Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation.

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

Sulfonamide Porphyrins as Potent Photosensitizers against Multidrug-Resistant Staphylococcus aureus (MRSA): The Role of Co-Adjuvants.

Sulfonamides are a conventional class of antibiotics that are well-suited to combat infections. However, their overuse leads to antimicrobial resistance. Porphyrins and analogs have demonstrated excellent photosensitizing properties and have been used as antimicrobial agents to photoinactivate microorganisms, including multiresistant Staphylococcus aureus (MRSA) strains. It is well recognized that the combination of different therapeutic agents might improve the biological outcome. In this present work, a novel meso-arylporphyrin and its Zn(II) complex functionalized with sulfonamide groups were synthesized and characterized and the antibacterial activity towards MRSA with and without the presence of the adjuvant KI was evaluated. For comparison, the studies were also extended to the corresponding sulfonated porphyrin TPP(SO3H)4. Photodynamic studies revealed that all porphyrin derivatives were effective in photoinactivating MRSA (>99.9% of reduction) at a concentration of 5.0 µM upon white light radiation with an irradiance of 25 mW cm-2 and a total light dose of 15 J cm-2. The combination of the porphyrin photosensitizers with the co-adjuvant KI during the photodynamic treatment proved to be very promising allowing a significant reduction in the treatment time and photosensitizer concentration by six times and at least five times, respectively. The combined effect observed for TPP(SO2NHEt)4 and ZnTPP(SO2NHEt)4 with KI seems to be due to the formation of reactive iodine radicals. In the photodynamic studies with TPP(SO3H)4 plus KI, the cooperative action was mainly due to the formation of free iodine (I2).

Understanding the chemical and mineralogical composition of commercial henna and jagua tattoos and dyes-a multi-analytical approach.

Temporary tattoos and dyes constitute a great analytical challenge in relation to the regulatory control of their ingredients. Most of these commercial products are not labeled according to their content and their chemical nature is highly diverse. Therefore, it is necessary to analyze these complex samples to evaluate the potential presence of metallic impurities, to ensure the safety of cosmetic products contributing to health protection. This study proposes a multi-analytical methodology, which includes handheld X-ray fluorescence (h-XRF) and X-ray diffraction (XRD), complemented by variable pressure scanning electron microscopy coupled with energy-dispersive X-ray spectrometry (VP-SEM-EDS) to fully characterize 34 commercial samples of jagua and henna tattoos and dyes. The approach allowed the identification of the main constituents providing complementary compositional data and differences between sample types were established. In addition, information on the degree of natural pigments homogeneity was also obtained. The results' discussion considering the current European cosmetics regulation may be useful to support the drafting of safety requirements and specific regulation.

Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer.

Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15-20% of BC and is extremely aggressive resulting in reduced survival rate, which is mainly due to the low therapeutic efficacy of available treatments. Photodynamic therapy (PDT) is an interesting therapeutic approach in the treatment of cancer; the photosensitizers with good absorption in the therapeutic window, combined with their specific targeting of cancer cells, have received particular interest. This review aims to revisit the latest developments on chlorin-based photoactive molecules for targeted therapy in TNBC. Photodynamic therapy, alone or combined with other therapies (such as chemotherapy or photothermal therapy), has potential to be a safe and a promising approach against TNBC.

Cationic Pyrrolidine/Pyrroline-Substituted Porphyrins as Efficient Photosensitizers against E. coli.

New porphyrin-pyrrolidine/pyrroline conjugates were prepared by revisiting 1,3-dipolar cycloaddition reactions between a porphyrinic azomethine ylide and a series of dipolarophiles. Cationic conjugates obtained by alkylation of the pyrrolidine/pyrroline cycloadducts showed ability to generate singlet oxygen and to produce iodine in presence of KI when irradiated with visible light. Some of the cationic derivatives showed photobactericidal properties towards a Gram-negative bioluminescent E. coli. In all cases, these features were significantly improved using KI as coadjutant, allowing, under the tested conditions, the photoinactivation of the bacterium until the detection limit of the method with a drastic reduction of the required photosensitizer concentration and irradiation time. The obtained results showed a high correlation between the ability of the cationic porphyrin derivative to produce singlet oxygen and iodine and its E. coli photoinactivation profile.

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.

PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

New nitroindazole-porphyrin conjugates: Synthesis, characterization and antibacterial properties.

The synthesis of new porphyrin-indazole hybrids by a Knoevenagel condensation of 2-formyl-5,10,15,20-tetraphenylporphyrin and N-methyl-nitroindazolylacetonitrile derivatives is reported. The target compounds were isolated in moderate to good yields (32-57%) and some of the isolated porphyrin-indazole conjugates showed good performance in the generation of singlet oxygen when irradiated with visible light. Their efficiency as photosensitizers in the photoinactivation of methicillin resistant Staphylococcus aureus-MRSA was evaluated. All derivatives showed to be able to photoinactivate the MRSA bacteria. Compound 3a appears to be the most promising photosensitiser (PS) in the photoinactivation of these bacteria, despite being the least efficient in singlet oxygen generation. The addition of potassium iodide (KI) significantly potentiated the antimicrobial Photodynamic Therapy (aPDT) process mediated by all the analysed porphyrin-indazole conjugates. The combined action of nitroindazole-porphyrins with potassium iodide (KI) action appears to be promising in the photoinactivation of MRSA.

Effect of different healing stages on stable isotope ratios in skeletal lesions.

INTRODUCTION: Physiological stress is one of the various factors that can have an impact on stable isotope ratios. However, its effect on bone collagen stable isotope ratios is still not fully understood. This study aims to build on previous research on how different disease stages may affect bone collagen stable isotope ratios. MATERIALS AND METHODS: Carbon (δ13 C) and nitrogen (δ15 N) isotope ratios were assessed in 33 skeletons that retained evidence of infectious disease and healed fractures. Samples were taken from active lesions (long bones n = 14; ribs n = 4), healed lesions (long bones n = 10; ribs n = 9), or a fracture callus (long bones n = 9; ribs n = 3). Results were compared to stable isotope ratios calculated for regions on these bones that did not retain evidence of disease or fracture. RESULTS: Long bones with active lesions had a significantly higher average δ15 N (δ15 N = 11.1 ± 0.9‰) compared to those without lesions (δ15 N = 10.7 ± 0.7‰; p = .02), while fracture calluses showed the largest range for both δ15 N and δ13 C. There were no significant differences in stable isotope ratios when compared between nonlesion and lesion sites in the ribs. DISCUSSION: The increase in δ15 N seen in active lesions, when compared with δ15 N from nonlesion regions on the same long bone, may be a consequence of altered protein metabolism. The high variability of δ15 N and δ13 C in fractures may be related to different healing stages of the calluses. This study suggests that stable isotope data can contribute information about diseases in the past, as well as an individual's response to diseases in the absence of modern medicine and antibiotics.

Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation.

An intergenic region of human chromosome 2 (2p25.3) harbors genetic variants which are among those most strongly and reproducibly associated with obesity. The gene closest to these variants is TMEM18, although the molecular mechanisms mediating these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.

Synthesis and photodynamic effects of new porphyrin/4-oxoquinoline derivatives in the inactivation of S. aureus.

New porphyrin/4-oxoquinoline conjugates were synthesized from the Heck coupling reaction of a ß-brominated porphyrin with 1-allyl-4-oxoquinoline derivatives, followed by demetallation and deprotection affording the promising photosensitizers 9a-e. Singlet oxygen studies have demonstrated that all the porphyrin/4-oxoquinoline conjugates 9a-e were capable of producing cytotoxic species and found to be excellent photosensitizing agents in the inactivation of S. aureus by the antimicrobial photodynamic therapy (aPDT) protocol.

Imported malaria in Rio de Janeiro state between 2007 and 2015: an epidemiologic approach.

Imported malaria is a malaria infection diagnosed outside the area where it was acquired and is induced by human migration and mobility. This retrospective study was performed based on secondary data from 2007 to 2015. In total, 736 cases of imported malaria (79.7% of 923 cases) were recorded in Rio de Janeiro state. Of the imported cases, 55.3% came from abroad, while 44.7% came from other regions of Brazil. Most cases of imported malaria in Brazil (85.5%) originated in Amazônia Legal, and Burundi (Africa) accounted for 59% of the cases from abroad. Analyses of the determinants of imported malaria in Rio de Janeiro state must be continued to understand the relationship between the origin and destination of cases.

Distribution, diversity, and habitat partitioning of Scolecitrichidae species (Copepoda: Calanoida) down to 1,200 m in the Southwestern Atlantic Ocean.

In this study, we analyzed the main distributional features of Scolecitrichidae species in the Southwestern Atlantic Ocean (northern region of Rio de Janeiro State) and determined and described their habitat partitioning, based on a night series of stratified samplings down to a depth of 1,200 m. A total of 18 species from seven genera were identified and grouped according to their depth distribution. Distinct vertical patterns of total density, richness, diversity, and evenness were observed, with a decrease in density and an increase in diversity and richness with increasing depth. The total scolecitrichid abundance was dominated by a few epipelagic migrant species (Scolecithrix danae, Scolecithricella minor, Amallothrix tenuiserrata, and Lophothrix frontalis). The nondominant species were distributed in different habitats in the mesopelagic layer (upper-mesopelagic, mesopelagic, and lower-mesopelagic species) according to their vertical patterns of abundance and occurrence in the two sampling periods (rainy and dry season). The total density of scolecitrichid copepods was positively related to temperature and nitrate, and negatively related to silicate at 1 m depth. The abundance of scolecitrichids copepods in the upper layer with warm and oligotrophic waters supports the hypothesis of the influence of different water masses on the scolecitrichid assemblage. High abundance of appendicularians (Oikopleura longicauda) at 1 m depth in the region implies a high production rate of discarded "houses", an important dietary component for Scolecitrichidae copepods. The observed patterns of seasonal cycles and vertical distribution suggest that the diverse scolecitrichid assemblage in the region may be structured mainly according to the partitioning of vertical habitats and food resources.

An insight on the role of photosensitizer nanocarriers for Photodynamic Therapy.

Photodynamic therapy (PDT) is a modality of cancer treatment in which tumor cells are destroyed by reactive oxygen species (ROS) produced by photosensitizers following its activation with visible or near infrared light. The PDT success is dependent on different factors namely on the efficiency of the photosensitizer deliver and targeting ability. In this review a special attention will be given to the role of some drug delivery systems to improve the efficiency of tetrapyrrolic photosensitizers to this type of treatment.

Revisiting Current Photoactive Materials for Antimicrobial Photodynamic Therapy.

Microbial infection is a severe concern, requiring the use of significant amounts of antimicrobials/biocides, not only in the hospital setting, but also in other environments. The increasing use of antimicrobial drugs and the rapid adaptability of microorganisms to these agents, have contributed to a sharp increase of antimicrobial resistance. It is obvious that the development of new strategies to combat planktonic and biofilm-embedded microorganisms is required. Photodynamic inactivation (PDI) is being recognized as an effective method to inactivate a broad spectrum of microorganisms, including those resistant to conventional antimicrobials. In the last few years, the development and biological assessment of new photosensitizers for PDI were accompanied by their immobilization in different supports having in mind the extension of the photodynamic principle to new applications, such as the disinfection of blood, water, and surfaces. In this review, we intended to cover a significant amount of recent work considering a diversity of photosensitizers and supports to achieve an effective photoinactivation. Special attention is devoted to the chemistry behind the preparation of the photomaterials by recurring to extensive examples, illustrating the design strategies. Additionally, we highlighted the biological challenges of each formulation expecting that the compiled information could motivate the development of other effective photoactive materials.

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013).

BACKGROUND: American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES: To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS: Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS: Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS: Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Effect of edible coatings with essential oils on the quality of red raspberries over shelf-life.

BACKGROUND: The objective of the present work was to develop strategies for increasing the shelf-life of red raspberries (Rubus idaeus L.), by preventing microorganism growth. RESULTS: Fruits coated with alginate plus lemon essential oil (0.2%) or orange essential oil (0.1%) after 15 days of storage had less red skin than the remaining samples. The less red color verified in these samples was also coincident with the lower concentration of anthocyanins at the end of the experiment as well as the lower capacity for scavenging ABTS free radicals or quenching singlet oxygen. Cyanidin and pelargonidin glucosides were found in raspberries fruits. The edible coatings supplemented with the essential oil of orange either at 0.1% or 0.2% were very efficient for controlling yeast and mold growth after 15 days of storage. To control the development of aerobic mesophilic bacteria the use of essential oil of lemon 0.2% and essential oil of orange 0.1% were the most efficient. CONCLUSION: The application of the film improved post-harvest quality of raspberry, since the addition of essential oils of citrus films promoted to the inhibitory effect of fungi and bacteria growth after 15 days of storage, without changing quality parameters. © 2016 Society of Chemical Industry.

The liturgical cope of D. Teotónio of Braganza: material characterization of a 16th century pluviale.

A 16th century liturgical cope belonging to D. Teotónio of Braganza (collection of the Museum of Évora, ME 172/1) was selected for a material study. The cope is made of a variety of materials that include two different types of metal threads, dyed silk yarns, and vegetable yarns used in the weft. Several samples from different points representing the different metal thread types and colored silk yarns were collected. Stereomicroscopy (optical microscopy) and scanning electron microscopy were used for morphological analysis of the textile fibers and evaluation of metal thread degradation products. Evaluation of mordants and metal thread composition was carried out by energy-dispersive X-ray spectroscopy. Liquid chromatography with diode array and mass spectrometry detection was used for dye identification, which allowed the determination of three different red dye sources and one yellow dye source in the colored silk yarns. Although different fabrics were used in the manufacturing of the cope, similarities identified in the characterization of the materials suggest that a single workshop was involved in its making.

On the Use of the Unusual Green Pigment Brochantite (Cu4(SO4)(OH)6) in the 16th-Century Portuguese-Flemish Paintings Attributed to The Master Frei Carlos Workshop.

This paper reports an unusual green pigment, brochantite (Cu4(SO4)(OH)6), on 16th-century Portuguese-Flemish paintings, attributed to the Master Frei Carlos workshop. This green mineral is usually identified as an impurity or alteration product in the green pigments verdigris (Cu(CH3COO)2 nCu(OH)2) or malachite (CuCO3 Cu(OH)2). However, after thorough investigation with a broad range of analytical techniques, it became clear that, in this case, brochantite was applied as a pigment. The abundance, pigment granulometry, and pigment morphology suggest intentional use by this Portuguese-Flemish Master as a natural pigment rather than its accidental use as an alteration product. This seems to be a distinguishable feature to other painters (Flemish and Portuguese) working in Portugal at the beginning of the 16th century. The multi-analytical study of these easel paintings was first performed by physical imaging techniques and material characterization was carried out by optical microscopy, micro-Fourier-transform infrared-spectroscopy, micro-Raman spectroscopy, scanning electron microscopy coupled with energy dispersive X-ray spectrometry, and micro-X-ray diffraction analysis (XRD).