Therapeutic response to four artemisinin-based combination therapies in Angola, 2021.

Monitoring antimalarial efficacy is important to detect the emergence of parasite drug resistance. Angola conducts in vivo therapeutic efficacy studies (TESs) every 2 years in its fixed sentinel sites in Benguela, Lunda Sul, and Zaire provinces. Children with uncomplicated Plasmodium falciparum malaria were treated with artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DP), or artesunate-pyronaridine (ASPY) and followed for 28 (AL and ASAQ) or 42 days (DP and ASPY) to assess clinical and parasitological response to treatment. Two drugs were sequentially assessed in each site in February-July 2021. The primary indicator was the Kaplan-Meier estimate of the PCR-corrected efficacy at the end of the follow-up period. A total of 622 patients were enrolled in the study and 590 (95%) participants reached a study endpoint. By day 3, ≥98% of participants were slide-negative in all study sites and arms. After PCR correction, day 28 AL efficacy was 88.0% (95% CI: 82%-95%) in Zaire and 94.7% (95% CI: 90%-99%) in Lunda Sul. For ASAQ, day 28 efficacy was 92.0% (95% CI: 87%-98%) in Zaire and 100% in Lunda Sul. Corrected day 42 efficacy was 99.6% (95% CI: 99%-100%) for ASPY and 98.3% (95% CI: 96%-100%) for DP in Benguela. High day 3 clearance rates suggest no clinical evidence of artemisinin resistance. This was the fourth of five rounds of TES in Angola showing a corrected AL efficacy <90% in a site. For Zaire, AL has had an efficacy <90% in 2013, 2015, and 2021. ASAQ, DP, and ASPY are appropriate choices as artemisinin-based combination therapies in Angola.

A systematic review on the emergence of terbinafine-resistant Trichophyton indotineae in Europe: Time to act?

BACKGROUND: There is a recent growing global concern regarding the rise in antifungal resistance of dermatophytosis. The emergence of terbinafine-resistant Trichophyton indotineae (T. indotineae), previously known as Trichophyton mentagrophytes genotype VIII, is particularly alarming given that terbinafine is considered the treatment of choice for dermatophyte infections and the limited number of available antimycotics. This strain surfaced in the Indian subcontinent in the mid-2010s and more recently there have been reports of its arrival in Europe. OBJECTIVE: The objective of this review is to document the presence of terbinafine-resistant T. indotineae in Europe with the aim to guide antifungal stewardship and ultimately prevent the spread of resistance. METHODS: This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic literature search was performed using PubMed, Scopus and Web of Science databases. RESULTS: We extracted information from 16 studies published between 2019 and 2023 that described a total of 63 cases of antifungal-resistant dermatophytosis caused by T. indotineae in Europe. Antifungal susceptibility testing (AFST) revealed a wide range of terbinafine minimum inhibitory concentrations (MICs), varying from 0.014 to ≥16 µg/mL. However, these values are hard to interpret due to variations among used methodologies as well as the lack of clinical breakpoints. In all cases included in this study, elevated terbinafine MICs were associated with mutations in the squalene epoxidase (SQLE) gene. Itraconazole was the most frequently used alternative to terbinafine in this study and complete remission of tinea lesions after treatment switch was shown. Nevertheless, relapse rates are concerningly high. CONCLUSION: We propose the implementation of surveillance programmes for a fast identification through sequencing of T. indotineae (and SQLE mutations) and standardization of procedures for AFST to facilitate the establishment of clinical breakpoints and enable guidance on the appropriate use of antifungals.

EGFR- and Integrin αVß3-Targeting Peptides as Potential Radiometal-Labeled Radiopharmaceuticals for Cancer Theranostics.

The burgeoning field of cancer theranostics has witnessed advancements through the development of targeted molecular agents, particularly peptides. These agents exploit the overexpression or mutations of specific receptors, such as the Epidermal Growth Factor receptor (EGFR) and αVß3 integrin, which are pivotal in tumor growth, angiogenesis, and metastasis. Despite the extensive research into and promising outcomes associated with antibody-based therapies, peptides offer a compelling alternative due to their smaller size, ease of modification, and rapid bioavailability, factors which potentially enhance tumor penetration and reduce systemic toxicity. However, the application of peptides in clinical settings has challenges. Their lower binding affinity and rapid clearance from the bloodstream compared to antibodies often limit their therapeutic efficacy and diagnostic accuracy. This overview sets the stage for a comprehensive review of the current research landscape as it relates to EGFR- and integrin αVß3-targeting peptides. We aim to delve into their synthesis, radiolabeling techniques, and preclinical and clinical evaluations, highlighting their potential and limitations in cancer theranostics. This review not only synthesizes the extant literature to outline the advancements in peptide-based agents targeting EGFR and integrin αVß3 but also identifies critical gaps that could inform future research directions. By addressing these gaps, we contribute to the broader discourse on enhancing the diagnostic precision and therapeutic outcomes of cancer treatments.

Leishmania donovani Induces Multiple Dynamic Responses in the Metabolome Associated with Amastigote Differentiation and Maturation Inside the Human Macrophage.

Leishmania donovani infection of macrophages drives profound changes in the metabolism of both the host macrophage and the parasite, which undergoes different phases of development culminating in replication and propagation. However, the dynamics of this parasite-macrophage cometabolome are poorly understood. In this study, a multiplatform metabolomics pipeline combining untargeted, high-resolution CE-TOF/MS and LC-QTOF/MS with targeted LC-QqQ/MS was followed to characterize the metabolome alterations induced in L. donovani-infected human monocyte-derived macrophages from different donors at 12, 36, and 72 h post-infection. The set of alterations known to occur during Leishmania infection of macrophages, substantially expanded in this investigation, characterized the dynamics of the glycerophospholipid, sphingolipid, purine, pentose phosphate, glycolytic, TCA, and amino acid metabolism. Our results showed that only citrulline, arginine, and glutamine exhibited constant trends across all studied infection time points, while most metabolite alterations underwent a partial recovery during amastigote maturation. We determined a major metabolite response pointing to an early induction of sphingomyelinase and phospholipase activities and correlated with amino acid depletion. These data represent a comprehensive overview of the metabolome alterations occurring during promastigote-to-amastigote differentiation and maturation of L. donovani inside macrophages that contributes to our understanding of the relationship between L. donovani pathogenesis and metabolic dysregulation.

Intramacrophage lipid accumulation compromises T cell responses and is associated with impaired drug therapy against visceral leishmaniasis.

Under perturbing conditions such as infection with Leishmania, a protozoan parasite living within the phagosomes in mammalian macrophages, cellular and organellar structures, and metabolism are dynamically regulated for neutralizing the pressure of parasitism. However, how modulations of the host cell metabolic pathways support Leishmania infection remains unknown. Herein, we report that lipid accumulation heightens the susceptibility of mice to L. donovani infection and promotes resistance to first-line anti-leishmanial drugs. Despite being pro-inflammatory, the in vitro generated uninfected lipid-laden macrophages (LLMs) or adipose-tissue macrophages (ATMs) display lower levels of reactive oxygen and nitrogen species. Upon infection, LLMs secrete higher IL-10 and lower IL-12p70 cytokines, inhibiting CD4+ T cell activation and Th1 response suggesting a key modulatory role for intramacrophage lipid accumulation in anti-leishmanial host defence. We, therefore, examined this causal relationship between lipids and immunomodulation using an in vivo high-fat diet (HFD) mouse model. HFD increased the susceptibility to L. donovani infection accompanied by a defective CD4+ Th1 and CD8+ T cell response. The white adipose tissue of HFD mice displays increased susceptibility to L. donovani infection with the preferential infection of F4/80+ CD11b+ CD11c+ macrophages with higher levels of neutral lipids reserve. The HFD increased resistance to a first-line anti-leishmanial drug associated with a defective adaptive immune response. These data demonstrate that the accumulation of neutral lipids contributes to susceptibility to visceral leishmaniasis hindering host-protective immune response and reducing the efficacy of antiparasitic drug therapies.

Molecular Markers of Sulfadoxine-Pyrimethamine Resistance in Samples from Children with Uncomplicated Plasmodium falciparum at Three Sites in Angola in 2019.

Sulfadoxine-pyrimethamine (SP) is used for prevention of malaria in pregnant women in Angola. We sequenced the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes, implicated in SP resistance, in samples collected during a 2019 study of artemisinin-based combination therapy efficacy in Benguela, Lunda Sul, and Zaire provinces. A total of 90 day 0 and day of failure samples were individually sequenced, while 508 day 0 samples from participants without recurrent parasitemia were pooled after DNA extraction into 61 pools. The N51I, C59R, and S108N pfdhfr mutations and A437G pfdhps mutations were present at high proportions in all provinces (weighted allele frequencies, 62% to 100%). The K540E pfdhps mutation was present at lower proportions (10% to 14%). The A581G pfdhps mutation was only observed in Zaire, at a 4.6% estimated prevalence. The I431V and A613S mutations were also only observed in Zaire, at a prevalence of 2.8% to 2.9%. The most common (27% to 66%) reconstructed haplotype in all three provinces was the canonical quadruple pfdhfr pfdhps mutant. The canonical quintuple mutant was absent in Lunda Sul and Benguela and present in 7.9% of samples in Zaire. A single canonical sextuple (2.6%) mutant was observed in Zaire Province. Proportions of the pfdhps K540E and A581G mutations were well below the World Health Organization thresholds for meaningful SP resistance (prevalence of 95% for K540E and 10% for A581G). Samples from therapeutic efficacy studies represent a convenient source of samples for monitoring SP resistance markers.

Prevalence of vitamin A deficiency in women of childbearing age in Brazil: a systematic review and meta-analysis.

Vitamin A is an essential micronutrient, especially during pregnancy. We aimed to assess the prevalence of vitamin A deficiency in Brazilian women of childbearing age. We conducted a systematic review with meta-analysis of studies that assessed vitamin A deficiency in women of childbearing age following the registered protocol (CRD42020171856). Independent peer researchers selected the studies retrieved from MEDLINE, Embase, Scopus and other sources. Data from the eligible studies were extracted in pairs and assessed for methodological quality. The prevalence of vitamin A deficiency (< 0·70 µmol/l or <0·20 µg/dl) and 95 % CI was combined by meta-analysis, and heterogeneity was estimated by I2. Out of 3610 screened records, thirty-two studies were included, which assessed 12 577 women from 1965 to 2017, mostly in maternity hospitals. Main limitations of the studies were in sample frame (30/32) and sampling method (29/32). Deficiency occurred in 13 % (95 % CI 9·4, 17·2 %; I² = 97 %) of all women and was higher in pregnant women (16·1 %; 95 % CI 5·6, 30·6 %; I² = 98 %) than non-pregnant women (12·3 %; 95 % CI 8·4, 16·8 %; I² = 96 %). The prevalence increased according to the decade, from 9·5 % (95 % CI 1·9­21·6 %; I² = 98 %) up to 1990, 10·8 % (95 % CI 7·9, 14·2 %; I² = 86 %) in the 2000s and 17·8 % (95 % CI 8·7, 29·0 %; I² = 98 %) in the 2010s. Over 10 % of Brazilian women in childbearing age were deficient in vitamin A. Higher prevalence was observed in pregnant women, and deficiency seemed to be increasing over the decades. Low representativeness of the studies, mainly based on convenience sampling that included pregnant, postpartum, lactating and non-pregnant women, as well as high heterogeneity, limits the findings.

Sphingolipids and acylcarnitines are altered in placentas from women with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and a severe threat to pregnant people and offspring health. The molecular origins of GDM, and in particular the placental responses, are not fully known. The present study aimed to perform a comprehensive characterisation of the lipid species in placentas from pregnancies complicated with GDM using high-resolution MS lipidomics, with a particular focus on sphingolipids and acylcarnitines in a semi-targeted approach. The results indicated that despite no major disruption in lipid metabolism, placentas from GDM pregnancies showed significant alterations in sphingolipids, mostly lower abundance of total ceramides. Additionally, very long-chain ceramides and sphingomyelins with twenty-four carbons were lower, and glucosylceramides with sixteen carbons were higher in placentas from GDM pregnancies. Semi-targeted lipidomics revealed the strong impact of GDM on the placental acylcarnitine profile, particularly lower contents of medium and long-chain fatty-acyl carnitine species. The lower contents of sphingolipids may affect the secretory function of the placenta, and lower contents of long-chain fatty acylcarnitines is suggestive of mitochondrial dysfunction. These alterations in placental lipid metabolism may have consequences for fetal growth and development.

Characteristics associated with Lactobacillus iners-dominated vaginal microbiota.

OBJECTIVE: The protective role of Lactobacillus iners in the vaginal microbiota has been questioned. Recent studies have shown that L. iners is the dominating taxon in a large subset of women worldwide. The aim of this study was to identify sociodemographic, behavioural and clinical variables associated with L. iners-dominated community state type (CST) III in Brazilian women of reproductive age. PARTICIPANTS AND METHODS: This study leveraged microbiota compositional data generated by sequencing of the V3-V4 16S rRNA gene from vaginal samples collected from 442 participants enrolled in a previous cross-sectional study that included 609 women in five geographical regions of Brazil. A total of 167 (27.4%) participants were excluded from the current study as they did not present a Lactobacillus-dominated vaginal microbiota. Data on sociodemographic and behavioural characteristics of the study population were obtained through face-to-face interviews. Participants were assigned to two study groups: those with L. iners-dominated CST III (n=222) and those with three distinct CSTs (I, II or V) dominated by another Lactobacillus spp. (n=220). Logistic regression analysis using a stepwise method was performed to test association between CST III and participants' characteristics, considering their OR and 95% CIs. RESULTS: Among the population characteristics assessed, L. iners-dominated CST III was independently associated with having two or more sexual partners (OR 3.27; 95% CI 1.50 to 7.11) and microscopic detection of Candida sp. on vaginal smears (OR 2.24; 95% CI 1.02 to 4.89). Other characteristics were inversely associated with CST III, including condom use (OR 0.59; 95% CI 0.38 to 0.91), higher educational level (OR 0.61; 95% CI 0.41 to 0.91) and diet containing milk/dairy intake (OR 0.43; 95% CI 0.20 to 0.90). CONCLUSION: Unprotected sex practices, number of sexual partners and lower educational levels may be useful for identifying women with L. iners-dominated microbiota and its suboptimal protective properties. L. iners microbiota does not seem to provide optimal protection against Candida sp. colonisation, warranting further investigation.

[68 Ga]Ga-FAPI-46 PET for non-invasive detection of pulmonary fibrosis disease activity.

PURPOSE: The lack of effective molecular biomarkers to monitor idiopathic pulmonary fibrosis (IPF) activity or treatment response remains an unmet clinical need. Herein, we determined the utility of fibroblast activation protein inhibitor for positron emission tomography (FAPI PET) imaging in a mouse model of pulmonary fibrosis. METHODS: Pulmonary fibrosis was induced by intratracheal administration of bleomycin (1 U/kg) while intratracheal saline was administered to control mice. Subgroups from each cohort (n = 3-5) underwent dynamic 1 h PET/CT after intravenously injecting FAPI-46 radiolabeled with gallium-68 ([68 Ga]Ga-FAPI-46) at 7 days and 14 days following disease induction. Animals were sacrificed following imaging for ex vivo gamma counting and histologic correlation. [68 Ga]Ga-FAPI-46 uptake was quantified and reported as percent injected activity per cc (%IA/cc) or percent injected activity (%IA). Lung CT density in Hounsfield units (HU) was also correlated with histologic examinations of lung fibrosis. RESULTS: CT only detected differences in the fibrotic response at 14 days post-bleomycin administration. [68 Ga]Ga-FAPI-46 lung uptake was significantly higher in the bleomycin group than in control subjects at 7 days and 14 days. Significantly (P = 0.0012) increased [68 Ga]Ga-FAPI-46 lung uptake in the bleomycin groups at 14 days (1.01 ± 0.12%IA/cc) vs. 7 days (0.33 ± 0.09%IA/cc) at 60 min post-injection of the tracer was observed. These findings were consistent with an increase in both fibrinogenesis and FAP expression as seen in histology. CONCLUSION: CT was unable to assess disease activity in a murine model of IPF. Conversely, FAPI PET detected both the presence and activity of lung fibrogenesis, making it a promising tool for assessing early disease activity and evaluating the efficacy of therapeutic interventions in lung fibrosis patients.

Macrophage-targeted shikonin-loaded nanogels for modulation of inflammasome activation.

This study reports the formulation and delivery of hyaluronic acid-Zein (HA-Zein) nanogels loaded with Shikonin (SK) to selectively attenuate macrophage inflammasome. The self-assembled nanogels, produced by nanoprecipitation, exhibited high encapsulation efficiency, and were selectively internalized by human THP-1-derived macrophages without eliciting cytotoxic responses. Cell treatment with HA-Zein-SK nanogels before stimulation with LPS and Nigericin significantly suppressed caspase-1 activation and IL-1ß production, indicating inflammasome inhibition. Importantly, HA-Zein-SK nanogels bioinstructed inflammasome activated macrophages towards an anti-inflammatory CD163highHLA-DRlow phenotype and led to a marked reduction in the release of pro-inflammatory mediators (TNF-α, IL-6 and IP-10). Extracellular metabolic profiling additionally revealed SK-mediated downregulation of cellular glycolytic activity, which was corroborated by a significant decrease of glycolytic genes transcription. All in all, our findings demonstrate the potential of bioactive SK-containing, self-assembled nanogels to modulate exacerbated responses in innate immune cells and, prospectively, in human tissues where NRLP3 inflammasome is abnormally activated upon injury or disease.

Ultrasmall Porous Silica Nanoparticles with Enhanced Pharmacokinetics for Cancer Theranostics.

Theranostic nanoparticles hold the potential to greatly improve cancer management by providing personalized medicine. Although many theranostic nanoconstructs have been successful in preclinical studies, clinical translation is still hampered by their limited targeting capability and lack of successful therapeutic efficacy. We report the use of novel ultrasmall porous silica nanoparticles (UPSN) with enhanced in vivo pharmacokinetics such as high target tissue accumulation (12% ID/g in the tumor) and evasion from the reticuloendothelial system (RES) organs. Herein, UPSN is conjugated with the isotopic pair 90/86Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with 86Y-DOTA-UPSN. Tumor-to-muscle and tumor-to-liver uptake values were significantly high (12.4 ± 1.7 and 1.5 ± 0.5, respectively), unprecedented for inorganic nanomaterials. 90Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.

Occurrence and Variability of the Efflux Pump Gene norA across the Staphylococcus Genus.

NorA is one of the main native MDR efflux pumps of Staphylococcus aureus, contributing to reduced susceptibility towards fluoroquinolones and biocides, but little is known about its variability within S. aureus or its distribution and conservation among other staphylococci. We screened for sequences homologous to S. aureus norA and found it in 61 out of the 63 Staphylococcus species described. To the best of our knowledge, this is the first study to report the occurrence of norA across the Staphylococcus genus. The norA phylogenetic tree follows the evolutionary relations of staphylococci and the closely related Mammalliicoccus genus. Comparative analyses suggest a conservation of the NorA function in staphylococci. We also analyzed the variability of norA within S. aureus, for which there are several circulating norA alleles, differing up to 10% at the nucleotide level, which may hamper proper norA detection. We demonstrate the applicability of a PCR-based algorithm to detect and differentiate norA alleles in 52 S. aureus representing a wider collection of 89 isolates from different hosts. Our results highlight the prevalence of norAI and norAII in different settings and the association of norA alleles with specific S. aureus clonal lineages. Ultimately, it confirms the applicability of our PCR-based algorithm to rapidly detect and assign the different norA alleles, a trait that may impact antimicrobial efflux capacity and the search for potential NorA inhibitors.

Continued Low Efficacy of Artemether-Lumefantrine in Angola in 2019.

Biennial therapeutic efficacy monitoring is a crucial activity for ensuring the efficacy of currently used artemisinin-based combination therapy in Angola. Children with acute uncomplicated Plasmodium falciparum infection in sentinel sites in the Benguela, Zaire, and Lunda Sul Provinces were treated with artemether-lumefantrine (AL) or artesunate-amodiaquine (ASAQ) and monitored for 28 days to assess clinical and parasitological responses. Molecular correction was performed using seven microsatellite markers. Samples from treatment failures were genotyped for the pfk13, pfcrt, and pfmdr1 genes. Day 3 clearance rates were ≥95% in all arms. Uncorrected day 28 Kaplan-Meier efficacy estimates ranged from 84.2 to 90.1% for the AL arms and 84.7 to 100% for the ASAQ arms. Corrected day 28 estimates were 87.6% (95% confidence interval [CI], 81 to 95%) for the AL arm in Lunda Sul, 92.2% (95% CI, 87 to 98%) for AL in Zaire, 95.6% (95% CI, 91 to 100%) for ASAQ in Zaire, 98.4% (95% CI, 96 to 100%) for AL in Benguela, and 100% for ASAQ in Benguela and Lunda Sul. All 103 analyzed samples had wild-type pfk13 sequences. The 76T pfcrt allele was found in most (92%; 11/12) ASAQ late-failure samples but in only 16% (4/25) of AL failure samples. The N86 pfmdr1 allele was found in 97% (34/35) of treatment failures. The AL efficacy in Lunda Sul was below the 90% World Health Organization threshold, the third time in four rounds that this threshold was crossed for an AL arm in Angola. In contrast, the observed ASAQ efficacy has not been below 95% to date in Angola, including this latest round.

ImmunoPET of CD146 in Orthotopic and Metastatic Breast Cancer Models.

The overexpression of CD146 in breast cancer is considered a hallmark of tumor progression and metastasis, particularly in triple negative breast cancer. Aimed at imaging differential CD146 expressions in breast cancer, a noninvasive method for predictive prognosis and diagnosis was investigated using a 64Cu-labeled CD146-specific monoclonal antibody, YY146. CD146 expression was screened in human breast cancer cell lines using Western blotting. Binding ability was evaluated using flow cytometry and immunofluorescent staining. YY146 was conjugated with 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu following standard procedures. Serial PET or PET/CT imaging was performed in orthotopic and metastatic breast cancer tumor models. Biodistribution was performed after the final time point of imaging. Finally, tissue immunofluorescent staining and hematoxylin and eosin (H&E) staining were performed on tumor tissues. The MDA-MB-435 cell line showed the highest CD146 expression level, whereas MCF-7 had the lowest level at the cellular level. ImmunoPET showed that MDA-MB-435 orthotopic tumors had high and clear radioactive accumulation after the administration of 64Cu-NOTA-YY146. The tumor uptake of 64Cu-NOTA-YY146 in MDA-MB-435 was significantly higher than that in MCF-7 and nonspecific IgG control groups (P < 0.01). Biodistribution verified the PET imaging results. For metastatic models, 64Cu-NOTA-YY146 allowed for the visualization of high radioactivity accumulation in metastatic MDA-MB-435 tumors, which was confirmed by ex vivo biodistribution of lung tissues. H&E staining proved the successful building of metastatic tumor models. Immunofluorescent staining verified the differential expression of CD146 in orthotopic tumors. Therefore, 64Cu-NOTA-YY146 could be used as an immunoPET probe to visualize CD146 in the breast cancer model and is potentially useful for cancer diagnosis, prognosis prediction, and monitoring therapeutic response.

A tree nymph of the Brazilian Atlantic Forest: Dryades (Galipeinae, Rutaceae), a new neotropical genus segregated from Conchocarpus.

Subtribe Galipeinae (tribe Galipeeae) is the most diverse group of Rutaceae (the orange family) in the Neotropics, with 27 genera and ca. 130 species. The largest genus in the subtribe is Conchocarpus, with ca. 50 species, distributed from Central America to southern Brazil, and is particularly diverse in the Brazilian Atlantic Forest. The circumscription of the genus was recently changed to accommodate the species of Almeidea. However, even with this inclusion, Conchocarpus did not appear as monophyletic because the position of C. concinnus, which appeared in a clade with the other genera of Galipeinae rather than in the clade with the other species of Conchocarpus. The objective of the present study is to investigate the phylogenetic position of four other species of Conchocarpus (hereafter called "C. gauchaudianus group") that share morphological traits and geographical distribution with C. concinnus suggesting a close phylogenetic affinity. Phylogenetic analyses were based on morphological and molecular data from nuclear regions ITS-1 and ITS-2 as well as plastid regions trnL-trnF and rps-16, and were conducted with parsimony and Bayesian inference as optimization criteria. Results showed Conchocarpus as polyphyletic with its species divided in two clades, one, herein called "the Conchocarpus sensu stricto group," includes the type species C. macrophyllus, and the other "the Conchocarpus gaudichaudianus group" includes C. concinnus. The latter group is here recognized as a new genus, Dryades, the name given by Carl Friederich von Martius (1794-1868) to the Domain of the Atlantic Forest in Brazil, inspired by the tree nymphs in Greek mythology. Floral structure and leaf morphology provided further support to the findings of phylogenetic analysis. A description of the new genus, new combinations, a key to the species of the new genus, discussions of the affinities of the species are also provided, as well as data on the conservation status of the species of Dryades. Additionally, new data on floral structure of C. heterophyllus, C. macrophyllus and C. minutiflorus (all from the Conchocarpus sensu stricto group) are provided.

Cytokines and metabolic regulation: A framework of bidirectional influences affecting Leishmania infection.

Leishmania, a protozoan parasite inflicting the complex of diseases called Leishmaniases, resides and replicates as amastigotes within mammalian macrophages. As macrophages are metabolically highly active and can generate free radicals that can destroy this parasite, Leishmania also devise strategies to modulate the host cell metabolism. However, the metabolic changes can also be influenced by the anti-leishmanial immune response mediated by cytokines. This bidirectional, dynamic and complex metabolic coupling established between Leishmania and its host is the result of a long co-evolutionary process. Due to the continuous alterations imposed by the host microenvironment, such metabolic coupling continues to be dynamically regulated. The constant pursuit and competition for nutrients in the host-Leishmania duet alter the host metabolic pathways with major consequences for its nutritional reserves, eventually affecting the phenotype and functionality of the host cell. Altered phenotype and functions of macrophages are particularly relevant to immune cells, as perturbed metabolic fluxes can crucially affect the activation, differentiation, and functions of host immune cells. All these changes can deterministically direct the outcome of an infection. Cytokines and metabolic fluxes can bidirectionally influence each other through molecular sensors and regulators to dictate the final infection outcome. Our studies along with those from others have now identified the metabolic nodes that can be targeted for therapy.

Membrane interactions of Ocellatins. Where do antimicrobial gaps stem from?

The antimicrobial peptides Ocellatin-LB1, -LB2 and -F1, isolated from frogs, are identical from residue 1 to 22, which correspond to the -LB1 sequence, whereas -LB2 carries an extra N and -F1 additional NKL residues at their C-termini. Despite the similar sequences, previous investigations showed different spectra of activities and biophysical investigations indicated a direct correlation between both membrane-disruptive properties and activities, i.e., ocellatin-F1 > ocellatin-LB1 > ocellatin-LB2. This study presents experimental evidence as well as results from theoretical studies that contribute to a deeper understanding on how these peptides exert their antimicrobial activities and how small differences in the amino acid composition and their secondary structure can be correlated to these activity gaps. Solid-state NMR experiments allied to the simulation of anisotropic NMR parameters allowed the determination of the membrane topologies of these ocellatins. Interestingly, the extra Asn residue at the Ocellatin-LB2 C-terminus results in increased topological flexibility, which is mainly related to wobbling of the helix main axis as noticed by molecular dynamics simulations. Binding kinetics and thermodynamics of the interactions have also been assessed by Surface Plasmon Resonance and Isothermal Titration Calorimetry. Therefore, these investigations allowed to understand in atomic detail the relationships between peptide structure and membrane topology, which are in tune within the series -F1 > > -LB1 ≥ -LB2, as well as how peptide dynamics can affect membrane topology, insertion and binding.

Self-report instruments for assessing adherence to warfarin therapy: a systematic review.

BACKGROUND: The assessment of adherence to warfarin therapy is useful in clinical practice due to its wide variability in dose-response and risks of complications. The aim of this study was to investigate validated instruments used to assess adherence to warfarin therapy. METHODS: Information was collected from the MEDLINE (PubMed), LILACS, EMBASE, and Cochrane Library databases. Search strategies were applied for each database, with no time limit or language restriction. Inclusion criteria consisted of study participants of ≥ 18 years of age, from both sexes, on chronic anticoagulation with warfarin for any indication and the use of validated instruments to assess adherence to warfarin therapy. Exclusion criteria consisted of duplicate articles, narrative or systematic reviews, and meta-analyses, as well as case reports/series and experimental studies involving animals. Two independent reviewers performed the following steps: evaluation of titles/abstracts, selection of studies after full reading, data extraction, and evaluation of potential bias. Discrepancies were resolved by a third reviewer. RESULTS: Overall, 19 articles were selected for this systematic review, including 17 cross-sectional studies, one cohort study, and one quasi-experimental study, published from 2009 to 2019. The validated instruments identified in this review were Morisky Medication Adherence Scale (MMAS), the eight-item Morisky Medication Adherence Scale (MMAS-8), Measurement of Treatment Adherence (MTA), and Brief Medication Questionnaire (BMQ). Only MMAS-8 was tested for reliability, using the internal consistency assessment, with Cronbach's α range 0.56-0.71. CONCLUSIONS: This review highlighted a gap in knowledge regarding the scarcity of validated instruments to assess adherence to warfarin therapy. Limitations were found in instruments that comprised the assessment of the isolated use of medication and the lack of analysis of other relevant therapeutic aspects. Future studies are needed to develop and validate more comprehensive instruments in an attempt to assess adherence to warfarin therapy. PROSPERO: Registration number CRD42019128324.

Relational mobility predicts social behaviors in 39 countries and is tied to historical farming and threat.

Biologists and social scientists have long tried to understand why some societies have more fluid and open interpersonal relationships and how those differences influence culture. This study measures relational mobility, a socioecological variable quantifying voluntary (high relational mobility) vs. fixed (low relational mobility) interpersonal relationships. We measure relational mobility in 39 societies and test whether it predicts social behavior. People in societies with higher relational mobility report more proactive interpersonal behaviors (e.g., self-disclosure and social support) and psychological tendencies that help them build and retain relationships (e.g., general trust, intimacy, self-esteem). Finally, we explore ecological factors that could explain relational mobility differences across societies. Relational mobility was lower in societies that practiced settled, interdependent subsistence styles, such as rice farming, and in societies that had stronger ecological and historical threats.