Miracle-dz/UniFAR-FTUs huggingface dataset:
Altered central pain processing in fibromyalgia—A multimodal neuroimaging case-control study using arterial spin labelling

Fibromyalgia is characterized by chronic pain and a striking discrepancy between objective signs of tissue damage and severity of pain. Function and structural alterations in brain areas involved in pain processing may explain this feature. Previous case-control studies in fibromyalgia focused on acute pain processing using experimentally-evoked pain paradigms. Yet, these studies do not allow conclusions about chronic, stimulus-independent pain. Resting-state cerebral blood flow (rsCBF) acquired by arterial spin labelling (ASL) may be a more accurate marker for chronic pain. The objective was to integrate four different functional and structural neuroimaging markers to evaluate the neural correlate of chronic, stimulus-independent pain using a resting-state paradigm. In line with the pathophysiological concept of enhanced central pain processing we hypothesized that rsCBF is increased in fibromyalgia in areas involved in processing of acute pain. We performed an age matched case-control study of 32 female fibromyalgia patients and 32 pain-free controls and calculated group-differences in rsCBF, resting state functional connectivity, grey matter density and cortical thickness using whole-brain and region of interest analyses. We adjusted all analyses for depression and anxiety. As centrally acting drugs are likely to interfere with neuroimaging markers, we performed a subgroup analysis limited to patients not taking such drugs. We found no differences between cases and control in rsCBF of the thalamus, the basal ganglia, the insula, the somatosensory cortex, the prefrontal cortex, the anterior cingulum and supplementary motor area as brain previously identified to be involved in acute processing in fibromyalgia. The results remained robust across all four neuroimaging markers and when limiting the study population to patients not taking centrally acting drugs and matched controls. In conclusion, we found no evidence for functional or structural alterations in brain areas involved in pain processing in fibromyalgia that could reflect neural correlates of chronic stimulus-independent pain.
Subsurface carbon monoxide oxidation capacity revealed through genome-resolved metagenomics of a carboxydotroph

Microbial communities play important roles in the biogeochemical cycling of carbon in the Earth’s deep subsurface. Previously, we demonstrated changes to the microbial community structure of a deep aquifer (1.4 km) receiving 150 tons of injected supercritical CO2 (scCO2) in a geosequestration experiment. The observed changes support a key role in the aquifer microbiome for the thermophilic CO-utilising anaerobe Carboxydocella, which decreased in relative abundance post-scCO2 injection. Here, we present results from more detailed metagenomic profiling of this experiment, with genome resolution of the native carboxydotrophic Carboxydocella. We demonstrate a switch in CO-oxidation potential by Carboxydocella through analysis of its carbon monoxide dehydrogenase (CODH) gene before and after the geosequestration experiment. We discuss the potential impacts of scCO2 on subsurface flow of carbon and electrons from oxidation of the metabolic intermediate carbon monoxide (CO). Originality-Significance Statement The research conducted in this study is associated with one of the world’s largest demonstrations of carbon geosequestration – The Cooperative Research Centre for Greenhouse Gas Technologies Otway Project (Victoria, Australia). Our results expand the ecology of CO-utilising microbes to include the terrestrial deep subsurface through genome-resolved metagenomics of an aquifer-native carboxydotroph.
Adaptation of STARR-seq method to be used with 3rd generation integrase-deficient promoterless lentiviral vectors

Ability to functionally screen gene regulatory sequences, such as promoters and enhancers, in high throughput manner is an important prerequisite for many basic and translational research programs. One of the methods that allow such screening is STARR-seq, or self-transcribing active regulatory region sequencing. It allows to quickly screen millions of candidate sequences in the cell type of interest. However, it does rely on transfection as a delivery method which can be a limiting-step for some hard-to-transfect cells such as senescent cells. Here we show that integration-deficient and integration-competent promoterless lentiviral particles can be used to deliver STARR-seq constructs into cells. These constructs reported CMV enhancer activity both at protein and mRNA level. While further validations are necessary, ability to deliver STARR-seq libraries using lentiviral particles will significantly improve the versatility and usability of such a method.
Histopathological Aspects and Etiology of Pneumonias in Stranded Marine Mammals from Lima, Peru

This study presents the histopathologic features of pneumonia in stranded marine mammals on the coast of Lima, Peru during the period of May 2003 to December 2008. Lung samples of 24 South American sea lions ( Otaria flavescens ), four bottlenose dolphins ( Tursiops truncatus ), one dusky dolphin ( Lagenorhynchus obscurus ), one Burmeisters porpoise ( Phocoena spinipinnis ) and one marine otter ( Lontra felina ) were fixed in 10% formalin and then processed and stained with haematoxylin and eosin, periodic acid-Shiff (PAS) and trichromic of Masson. From the 31 samples collected only 29 were suitable for microscopic evaluation. The results show a rate of 29/29 pneumonias (100%), five of which were associated to parasites (17%), six of bacteria (21%), four of mixed (parasites and bacteria) (14%) and 14 were of nonspecific cause (48%). The present research indicates that those marine mammals from Lima, Peru are exposed to lungworms, flukes and bacteria that alone or mixed may cause pneumonias, which could be contributed or to be the primary cause of the stranding in these animals.
Ganho de peso de novilhas mestiças submetidas ou não à esterilização pela introdução intrauterina de esferas inoxidáveis e ao uso ou não de modificador orgânico

The weight gain in 1/4 Simental and 3/4 Nelore crossbred heifers was evaluated using an experimental method of castration, which consisted of stainless globes intra-uterine introduction. A total of 100 nulliparous heifers, destined to slaughter, aging from 12 to 24-months old and averaging 275kg were used. The animals were randomly distributed in four experimental groups: G1: control; G2: sterilized heifers plus application of organic modifier; G3: sterilized heifers; and G4: non sterilized heifers plus application of organic modifier. It was concluded that G2 showed higher weight gain - 140,50kg and 0,578g/day vs 108,58kg and 0,447g/day (G1), 103,73kg and 0,427g/day (G3), 102,68kg and 0,423g/day (G4). The sterilized heifers plus application of organic modifier is a method of castration recommended to the cattle farmers.
Conservation of the Toxoplasma conoid proteome in Plasmodium reveals a cryptic conoid feature that differentiates between blood- and vector-stage zoites

The apical complex is the instrument of invasion used by apicomplexan parasites, and the conoid is a conspicuous feature of this apparatus found throughout this phylum. The conoid, however, is believed to be heavily reduced or missing from Plasmodium species and other members of the Class Aconoidasida. Relatively few conoid proteins have previously been identified, making it difficult to address how conserved this feature is throughout the phylum, and whether it is genuinely missing from some major groups. Moreover, parasites such as Plasmodium species cycle through multiple invasive forms and there is the possibility of differential presence of the conoid between these stages. We have applied spatial proteomics and high-resolution microscopy to develop a more complete molecular inventory and understanding of the organisation of conoid-associated proteins in the model apicomplexan Toxoplasma gondii. These data revealed molecular conservation of all conoid substructures throughout Apicomplexa, including Plasmodium and even in allied Myzozoa, such as Chromera. We reporter-tagged and observed the expression and location of several conoid proteins in the malaria model P. berghei and revealed equivalent structures in all zoite forms, as well as evidence of molecular differentiation between blood-stage merozoites and the ookinetes and sporozoites of the mosquito vector. Collectively we show that the conoid is a conserved apicomplexan element at the heart of the invasion mechanisms of these highly successful and often devastating parasites.
Causes and effects of fitness landscapes in unit test generation

Search-based unit test generation applies evolutionary search to maximize code coverage. Although the performance of this approach is often good, sometimes it is not, and how the fitness landscape affects this performance is poorly understood. This paper presents a thorough analysis of 331 Java classes by (i) characterizing their fitness landscape using six established fitness landscape measures, (ii) analyzing the impact of these fitness landscape measures on the search, and (iii) investigating the underlying properties of the source code influencing these measures. Our results reveal that classical indicators for rugged fitness landscapes suggest well searchable problems in the case of unit test generation, but the fitness landscape for most problem instances is dominated by detrimental plateaus. A closer look at the underlying source code suggests that these plateaus are frequently caused by code in private methods, methods throwing exceptions, and boolean flags. This suggests that inter-procedural distance metrics and testability transformations could improve search-based test generation.
Nucleosome composition regulates the histone H3 tail conformational ensemble and accessibility

Sub-nucleosomal complexes including hexasomes and tetrasomes have been identified as intermediates in nucleosome assembly and disassembly. Their formation is promoted by certain histone chaperones and ATP-dependent remodelers, as well as through transcription by RNA polymerase II. In addition, hexasomes appear to be maintained in transcribed genes and could be an important regulatory factor. While nucleosome composition affects the structure and accessibility of the nucleosomal DNA, its influence on the histone tails is largely unknown. Previously, we found that the H3 tail accessibly is occluded in the context of the nucleosome due to interactions with DNA (Morrison et al, 2018). Here, we investigate the conformational dynamics of the H3 tail in the hexasome and tetrasome. Using a combination of NMR spectroscopy, MD simulations, and trypsin proteolysis, we find that the conformational ensemble of the H3 tail is regulated by nucleosome composition. Similar to what we previously found for the nucleosome, the H3 tails bind robustly to DNA within the hexasome and tetrasome, but upon loss of the H2A/H2B dimer, we determined that the adjacent H3 tail has an altered conformational ensemble, increase in dynamics, and increase in accessibility. Similar to observations of DNA dynamics, this is seen to be asymmetric in the hexasome. Our results indicate that nucleosome composition has the potential to regulate chromatin signaling at the histone tails and ultimately help shape the chromatin landscape.
Development of a coronavirus disease 2019 nonhuman primate model using airborne exposure

Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comprehensive and comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to define parameters critical to disease progression and the extent to which they correlate with human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation. One Sentence Summary Nonhuman primates develop COVID-19 following airborne virus exposure.
Capsaicin inhibits arginine kinase and exerts anti-Trypanosoma cruzi activity

Trypanosoma cruzi is the causative agent of Chagas disease, considered within the list of twenty neglected diseases according to the World Health Organization. There are only two therapeutic drugs for Chagas disease, both of them unsuitable for the chronic phase, therefore the development of new drugs is a priority. T. cruzi arginine kinase (TcAK) is a promising drug target since it is absent in humans and it is involved in cellular stress responses. In a previous study from our laboratory, possible TcAK inhibitors were identified through computer simulations, resulting in the best-scoring compounds cyanidin derivatives and capsaicin. Considering these results, in this work we evaluate the effect of capsaicin on TcAK activity and its trypanocidal effect. Although capsaicin produced a weak inhibition on the recombinant TcAK activity (IC50 ≈ 800 µM), it had a strong trypanocidal effect on epimastigotes and trypomastigotes (IC50 = 6.26 µM and 0.26 µM, respectively) being 20-fold more active on trypomastigotes than mammalian cells. Epimastigotes that overexpress TcAK were 37% more resistant to capsaicin than wild type parasites, suggesting that trypanocidal activity could be due, in part, to the enzyme inhibition. However, the difference between the concentrations at which the enzyme is inhibited and the parasite death is caused implies the presence of other targets. In this sense, the prohibitin-2 and calmodulin were identified as other possible capsaicin targets. Capsaicin is a strong and selective trypanocidal agent active in nanomolar concentrations, with an IC50 57-fold lower than benznidazole, the drug currently used for treating Chagas disease.
Design and Implementation of Scalable Massive-MIMO Networks

Massive-MIMO technology promises many-fold improvement in the capacity of wireless mobile networks by scaling up the number of base station antennas. Hence, it has become a key technology for upcoming fifth generation (5G) mobile networks. Previous work has mainly focused on building proof-of-concept systems to show the feasibility of massive-MIMO and its benefits. However, much work remains to demonstrate the performance of massive-MIMO in at-scale dense deployments. In this paper, we present our experience in building ArgosNet, a scalable multi-cell campus-wide massive-MIMO testbed. The goal of ArgosNet is to provide scalability, programmability, and ease of deployment for this technology in realistic large-scale environments. We present the design choices we made in architecting ArgosNet and provide details in how they helped us achieve these goals. By characterizing the performance of major components, we discuss how ArgosNet unlocks our ability to do research that is not possible with existing systems.
Recruitment of MRE-11 to complex DNA damage is modulated by meiosis-specific chromosome organization

DNA double-strand breaks (DSBs) are one of the most dangerous assaults on the genome, and yet their natural and programmed production are inherent to life. When DSBs arise close together (clustered) they are particularly deleterious, and their repair may require an altered form of the DNA damage response. Our understanding of how clustered DSBs are repaired in the germline is unknown. Using UV laser microirradiation, we examine early events in the repair of clustered DSBs in germ cells within whole, live, Caenorhabditis elegans. We use precise temporal resolution to show how the recruitment of MRE-11 to complex damage is regulated, and that clustered DNA damage can recruit proteins from various repair pathways. Abrogation of non-homologous end joining or COM-1 attenuates the recruitment of MRE-11 through distinct mechanisms. The synaptonemal complex plays both positive and negative regulatory roles in these mutant contexts. These findings together indicate that MRE-11 is regulated by modifying its accessibility to chromosomes.
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.
High Fat Content in Diets and Oxidative Stress in Livers of Non-Diabetic and Diabetic Rats

Environmental factors such as high fat content in a diet affect pro- and antioxidative balances in tissues. Our study was designed to determine whether a four-week diet enriched to a total of 15% fat content with either a polyunsaturated (linoleic) or saturated (palmitic) fatty acid predisposes or protects the liver tissue against oxidative stress in both non-diabetic and diabetic rats. In the rat liver the activity of catalase, superoxide dismutase, glutathione peroxidase, and the level of thiobarbituric acid reactive substances were determined. Our study suggests that both diets induce oxidative stress in livers of non-diabetic rats. However, in diabetic rats a diet enriched in linoleic acid appears to attenuate oxidative stress.
In vitro fungicidal activity of humic acid fraction from oil palm compost

Fungicidal activity of humic acids isolated from empty fruit bunch of oil palm compost EFB-HA and commercial grade humic acid Co-HA were evaluated on the conidial germination and mycelial growth of Choanephora cucurbitarum. EFB-HA and Co-HA significantly (P ≤ 0.05) inhibited the mycelial growth and conidial germination of C. cucurbitarum in vitro compared to control. The inhibition in mycelial growth increased with increase in humic acid concentrations tested, suggesting the presence of fungicidal activity. The maximum inhibition of conidial germination (71.96% after 24 h) was exerted by EFB-HA at the highest concentration (1000 mg L -1 ). It was concluded that the efficiency of HA studied in controlling fungal growth was apparently related not only to their concentration and the pathogen examined, but also to HA origin and nature and in particular, HA structural and functional properties, especially COOH group content.
Expression of HPV oncogenes from a single integration site in cervical cancer cell lines

Integration of a virus genome into human chromosomal DNA is critical in viral carcinogenesis. In this report, we discovered that virus-host fusion transcripts are characteristically originated mainly from a single integration site in three cervical cancer cell lines, CaSki and SiHa cells with multiple HPV16 DNA integration sites and HeLa cells with multiple HPV18 DNA integration sites. The host genomic elements surrounding the integrated HPV genome are critical for efficient expression of the viral oncogenes. We found that HPV E6 and E7 are expressed by hijacking a host 3’ splice site and/or RNA polyadenylation signal for their production. The viral-host fusion transcripts may encode a chimeric viral-host fusion protein through alternative RNA splicing. One such E6* protein in SiHa cells was found to antagonize E6 function and knockdown of its expression further decreased p53 protein level and increased cell growth by promoting S phase entry. Together, our findings of the integrated virus genome expression only from a given integrated host genomic site will shed new light on possible application of precision medicine and the understanding of HPV carcinogenesis.
Spinal Column Architecture of the Flexible SPP1 Bacteriophage Tail Tube

Phage therapy has recently regained attention at combating multidrug-resistant bacteria. In 2019, tailed bacteriophages of the Siphoviridae family were engineered to successfully treat a disseminated bacterial infection after all other drugs had failed. (1) This family of phages features a long, flexible, non-contractile tail that has been difficult to characterize structurally. Here, we present the atomic structure of the tail-tube of the bacteriophage SPP1 – a member of this family. Our hybrid structure is based on the integration of structural restraints from solid-state NMR and a density map from cryo-EM. We show that the tail tube protein (TTP) gp17.1 organizes into hexameric rings that are stacked by flexible linker domains and, thus, form a hollow flexible tube with a negatively charged lumen suitable for the transport of DNA. One sentence summary Integrative structural biology by solid-state NMR and cryo-EM enables structure determination of the flexible tail of the bacteriophage SPP1.
Pharmacological Properties and Identification of Cardiotonic Principles from the Indian Snuff, Maquira sclerophylla, Ducke

The powdered bark obtained from Maquira sclerophylla Ducke is a snuff used by Amazonian natives. Pharmacological studies on rodents, guinea‐pigs, rabbits and dogs revealed cardiovascular changes as the major effects produced by the polar phase of the bark ethanol extract. Oriented by this pharmacological activity a cardenolide fraction was chemically purified from the crude extract. Both crude extract and the purified fraction produced a positive inotropic effect in isolated heart preparations from guinea‐pigs and rabbits, and inhibited the Na+, K+‐ATPase activity of the enzyme isolated from bovine ventricles. The fraction yielded two major purified cardenolides identified as Maquiroside A (C30H46O8) and Cymarin (C30H44O9). Simultaneous intracellular recordings of the resting membrane potential (RMP) and miniature endplate potentials in rat diaphragm muscle fibres showed that the effect of the purified fraction predominated on the motor nerve terminals enhancing the spontaneous transmitter release, without major changes of RMP values. Comparatively, the effect of ouabain prevailed on the muscle fibre membrane. Considering that both effects depend on the Na+, K+‐ATPase activity, the results indicated that the compounds derived from Maquira exert differential actions on this enzyme in the nerve and muscle membrane. These observations may explain the use of this toxic snuff in native festivities. © 1997 by John Wiley & Sons, Ltd.