Host-guest systems for the SAMPL9 blinded prediction challenge: phenothiazine as a privileged scaffold for binding to cyclodextrins.

Model systems are widely used in biology and chemistry to gain insight into more complex systems. In the field of computational chemistry, researchers use host-guest systems, relatively simple exemplars of noncovalent binding, to train and test the computational methods used in drug discovery. Indeed, host-guest systems have been developed to support the community-wide blinded SAMPL prediction challenges for over a decade. While seeking new host-guest systems for the recent SAMPL9 binding prediction challenge, which is the focus of the present PCCP Themed Collection, we identified phenothiazine as a privileged scaffold for guests of ß cyclodextrin (ßCD) and its derivatives. Building on this observation, we used calorimetry and NMR spectroscopy to characterize the noncovalent association of native ßCD and three methylated derivatives of ßCD with five phenothiazine drugs. The strongest association observed, that of thioridazine and one of the methyl derivatives, exceeds the well-known high affinity of rimantidine with ßCD. Intriguingly, however, methylation of ßCD at the 3 position abolished detectible binding for all of the drugs studied. The dataset has a clear pattern of entropy-enthalpy compensation. The NMR data show that all of the drugs position at least one aromatic proton at the secondary face of the CD, and most also show evidence of deep penetration of the binding site. The results of this study were used in the SAMPL9 blinded binding affinity-prediction challenge, which are detailed in accompanying papers of the present Themed Collection. These data also open the phenothiazines and, potentially, chemically similar drugs, such as the tricyclic antidepressants, as relatively potent binders of ßCD, setting the stage for future SAMPL challenge datasets and for possible applications as drug reversal agents.

Could the Urease of the Gut Bacterium Proteus mirabilis Play a Role in the Altered Gut-Brain Talk Associated with Parkinson's Disease?

Intestinal dysbiosis seems to play a role in neurodegenerative pathologies. Parkinson's disease (PD) patients have an altered gut microbiota. Moreover, mice treated orally with the gut microbe Proteus mirabilis developed Parkinson's-like symptoms. Here, the possible involvement of P. mirabilis urease (PMU) and its B subunit (PmUreß) in the pathogenesis of PD was assessed. Purified proteins were given to mice intraperitoneally (20 µg/animal/day) for one week. Behavioral tests were conducted, and brain homogenates of the treated animals were subjected to immunoassays. After treatment with PMU, the levels of TNF-α and IL-1ß were measured in Caco2 cells and cellular permeability was assayed in Hek 293. The proteins were incubated in vitro with α-synuclein and examined via transmission electron microscopy. Our results showed that PMU treatment induced depressive-like behavior in mice. No motor deficits were observed. The brain homogenates had an increased content of caspase-9, while the levels of α-synuclein and tyrosine hydroxylase decreased. PMU increased the pro-inflammatory cytokines and altered the cellular permeability in cultured cells. The urease, but not the PmUreß, altered the morphology of α-synuclein aggregates in vitro, forming fragmented aggregates. We concluded that PMU promotes pro-inflammatory effects in cultured cells. In vivo, PMU induces neuroinflammation and a depressive-like phenotype compatible with the first stages of PD development.

Age-dependent memory impairment induced by co-exposure to nicotine and a synthetic cannabinoid in mice.

Co-use of marijuana and tobacco products is the second most common drug combination among adolescents. Nicotine (NIC) and cannabinoid use during adolescence induce similar detrimental changes, raising the hypothesis that simultaneous exposure could result in even more severe outcomes. Thus, we investigated whether the co-exposure to NIC and the synthetic cannabinoid WIN 55,212-2 (WIN) in adolescent mice causes behavioral outcomes different from those observed after exposure to a single drug. Male Swiss mice were exposed twice daily to NIC, WIN, or NIC + WIN during adolescence (PND28-47) or adulthood (PND70-89). Drug combination led to a greater reduction in weight gain in adolescent mice, while NIC-induced weight loss was observed in adults. During administration, NIC provoked hypothermia, and WIN produced hyperlocomotion in adolescent and adult mice. Animals exposed to NIC + WIN presented a profile of changes similar to those exposed to NIC. After drug exposure, changes in locomotion, thigmotaxis, social preference, prepulse inhibition, and working and recognition memory were evaluated. Adolescent but not adult mice exposed to NIC showed withdrawal-related hyperlocomotion unaffected by WIN co-administration. An age-specific impairment in object recognition memory was induced only by drug co-exposure during adolescence, which resolved spontaneously before reaching early adulthood. A transient decrease in hippocampal α7 nAChR subunit and CB1 receptor mRNA levels was induced by NIC exposure, which may be involved but is not enough to explain the memory impairment. Our work confirms the potential of NIC and cannabinoids association to aggravate some of the individual drug effects during critical neurodevelopmental periods.

Different outcomes of neonatal and adult Zika virus infection on startle reflex and prepulse inhibition in mice.

Zika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and cognitive impairments observed in ZIKV-infected patients. However, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes according to the age of infection and sex in mice: neonatally infected animals presented an increase in PPI and delayed startle latency. However, adult-infected male mice presented lower startle amplitude, while a PPI impairment was observed 14 days after infection in both sexes. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the startle reflex testing in ZIKV-exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.

Effect of saffron and fenugreek on lowering blood glucose: A systematic review with meta-analysis.

Saffron and fenugreek have been shown to have an effect on lowering blood glucose; therefore, this study aims to evaluate the effects of using saffron and fenugreek on blood glucose control. PubMed, Cochrane Library, Scopus, and Web of Science databases were searched for relevant articles. Articles on the use of saffron or fenugreek to control blood glucose were selected in compliance with PRISMA guidelines. R software was used for statistical analysis. The mean difference (MD) and the standardized MD (SMD) were adopted, and subgroup analyses were performed according to patient's clinical condition. Nineteen studies comprised this meta-analysis. Overall, using fenugreek decreased fasting blood glucose (FBG) (SMD: -0.90; 95%CI: -1.43 to -0.38; I2  = 87%; p < 0.001), postprandial blood glucose (PPBG) (SMD: -1.13; 95%CI: -1.99 to -0.28; I2  = 94%; p < 0.001), and glycated hemoglobin (HbA1c) (SMD: -0.43; 95%CI: -0.75 to -0.12; I2  = 20%; p = 0.29). Saffron supplementation reduced FBG (MD: -9.06 mg/dl; 95%CI: -16.25 to -1.86; I2  = 40%; p = 0.12) and HbA1c (MD: -0.19%; 95%CI: -0.23 to -0.14; I2  = 0%; p > 0.99). Our results show that using saffron and fenugreek can reduce FBG, PPBG, and HbA1c; however, there are some shortcomings that require attention for these results. Further high-quality studies should be conducted to establish the clinical efficacy of herbal medicines.

Alkylamides from Acmella oleracea: antinociceptive effect and molecular docking with cannabinoid and TRPV1 receptors.

Alkylamides are secondary metabolites in Acmella oleracea and display wide applications in treating several diseases. Since alkylamides can inhibit pain, this work aims to evaluate the antinociceptive profile of A. Oleracea methanolic extracts used in vivo and in silico assays. The extracts inhibited the neurogenic and inflammatory phases of the formalin test, ratifying the antinociceptive effect of alkylamides. Furthermore, the results from molecular docking demonstrated the interaction of A. oleracea alkylamides with the CB1/CB2 and TRPV1 receptors. Additionally, the crude methanolic extract of flowers did not induce potential side effects related to the classical cannabinoid tetrad: hypolocomotion and catalepsy. In conclusion, this work confirms the potential of the alkylamides of A. Oleracea as antinociceptive agents and, for the first time, correlates its effects with the endocannabinoid and vanilloid systems through in silico assays.

COVID-19 threatens faculty diversity: postdoctoral scholars call for action.

Despite substantial investment and effort by federal agencies and institutions to improve the diversity of the professoriate, progress is excruciatingly slow. One program that aims to enhance faculty diversity is the Institutional Research and Academic Career Development Award (IRACDA) funded by the National Institutes of Health/National Institute of General Medical Sciences. IRACDA supports the training of a diverse cohort of postdoctoral scholars who will seek academic research and teaching careers. The San Diego IRACDA program has trained 109 postdoctoral scholars since its inception in 2003; 59% are women and 63% are underrepresented (UR) Black/African-American, Latinx/Mexican-American, and Indigenous scientists. Sixty-four percent obtained tenure-track faculty positions, including a substantial 32% at research-intensive institutions. However, the COVID-19 pandemic crisis threatens to upend IRACDA efforts to improve faculty diversity, and academia is at risk of losing a generation of diverse, talented scholars. Here, a group of San Diego IRACDA postdoctoral scholars reflects on these issues and discusses recommendations to enhance the retention of UR scientists to avoid a "lost generation" of promising UR faculty scholars.

A polymeric approach toward resistance-resistant antimicrobial agent with dual-selective mechanisms of action.

Antibiotic resistance is now a major threat to human health, and one approach to combating this threat is to develop resistance-resistant antibiotics. Synthetic antimicrobial polymers are generally resistance resistant, having good activity with low resistance rates but usually with low therapeutic indices. Here, we report our solution to this problem by introducing dual-selective mechanisms of action to a short amidine-rich polymer, which can simultaneously disrupt bacterial membranes and bind to bacterial DNA. The oligoamidine shows unobservable resistance generation but high therapeutic indices against many bacterial types, such as ESKAPE strains and clinical isolates resistant to multiple drugs, including colistin. The oligomer exhibited excellent effectiveness in various model systems, killing extracellular or intracellular bacteria in the presence of mammalian cells, removing all bacteria from Caenorhabditis elegans, and rescuing mice with severe infections. This "dual mechanisms of action" approach may be a general strategy for future development of antimicrobial polymers.

Estudo da espessura labial com finalidade pericial ­ comparação entre autoavaliação e avaliação técnica / Study of lip thickness for expert purposes-comparison between self-assessment and technical assessment

O exame da espessura labial pode se apresentar como uma útil ferramenta orientadora da identificação humana. Neste sentido, este estudo teve como objetivo a avaliação de 200 imagens dos lábios superior e inferior de estudantes da área de saúde da Universidade Federal de Pernambuco, por 02 examinadores, a fim de verificar a concordância entre a avaliação técnica, realizada por eles, e a autoavaliação, realizada pelos examinados, quanto à espessura dos lábios. Para isso, cada examinado inicialmente, após recebimento de instruções e assinatura do TCLE, olhando para um espelho, classificou, sem experiência prévia, seus lábios em finos, médios, grossos ou mistos, segundo sua autoavaliação, o que consideramos como avaliação empírica. Em seguida, o vermelhão dos lábios foi fotografado, associado a uma régua ABFO nº2, e mensurado pelos dois examinadores. Os resultados demonstraram que a concordância inter-examinadores técnicos, quanto a indicação do tipo de lábios foi alta, se apresentando com um percentual de 98,5%. Em relação à concordância entre a avaliação técnica com a avaliação empírica, foram obtidos valores baixos, ou seja, apresentaram uma concordância pequena, com percentual de 35%. Segundo a avaliação técnica, os lábios grossos se apresentaram com maior porcentagem, 49,5%, contra 54% da autoavaliação. Na autoavaliação, o tipo mais destacado foi lábios médios (54%). Pode-se concluir que a concordância entre a avaliação técnica e a autoavaliação realizada por pessoa sem experiência (avaliação empírica), neste estudo, quanto ao exame dos tipos de lábio, foi pouco exitosa, em face da pequena coincidência observada, destacando a importância de se considerar seriamente o fato de que tais divergências podem ser altas também em situações onde informações são obtidas a partir de pessoas comuns.

Nonionic Surfactant Properties of Amphiphilic Hyperbranched Polyglycerols.

The surfactant properties of amphiphilic hyperbranched polyglycerols (HPGs) were investigated. The HPGs were prepared by ring-opening multibranching polymerization of glycidol using hydrophobic initiators of varying size and structure. The cloud points for all HPG surfactants were found to be >80 °C in deionized water with >1 wt % NaCl. The HPG surfactants with hydrophilic-lipophilic balance values between 16 and 18 were found to form stable octanol/water (o/w) emulsions within a 24 h period. Several surface properties, including critical micelle concentration (CMC), efficiency of surface tension reduction (pC20), effectiveness of surface tension reduction (γCMC), surface excess concentration at the CMC (Γmax), minimum area/molecule at the interface (Amin), and the CMC/C20 ratio of the HPG surfactants were measured in deionized water at 22.6 °C. In general, increasing HPG size was marked by an increase in minimum surface area per molecule (Amin) at the aqueous liquid/air interface. This increase in size also led to lower CMC and greater pC20 values of HPG surfactants prepared with Tergitol 15-S-7 initiator (HPG 5a-5d), a commercially available ethylene glycol oligomer with a branched hydrophobic tail.

Fluoteração das águas de abastecimento público no estado de Pernambuco: do estado da arte à vigilância da saúde bucal / Fluoridation of the waters of public supply in the state of Pernambuco: the state of the art and the vigilance of oral health / Fluoteración de aguas de suministro público en el estado de Pernambuco: del estado del arte a la vigilancia de la salud

A cárie dentária representa, em termos de saúde bucal, o principal agravo em saúde pública no Brasil, atingindo, ainda que de modo desigual, grande parte da população brasileira. O uso do flúor em saúde pública, sob a forma de fluoreto, é considerado o principal fator de proteção, decisivo para a obtenção de expressiva redução na prevalência da doença. A fluoretação das águas é considerada a principal medida para reduzir a prevalência da doença. Apesar da fluoretação ser obrigatória no Brasil desde 1974, várias cidades brasileiras não fluoretam suas águas. O objetivo deste estudo foi analisar teores de flúor nas águas de abastecimento público da 3ª macrorregião de saúde de Pernambuco, em municípios com 50.000 habitantes ou mais.Trata-se de uma pesquisa de estudo analítico transversal a partir da comparação obtida pelos dados primários do projeto VIGIFLÚOR e secundários disponibilizados pela COMPESA,Sistema de Informação de Vigilância da Qualidade da Água para Consumo Humano (SISÁGUA), do Instituto Brasileiro de Geografia e Estatística (IBGE) e do Sistema Nacional de Informação sobre Saneamento (SNIS). Foi observado a presença de flúor natural em teores significativos nos mananciais, porém essa concentração não chega na ponta da rede de abastecimento público. Este estudo reforça a necessidade de que a água de abastecimento dos municípios de Serra Talhada, Arcoverde e Buíque sejam fluoretados artificialmente e o seu controle de vigilância seja realizado por meio de programas de heterocontrole, para atingir seu benefício máximo para proteção da cárie e evitar o risco de causar fluorose. (AU)

The dental cavity representsen terms of oral health, the main lamafe in public health in Brazil, reacleing thongh in anunequal way, a great part of the Brazilian population. The use offl uorine in public health under the formof fluorideis considered the major factor of protection, decisive for the attainmentofan expressive reduction in theprevalenceofthedisease. Al though fluoridation has heen compulsory since 1974 in Brazil, several Brazilian town sdon't fluoridate their waters as is the case of the muncipality in the state of Pernambuco. The ainofthis study was to analyze the proportion off luoride in the waters of public supply of the third health macroregion of Pernambuco, in towns with 50.000 in habitants more. It refersto a researdeof a crossan alyticalstudy from the comparison obtained by the secondary data forwarded by" COMPESA", by the primary data of the project " VIGIFLÚOR", system of information of vigilance of the water quality for human consume (SISÁGUA), data of the Brazilian Institute of Geograph and Statistics (IBGE) andthenational system of information about samitation (SNIS). It wasobservedthepresenceof natural fluoride in a meaningfulproportion in thefountain'tget to thetipof the net of publicheads, butthisconcentrationdoesn'tsupply. This study high lights the need for the water supply of thet owns of Serra Talhada, Arcoverde and Buíque to be fluoridated artificially and the ircontrol of vigilance to be carried out byprogramsofheterocontrol in ordertoreachtheirmaximumbenefits for theprotectionagainstcavities anda theriskofcausingfluorosis. (AU)

La caries dental representa, en términos de salud bucal, el principal problema de salud pública en Brasil, que afecta, aunque de manera desigual, a una gran parte de lapoblación brasileña. El uso de flúor enlasalud pública en forma de flúor se considera el principal factor de protección, decisivo para obtener una reducción significativa enla prevalencia de laenfermedad. La fluoracióndel agua se considera la medida principal para reducirla prevalencia de laenfermedad. Aunquelafluoraciónha sido obligatoriaen Brasil desde 1974, variasciudadesbrasileñas no hanfluorizado sus aguas. El objetivo de este estudiofueanalizarelcontenido de fluoruroenelsuministro público de agua de la 3ra macro región sanitaria de Pernambuco, enmunicipios con 50,000 habitantes o más. Este es unestudio analítico transversal basadoen una comparación de datosprimariosdelproyecto VIGIFLÚOR y datossecundarios proporcionados por COMPESA, el Sistema de Informaciónde Vigilancia de la Calidad del Agua para el Consumo Humano (SISÁGUA) del Instituto Brasileño de Geografía y Estadística. (IBGE) y el Sistema Nacional de Información sobre Saneamiento (SNIS). Se observóla presencia de fluoruro natural en niveles significativos enlosmanantiales, pero esta concentración no llega al final de lared de suministro público. Este estudiorefuerzalanecesidad de unsuministro de agua fluorada artificialmente enlosmunicipios de Serra Talhada, Arcoverde y Buíque y sucontrol de vigilancia se llevará a cabo a través de programas de heterocontrol para lograr su máximo beneficio para laprotección de la caries y prevenir riesgo de causar fluorosis. (AU)

The Global Burden of Disease Study Estimates of Brazil's Cervical Cancer Burden.

Background: Cervical cancer represents an important preventable cause of morbidity and mortality in developing countries such as Brazil. Investigating temporal evolution of a disease burden in the different realities of the country is essential for improving public policies. Objective: To describe the national and subnational burden of cervical cancer, based on the estimates of the 2017 Global Burden of Disease study. Methods: Descriptive study of premature mortality (years of life lost [YLL]) and burden of disease (disability-adjusted life years [DALYs]) associated with cervical cancer among Brazilian women aged 25-64 years, between 2000 and 2017. Findings: During the study period, age-standardized incidence decreased from 23.53 (22.79-24.26) to 18.39 (17.63-19.17) per 100,000 women, while mortality rates decreased from 11.3 (11.05-11.56) to 7.74 (7.49-8.02) per 100,000 women. These rates were about two to three times greater than equivalent rates in a developed country, such as England: 11.98 (11.45-12.55) to 10.37 (9.85-10.9), and 3.75 (3.68-3.84) to 2.82 (2.75-2.9) per 100,000 women, respectively. Poorer regions of Brazil had greater rates of the disease; for instance, Amapá State in the Northern Region had rates twice as high as the national rates during the same period. Cervical cancer was the leading cause of premature cancer-related mortality (YLL = 100.69, 91.48-110.61 per 100,000 women) among young women (25-29 years) in Brazil and eight federation units of all country regions except the Southeast in 2017. There was a decrease in the burden of cervical cancer in Brazil from 339.59 (330.82-348.83) DALYs per 100,000 women in 2000 to 238.99 (230.45-247.99) DALYs per 100,000 women in 2017. Conclusion: Although there has been a reduction in the burden of cervical cancer in Brazil, the rates remain high, mainly among young women. The persistence of inequalities between regions of Brazil suggests the importance of socioeconomic determinants in the burden for this cancer.

Engineering the Surface of Therapeutic "Living" Cells.

Biological cells are complex living machines that have garnered significant attention for their potential to serve as a new generation of therapeutic and delivery agents. Because of their secretion, differentiation, and homing activities, therapeutic cells have tremendous potential to treat or even cure various diseases and injuries that have defied conventional therapeutic strategies. Therapeutic cells can be systemically or locally transplanted. In addition, with their ability to express receptors that bind specific tissue markers, cells are being studied as nano- or microsized drug carriers capable of targeted transport. Depending on the therapeutic targets, these cells may be clustered to promote intercellular adhesion. Despite some impressive results with preclinical studies, there remain several obstacles to their broader development, such as a limited ability to control their transport, engraftment, secretion and to track them in vivo. Additionally, creating a particular spatial organization of therapeutic cells remains difficult. Efforts have recently emerged to resolve these challenges by engineering cell surfaces with a myriad of bioactive molecules, nanoparticles, and microparticles that, in turn, improve the therapeutic efficacy of cells. This review article assesses the various technologies developed to engineer the cell surfaces. The review ends with future considerations that should be taken into account to further advance the quality of cell surface engineering.

Patterning Three-Dimensional Hydrogel Microenvironments Using Hyperbranched Polyglycerols for Independent Control of Mesh Size and Stiffness.

The extracellular matrix is an environment rich with structural, mechanical, and molecular signals that can impact cell biology. Traditional approaches in hydrogel biomaterial design often rely on modifying the concentration of cross-linking groups to adjust mechanical properties. However, this strategy provides limited capacity to control additional important parameters in 3D cell culture such as microstructure and molecular diffusivity. Here we describe the use of multifunctional hyperbranched polyglycerols (HPGs) to manipulate the mechanical properties of polyethylene glycol (PEG) hydrogels while not altering biomolecule diffusion. This strategy also provides the ability to separately regulate spatial and temporal distribution of biomolecules tethered within the hydrogel. The functionalized HPGs used here can also react through a copper-free click chemistry, allowing for the encapsulation of cells and covalently tethered biomolecules within the hydrogel. Because of the hyperbranched architecture and unique properties of HPGs, their addition into PEG hydrogels affords opportunities to locally alter hydrogel cross-linking density with minimal effects on global network architecture. Additionally, photocoupling chemistry allows micropatterning of bioactive cues within the three-dimensional gel structure. This approach therefore enables us to tailor mechanical and diffusive properties independently while further allowing for local modulation of biomolecular cues to create increasingly complex cell culture microenvironments.

Worm-Like Superparamagnetic Nanoparticle Clusters for Enhanced Adhesion and Magnetic Resonance Relaxivity.

Nanosized bioprobes that can highlight diseased tissue can be powerful diagnostic tools. However, a major unmet need is a tool with adequate adhesive properties and contrast-to-dose ratio. To this end, this study demonstrates that targeted superparamagnetic nanoprobes engineered to present a worm-like shape and hydrophilic packaging enhance both adhesion efficiency to target substrates and magnetic resonance (MR) sensitivity. These nanoprobes were prepared by the controlled self-assembly of superparamagnetic iron oxide nanoparticles (SPIONs) into worm-like superstructures using glycogen-like amphiphilic hyperbranched polyglycerols functionalized with peptides capable of binding to defective vasculature. The resulting worm-like SPION clusters presented binding affinity to the target substrate 10-fold higher than that of spherical ones and T2 molar MR relaxivity 3.5-fold higher than that of conventional, single SPIONs. The design principles discovered for these nanoprobes should be applicable to a range of other diseases where improved diagnostics are needed.

New frontiers for encapsulation in the chemical industry.

Encapsulation of actives comprises an area of exploration undergoing rapid growth in both academic and industrial research settings. Encapsulation processes are employed as a part of product synthesis processes for improved efficiency, enhanced stability, active ingredient compatibility, increased safety, targeted delivery, and novel performance of the end product. Such technical benefits enable producers to offer products with increased formulation complexity, access new markets, differentiate products, and improve compatibility and stability, while meeting consumer demands with improved performance, reduced costs, and new actives. In this review, we highlight several emerging academic areas of encapsulation that we believe have specific relevance to industrial formulation, with a focus on three primary areas: supramolecular encapsulation, aqueous self-assembled systems, and emulsion-based capsules. The goal of this review is to help identify the major challenges facing encapsulation technology adoption in the chemical industry, bringing focus and maximizing the potential value of ongoing research efforts.