Unraveling the Concept of Childhood Adversity in Psychosis Research: A Systematic Review.

BACKGROUND: During the last decades, an abundance of studies has investigated childhood adversity in relation to psychosis. This systematic review critically examines the methodologies employed to investigate childhood adversity in psychosis over the past decade, including operational definitions, measurement tools and characteristics, and psychometric properties of instruments used in these studies. STUDY DESIGN: This systematic review followed the PRISMA guidelines (registration number CRD42022307096), and the search used the following electronic databases: PsychINFO, SCOPUS, Web of Science, African Index Medicus (AIM), LILACS, CINAHL, EMBASE, and MEDLINE. The search included variations and combinations of the terms targeting childhood adversity and psychosis. STUDY RESULTS: Out of 585 identified studies published between 2010 and 2023, 341 employed a validated instrument to investigate childhood adversity. Our findings show "childhood trauma" being the most frequently examined construct, followed by "child maltreatment" or "child abuse." The short version of the Childhood Trauma Questionnaire was the dominant instrument. Physical abuse, emotional abuse, and sexual abuse were most frequently investigated, and indeed the field appears generally to focus on child abuse and neglect over other adversities. Significant psychometric heterogeneity was observed in the selection and summarization of instrument items, with only 59% of studies documenting original psychometric validation and 22% reporting reliability in their datasets. CONCLUSION: This review highlights substantial methodological heterogeneity in the field, pointing out biases in the research on childhood adversity and psychosis. These findings underline the need for standardized definitions and high-quality measurement tools to enhance the validity of future research in this area.

Palladium(II)-catalyzed annulation of N-methoxy amides and arynes: computational mechanistic insights and substituents effects.

CONTEXT: The combined use of transition metal-catalyzed C-H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C-H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C-H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd-C bond formation and a late C-H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. METHODS: All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent.

In vitro comparison of the acetylcholinesterase inhibition caused by V- and A-series nerve agents' surrogates.

Nerve agents (NA) pose as a great risk in the modern world. NA from the V-series, such as VX, are currently recognized as the most toxic among those compounds. However, the emergence of new classes of toxicants recently included in the Chemical Weapons Convention (CWC), such as the A-series NA, a class of organophosphorus compounds related to phosphoramidates, pose a new source of concern due to the lack of information. In order advance in the investigation on the toxicity of such toxic chemicals, we performed in vitro studies to compare representatives of the V- and A-series using affordable surrogates. Results suggest a similar inhibition potency between both agents.

Are the current commercially available oximes capable of reactivating acetylcholinesterase inhibited by the nerve agents of the A-series?

The misuse of novichok agents in assassination attempts has been reported in the international media since 2018. These relatively new class of neurotoxic agents is claimed to be more toxic than the agents of the G and V series and so far, there is no report yet in literature about potential antidotes against them. To shed some light into this issue, we report here the design and synthesis of NTMGMP, a surrogate of A-242 and also the first surrogate of a novichok agent useful for experimental evaluation of antidotes. Furthermore, the efficiency of the current commercial oximes to reactivate NTMGMP-inhibited acetylcholinesterase (AChE) was evaluated. The Ellman test was used to confirm the complete inhibition of AChE, and to compare the subsequent rates of reactivation in vitro as well as to evaluate aging. In parallel, molecular docking, molecular dynamics and MM-PBSA studies were performed on a computational model of the human AChE (HssAChE)/NTMGMP complex to assess the reactivation performances of the commercial oximes in silico. Experimental and theoretical studies matched the exact hierarchy of efficiency and pointed to trimedoxime as the most promising commercial oxime for reactivation of AChE inhibited by A-242.

Searching for potential drugs against SARS-CoV-2 through virtual screening on several molecular targets.

The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators.

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer's disease.

In search of a novel class of compounds against Alzheimer's disease (AD), a new series of 7-chloro-aminoquinoline derivatives containing methylene spacers of different sizes between the 7-chloro-4-aminoquinoline nucleus and imino methyl substituted phenolic rings, and also their reduced analogues, were designed, synthesized and evaluated as neuroprotective agents for AD in vitro. In spite of the multifaceted feature of AD, cholinesterases continue to be powerful and substantial targets, as their inhibition increases both the level and duration of the acetylcholine neurotransmitter action. The compounds presented inhibitory activity in the micromolar range against acetylcholinesterase (AChE) (imines and amines) and butyrylcholineterase (BChE) (amines). The SAR study revealed that elongation of the imine side chain improved AChE activity, whereas the reduction of these compounds to amines was crucial for higher activity and indispensable for BChE inhibition. The most promising selective inhibitors were not cytotoxic and did not stimulate pro-inflammatory activity in glial cells. Kinetic and molecular modeling studies indicated that they also show mixed-type inhibition for both enzymes, behaving as dual-site inhibitors, which can interact with both the peripheral anionic site and the catalytic anionic site of AChE. They could therefore restore cholinergic transmission and also may inhibit the aggregation of Aß promoted by AChE. Additionally, one compound showed promising anti-inflammatory activity by reducing the microglial release of NO• at a concentration that is equivalent to the IC50 against BChE (30.32 ± 0.18 µM) and 15-fold greater than the IC50 against AChE (1.97 ± 0.20 µM).Communicated by Ramaswamy H. Sarma.

Determination of rare earth elements in Fe-minerals using external calibration by LA-ICP-MS and application on Cauê Iron Formation (Brazil).

The rare earth elements (REE) composition in Fe-mineral phases is an important tool in iron formation studies to obtain information about parent rocks and environmental and paragenetic processes. However, the determination of REE presents some difficulties, such as the low concentration of these elements, matrix complexity and lack of iron matrix certified reference materials. The aim of the present work is to propose an analytical method to determine the REE plus Y (REE + Y) contents at trace levels in Fe-(hydr)oxides by the laser ablation ICP-quadrupoleMS technique, using external calibration. The calibration curves were obtained from analyses of reference materials with different matrices, and the analytical conditions were checked on the NIST 614 glass. The linearity (R2 ≥ 0.98), limit of detection (0.002-0.044 µg g-1), limit of quantification (0.008-0.146 µg g-1), recovery (88.4-112.4%), and intraday (0.1-14.1%) and interday (1.6-17.8%) precision were systematically assessed. The results obtained showed that the method is fit for the purpose and showed evidence of a nonsignificant interference of the matrix. Thus, the developed procedure was applied in the analyses of magnetite, martite, hematite, and goethite grains from Cauê Iron Formation (Brazil). The REE + Y patterns of the minerals are consistent with the previous study of bulk analyses on whole rocks and highlight the postdepositional signature of these elements in banded iron formations.

In Vitro Evaluation of Neutral Aryloximes as Reactivators for Electrophorus eel Acetylcholinesterase Inhibited by Paraoxon.

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.

Synthesis and in vitro evaluation of neutral aryloximes as reactivators of Electrophorus eel acetylcholinesterase inhibited by NEMP, a VX surrogate.

Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.

Interactive effects of temperature and nutrients on mangrove seedling growth and implications for establishment.

The establishment and wellbeing of seedlings governs the spread and survival of mangrove forests. Eutrophication and global warming are major challenges endangering mangrove ecosystem integrity. How these stressors affect seedling growth is not well understood. In a mesocosm experiment we grew mangrove seedlings in temperature-controlled chambers and investigated single and combined effects of temperature (23 and 33 °C), organic matter and dissolved nutrients on seedling trait morphology. Seedling survival was lowest in organic matter treatments. Combined effects of temperature and nutrients caused significant differences in root morphology with fewer but longer and thicker 3rd order roots, fewer 2nd and no 1st order roots in nutrient-enriched (23 °C) compared to non-enriched treatments (33 °C). Our results indicate these seedlings are less resilient to withstand their dynamic environment, in which they must settle and establish, due to lower root complexity. Mangrove ecosystems are negatively affected by global and local stresses; if new seedlings, which support forest recovery, are also affected then this amplifies stresses.

Novichoks: The Dangerous Fourth Generation of Chemical Weapons.

"Novichoks" is the name given to the controversial chemical weapons supposedly developed in the former Soviet Union between the 1970s and the 1990s. Designed to be undetectable and untreatable, these chemicals became the most toxic of the nerve agents, being very attractive for both terrorist and chemical warfare purposes. However, very little information is available in the literature, and the Russian government did not acknowledge their development. The intent of this review is to provide the IJMS readers with a general overview on what is known about novichoks today. We briefly tell the story of the secret development of these agents, and discuss their synthesis, toxicity, physical-chemical properties, and possible ways of treatment and neutralization. In addition, we also wish to call the attention of the scientific community to the great risks still represented by nerve agents worldwide, and the need to keep constant investments in the development of antidotes and ways to protect against such deadly compounds.

Correction: Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes.

[This corrects the article DOI: 10.1371/journal.ppat.1006906.].

Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes.

HIV-1 arose as the result of spillover of simian immunodeficiency viruses (SIVs) from great apes in Africa, namely from chimpanzees and gorillas. Chimpanzees and gorillas were, themselves, infected with SIV after virus spillover from African monkeys. During spillover events, SIV is thought to require adaptation to the new host species. The host barriers that drive viral adaptation have predominantly been attributed to restriction factors, rather than cofactors (host proteins exploited to promote viral replication). Here, we consider the role of one cofactor, RanBP2, in providing a barrier that drove viral genome evolution during SIV spillover events. RanBP2 (also known as Nup358) is a component of the nuclear pore complex known to facilitate nuclear entry of HIV-1. Our data suggest that transmission of SIV from monkeys to chimpanzees, and then from chimpanzees to gorillas, both coincided with changes in the viral capsid that allowed interaction with RanBP2 of the new host species. However, human RanBP2 subsequently provided no barrier to the zoonotic transmission of SIV from chimpanzees or gorillas, indicating that chimpanzee- and gorilla-adapted SIVs are pre-adapted to humans in this regard. Our observations are in agreement with RanBP2 driving virus evolution during cross-species transmissions of SIV, particularly in the transmissions to and between great ape species.

A nano-magnetic electrochemical sensor for the determination of mood disorder related substances.

The simultaneous electrochemical detection of mood disorder related substances, such as amitriptyline, melatonin and tryptophan, was successfully achieved by using a novel nano-magnetic electrochemical sensor design, encompassing Fe3O4 nanoparticles decorated with carbon quantum dots (MagNPs/Cdots). The magnetic composite was characterized using HR-TEM microscopy, XRD and Raman spectroscopy, and was applied onto a glassy carbon electrode using a miniature neodymium magnet. The determination of amitriptyline, melatonin and tryptophan was performed by monitoring oxidation promoted by MagNPs/Cdots in BR-buffer at pH 3.0, which proceeded according to well-defined differential pulse voltammetry peaks, with detection limits of 5.9, 4.4 and 4.2 nmol L-1, respectively. No significant interference was seen from biological interferents such as uric acid, ascorbic acid, dopamine, estriol and 17ß-estradiol. The magnetic hybrid material was highly stable in solution, opening exciting opportunities for the development of low cost and practical electrochemical sensors for the determination of mood disorder related substances in real clinical samples.

Isomeric Separation of Permethylated Glycans by Porous Graphitic Carbon (PGC)-LC-MS/MS at High Temperatures.

Permethylation is a common derivatization method for MS-based glycomic analyses. Permethylation enhances glycan ionization efficiency in positive MS analysis and improves glycan structural stability. Recent biological glycomic studies have added to the growing body of knowledge and suggest the need for complete structural analysis of glycans. However, reverse phase LC analysis of permethylated glycans usually results in poor isomeric separation. To achieve isomeric separation of permethylated glycans, a porous graphitic carbon (PGC) column was used. PGC columns are well-known for their isomeric separation capability for hydrophilic analyses. In this study, we have optimized temperature conditions to overcome the issues encountered while separating permethylated glycans on a PGC column and found that the highest temperature examined, 75 °C, was optimal. Additionally, we utilized tandem MS to elucidate detailed structural information for the isomers separated. Glycan standards were also utilized to facilitate structural identifications through MS/MS spectra and retention time comparison. The result is an efficient and sensitive method capable of the isomeric separation of permethylated glycans. This method was successfully applied for the isomeric characterization of N-glycans released from the breast cancer cell lines MDA-MB-231 and MDA-MB-231BR (brain seeking). A total of 127 unique glycan structures were identified with 39 isobaric structures, represented as 106 isomers, with 21 nonisomeric glycans. Thirty seven structures exhibited significant differences in isomeric distribution (P < 0.05). Additionally, alterations in the distribution of isomeric sialylated glycans, structures known to be involved in cell attachment to the blood-brain barrier during brain metastasis, were observed.

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells.

UNLABELLED: MxB restricts HIV-1 infection by directly interacting with the HIV-1 core, which is made of viral capsid; however, the contribution of MxB to the HIV-1 restriction observed in alpha interferon (IFN-α)-treated human cells is unknown. To understand this contribution, we used HIV-1 bearing the G208R capsid mutant (HIV-1-G208R), which overcomes the restriction imposed by cells expressing MxB. Here we showed that the reason why MxB does not block HIV-1-G208R is that MxB does not interact with HIV-1 cores bearing the mutation G208R. To understand whether MxB contributes to the HIV-1 restriction imposed by IFN-α-treated human cells, we challenged IFN-α-treated cells with HIV-G208R and found that MxB does not contribute to the restriction imposed by IFN-α-treated cells. To more directly test the contribution of MxB, we challenged IFN-α-treated human cells that are knocked out for the expression of MxB with HIV-1. These experiments suggested that MxB does not contribute to the HIV-1 restriction observed in IFN-α-treated human cells. IMPORTANCE: MxB is a restriction factor that blocks HIV-1 infection in human cells. Although it has been postulated that MxB is the factor that blocks HIV-1 infection in IFN-α-treated cells, this is a hard concept to grasp due to the great number of genes that are induced by IFN-α in cells from the immune system. The work presented here elegantly demonstrates that MxB has minimal or no contribution to the ability of IFN-α-treated human cells to block HIV-1 infection. Furthermore, this work suggests the presence of novel restriction factors in IFN-α-treated human cells that block HIV-1 infection.

Biochemical and Molecular Chitotriosidase Profiles in Patients with Gaucher Disease Type 1 in Minas Gerais, Brazil: New Mutation in CHIT1 Gene.

Chitotriosidase (ChT) is a human chitinase secreted by activated macrophages and its activity is used in therapeutic monitoring of Gaucher disease (GD), the most common lysosomal storage disease. About 6% of the population is homozygous for a duplication of 24 bp in exon 11 of the CHIT1 gene (dup24), which is the main polymorphism that results in the absence of ChT. As ChT enzyme activity can be used as a biomarker in GD, it is important to know the CHIT1 genotype of each patient. In this study, ChT activity and CHIT1 genotype were evaluated in 33 GD type 1 patients under treatment in the state of Minas Gerais, Brazil, and compared to healthy controls. As expected, the enzyme activity was found to be higher in GD type 1 patients than in healthy subjects. Four patients had no ChT activity. Their genotype revealed three patients (9%) homozygous for dup24 allele and one patient with two polymorphisms in exon 11: G354R and a 4 bp deletion at the exon-intron 11 boundary (g.16993_16996delGAGT), the later described for the first time in literature. Two other patients with lower ChT activity presented a polymorphism in exon 4 (c.304G>A, p.G102S), without dup24 allele. In conclusion, this study demonstrated that ChT activity can be used for therapeutic monitoring in 82% of GD patients of the state of Minas Gerais, Brazil.

Methods for predicting the rate constant for uptake of organic chemicals from water by fish.

Bioaccumulation is an important information requirement for chemicals risk assessment. The most widely used test guideline for measuring bioaccumulation in fish is the OECD 305 test guideline and, in the future, it is likely to include a dietary exposure method for substances that are difficult to test by the more usual aqueous exposure route. This new method results in a biomagnification factor (BMF), whereas for regulatory purposes a bioconcentration factor (BCF) is often required. Therefore, being able to estimate a BCF quantitatively from the data generated in the dietary study would meet an accepted regulatory need. The information generated by the dietary study includes the depuration rate constant. To use these data to estimate a BCF, an estimate of the rate constant for uptake from water is needed, allowing a kinetic BCF to be calculated. The present study considers and tests methods that are currently available for predicting uptake rate constants from water using a database of bioconcentration data. A number of methods were found to perform similarly when tested with substances with a log K(OW) range of approximately 3.5 to 8.2. The uncertainty in the estimated uptake rate constant was relatively large, however, even for the best performing methods.

Guarana (Paullinia cupana var. sorbilis), an anciently consumed stimulant from the Amazon rain forest: the seeded-fruit transcriptome.

Guarana (Paullinia cupana var. sorbilis) is a plant native to the central Amazon basin. Roasted seed extracts have been used as medicinal beverages since pre-Colombian times, due to their reputation as stimulants, aphrodisiacs, tonics, as well as protectors of the gastrointestinal tract. Guarana plants are commercially cultivated exclusively in Brazil to supply the national carbonated soft-drink industry and natural product stores around the world. In this report, we describe and discuss the annotation of 15,387 ESTs from guarana seeded-fruits, highlighting sequences from the flavonoid and purine alkaloid pathways, and those related to biotic stress avoidance. This is the largest set of sequences registered for the Sapindaceae family.