL) of which 5,187 years are attributable to economically active age groups. RESULTS: The total cost of schistosomiasis mansoni in Brazil was estimated to be US$ 41,7million in 2015 with 94.61% of this being indirect costs. CONCLUSIONS: The economic burden of schistosomiasis mansoni in Brazil is high and results in the loss of productivity. Its persistence in Brazil is a challenge to public health and requires inter-sectorial interventions in areas such as indoor water supply, basic sanitation, and education.

Ultrasonic Power and Data Transfer through Multiple Curved Layers Applied to Pipe Instrumentation.

Ultrasonic power and data transfer through multilayered curved walls was investigated using numerical and experimental analysis. The acoustic channel used in this paper was formed by two concentric pipes filled with water, aiming for applications that involve powering and monitoring sensors installed behind the pipe walls. The analysis was carried out in the frequency and time domains using numerical and experimental models. Power and data were effectively simultaneously transferred through the channel. A remote temperature and pressure sensor was powered and interrogated throughout all the layers, and the power insertion loss was 10.72 dB with a data transmission rate of 1200 bps using an amplitude modulated scheme with Manchester coding. The efficiency of the channel was evaluated through an experimental analysis of the bit error rate (BER) with different values of signal-to-noise ratio (SNR), showing a decrease in the number of errors compared with detection without Manchester coding.

Signature of Aberrantly Expressed microRNAs in the Striatum of Rotenone-Induced Parkinsonian Rats.

Parkinson's disease (PD) is a highly complex brain disorder regarding clinical presentation, pathogenesis, and therapeutics. The cardinal motor signs, i.e., rigidity, bradykinesia, and unilateral tremors, arise in consequence of a progressive neuron death during the prodromal phase. Although multiple transmission systems are involved in disease neurobiology, patients will cross the line between the prodromal and early stage of diagnosed PD when they had lost half of the dopaminergic nigrostriatal cells. As the neurons continue to die ascending the neuroaxis, patients will face a more disabling disease with motor and nonmotor signs. Shedding light on molecular mechanisms of neuron death is an urgent need for understanding PD pathogenesis and projecting therapeutics. This work examined the expression of microRNAs in the striatum of parkinsonian rats chronically exposed to rotenone (2.5 mg/Kg, i.p., daily for 10 days). Rotenone caused motor deficits, the loss of TH(+) cells in the nigrostriatal pathway, and a marked microgliosis. This parkinsonian rat striatum was examined at 26 days after the last rotenone injection, for quantification of microRNAs, miR-7, miR-34a, miR-26a, miR-132, miR-382, and Let7a, by qPCR. Parkinsonian rats presented a significant increase in miR-26a and miR-34a (1.5 and 2.2 fold, respectively, P < 0.05), while miR-7 (0.5 fold, P < 0.05) and Let7a were downregulated. This work reports for first time microRNAs aberrantly expressed in the striatum of rotenone-induced parkinsonian rats, suggesting that this dysregulation may contribute to PD pathogenesis. Beyond revealing new clues of neurodegeneration, our findings might prime further studies targeting miRNAs for neuroprotection or even for diagnosis proposal.

Schistosomiasis and hepatopulmonary syndrome: the role of concomitant liver cirrhosis.

BACKGROUND: Hepatopulmonary syndrome (HPS) is defined as an oxygenation defect induced by intrapulmonary vasodilation in patients with liver disease or portal hypertension. It is investigated in patients with liver cirrhosis and less frequently in those with portal hypertension without liver cirrhosis, as may occur in hepatosplenic schistosomiasis (HSS). OBJECTIVES: To investigate the prevalence of HPS in patients with HSS, and to determine whether the occurrence of HPS is influenced by concomitant cirrhosis. METHODS: We evaluated patients with HSS with or without concomitant liver cirrhosis. All patients underwent laboratory testing, ultrasound, endoscopy, contrast echocardiography, and arterial blood gas analysis. FINDINGS: Of the 121 patients with HSS, 64 were also diagnosed with liver cirrhosis. HPS was diagnosed in 42 patients (35%) and was more frequent among patients with concomitant liver cirrhosis than in those without cirrhosis (42% vs. 26%), but the difference was not significant (p = 0.069). HPS was more common in those with spider naevi, Child-Pugh classes B or C and high model for end stage liver disease (MELD) scores (p < 0.05 each). MAIN CONCLUSIONS: The prevalence of HPS was 35% in this study. The occurrence of liver cirrhosis concomitantly with HSS may have influenced the frequency of patients presenting with HPS.

Sustainability reporting in public sector organisations: Exploring the relation between the reporting process and organisational change management for sustainability.

Sustainability Reporting has become a key element in different organisations. Although there have been a number of academic publications discussing the adoption of sustainability reports in the public sector, their numbers have been quite low when compared to those focussing on corporate reports. Additionally, there has been little research on the link between sustainability reporting in Public Sector Organisations (PSOs) and Organisational Change Management for Sustainability (OCMS). This paper focuses on the contribution of sustainability reporting to OCMS. A survey was sent to all PSOs that have published at least one sustainability report based on the GRI guidelines. The study provides a critical analysis of the relation between sustainability reporting and OCMS in PSOs, including the drivers for reporting, the impacts on organisation change management, and the role of stakeholders in the process. Despite still lagging in sustainability reporting journey, PSOs are starting to use sustainability reporting as a communication tool, and this could drive organisational changes for sustainability.

Induction of labour vs. spontaneous vaginal delivery in twin pregnancy after 36 weeks of gestation.

Time for delivery and delivery pathway in twin pregnancies are still in great debate. Our study goal was to compare the characteristics of delivery and maternal-foetal outcome in uncomplicated near-term twin pregnancies undergoing labour induction and those with spontaneous labour. We found no statistical differences in patients with twin pregnancies who underwent labour induction and those with spontaneous labour regarding the history of previous caesarean delivery, parity, pregnancy achieved by assisted reproductive techniques (ART), chorionicity and cervical dilation at the admission as well as maternal and neonatal morbidity, and admission to the neonatal intensive care unit. There were significant differences in the caesarean section rate (60.6 vs. 33.3%, p < .05) and the time interval between delivery of the first and second foetus (9.8 vs. 11.7 min, p = .024). There was an increased incidence of caesarean section after the induction of labour. However, it appears to be a safe option.

Studies of selective adsorption, desorption and reuse of chemically altered biomass produced from aquatic macrophytes for treatment of metal-containing wastewater.

The aquatic macrophytes Salvinia sp. and Pistia stratiotes have a natural capacity to adsorb various elements, including heavy metals. This capacity was enhanced with a chemical treatment using NaOH alkaline solution for Salvinia sp. and a mixture of both Salvinia sp. and Pistia stratiotes at a proportion of 1:1, whose respective biosorbents were called SSOH and MBOH. Adsorption tests were done in a ternary system containing the metals copper, lead and manganese; the parameters considered were: starting concentration, kinetics, pH and temperature. The adsorption isotherms for SSOH had a maximum adsorptive capacity of 50.20, 53.85 and 14.68 mg g-1 for Cu, Pb and Mn, respectively; for MBOH, maximum values were 44.62, 35.17 and 15.74 mg g-1 for Cu, Pb and Mn, respectively. The metals displayed different behaviors with pH variation. The results also showed an adsorption preference of Cu > Pb > Mn for SSOH. Desorption and readsorption studies were also carried out, showing 100% desorption and increased adsorption capacity in readsorption tests. Surface area and porosity analysis with the Brunauer-Emmett-Teller (BET) method indicate that after chemical modification, MBOH and SSOH biomasses had their surface increased in comparison to SS, with values of 165.5657 (MBOH), 157.4392 (SSOH) and 78.9432 m2 g-1 (SS).

Increased Hepatic Arterial Blood Flow Measured by Hepatic Perfusion Index in Hepatosplenic Schistosomiasis: New Concepts for an Old Disease.

BACKGROUND: Portal vein obstructive lesions associated with hypertrophy of the hepatic artery territory are observed in Schistosoma mansoni schistosomiasis. Liver perfusion scintigraphy is a method used for evaluation of hepatic perfusion changes in liver diseases. It has been suggested that, like in cirrhosis, where compensatory increase in perfusion through the hepatic artery is documented, perfusion changes occur in hepatosplenic schistosomiasis (HSS). AIMS: This study aims to determine changes in liver hemodynamics using hepatic perfusion scintigraphy and correlate them with clinical and laboratory variables and ultrasound findings in HSS. METHODS: Nineteen patients with schistosomiasis underwent ultrasound evaluation of degree of liver fibrosis, splenic length, and splenic and portal vein diameter, digestive endoscopy, and quantification of platelets. Subsequently, perfusion scintigraphy with measurement of hepatic perfusion index (HPI) was performed. RESULTS: It was observed that patients with hepatosplenic schistosomiasis had significantly higher HPI compared with normal individuals (p = 0.0029) and that this increase correlated with splenic length (p = 0.038) and diameter of esophageal varices (p = 0.0060). Angioscintigraphy showed high accuracy for predicting presence of large esophageal varices. CONCLUSIONS: Angioscintigraphy could show that patients with HSS had increased HPI, featuring greater liver "arterialization," as previously described for cirrhotic patients. Correlations were also observed between HPI and longitudinal splenic length, caliber of esophageal varices, caliber of portal vein, and blood platelet count. Angioscintigraphy is a promising technique for evaluation of hepatosplenic schistosomiasis.