Tumor versus Tumor Cell Targeting in Metal-Based Nanoparticles for Cancer Theranostics.

The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of "tumor targeting" and "tumor cell targeting" are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where 'smart design' refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.

Changes in Breastfeeding and Related Maternity Care Practices After Hurricanes Irma and Maria in Puerto Rico.

Background: Breastfeeding is recommended globally for most infants, especially during and after natural disasters when risk of adverse outcomes increases because of unsanitary conditions and lack of potable water. Materials and Methods: Using 2017-2019 data from Puerto Rico's Pregnancy Risk Assessment Monitoring System for 2,448 respondents with a recent live birth, we classified respondents into 4 hurricane exposure time periods based on infant birth month and year relative to when Hurricanes Irma and Maria occurred: (1) prehurricane; (2) acute hurricane; (3) posthurricane, early recovery; and (4) posthurricane, long-term recovery. We examined the association between maternity care practices during delivery hospitalization and exclusive breastfeeding at 3 months overall and stratified by time period. We also examined the associations between each maternity care practice and exclusive breastfeeding separately by time period. Results: Exclusive breastfeeding at 3 months was higher during the acute hurricane time period (adjusted prevalence ratio [aPR]: 1.43, 95% confidence interval: 1.09-1.87) than the prehurricane time period. Supportive maternity care practices were positively associated with exclusively breastfeeding, and practices that are risk factors for discontinuing breastfeeding were negatively associated with exclusive breastfeeding. Breastfeeding in the first hour (aPR range: 1.51-1.92) and rooming-in (aPR range: 1.50-2.58) were positively associated with exclusive breastfeeding across all time periods, except the prehurricane time period. Receipt of a gift pack with formula was negatively associated with exclusive breastfeeding (aPR range: 0.22-0.54) across all time periods. Conclusions: Maternity care practices during delivery hospitalization may influence breastfeeding behaviors and can improve breastfeeding during and after natural disasters. Strategies to maintain and improve these practices can be further supported during and after natural disasters.

Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.

Inflammatory Bowel Diseases (IBD) are a group of chronic, inflammatory disorders of the gut. The incidence and activity of IBD are determined by both genetic and environmental factors. Among these factors, polymorphisms in genes related to autophagy and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have been consistently associated with IBD. We show that NSAIDs induce mitochondrial stress and mitophagy in intestinal epithelial cells. In an altered mitophagy context simulating that observed in IBD patients, NSAID-induced mitochondrial stress leads to the release of mitochondrial components, which act as Danger Associated Molecular Patterns with pro-inflammatory potential. Furthermore, colonic organoids from Crohn's disease patients and healthy donors show activation of the mitochondrial Unfolded Protein Response (UPRmt) upon treatment with ibuprofen. Finally, colon biopsies from Crohn's disease patients in remission or with low-to-moderate activity also show expression of genes involved in UPRmt, while patients with severe activity show no increase compared to healthy donors. Our results suggest the involvement of mitochondria in the mechanisms triggering inflammation in IBD after NSAID use. Moreover, our results highlight the clinical relevance of mitochondrial stress and activation of the UPRmt pathway in the pathophysiology of Crohn's disease.

New insights in the targets of action of dimethyl fumarate in endothelial cells: effects on energetic metabolism and serine synthesis in vitro and in vivo.

Dimethyl fumarate is an ester from the Krebs cycle intermediate fumarate. This drug is approved and currently used for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity was reported some years ago. Due to the current clinical relevance of this compound and the recently manifested importance of endothelial cell metabolism on the angiogenic switch, we wanted to elucidate whether dimethyl fumarate has an effect on energetic metabolism of endothelial cells. Different experimental approximations were performed in endothelial cells, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration in endothelial cells, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in these cells. Dimethyl fumarate alters the energetic metabolism of endothelial cells in vitro and in vivo through an unknown mechanism, which could be the cause or the consequence of its pharmacological activity. This new discovery on the targets of this compound could open a new field of study regarding the mechanism of action of dimethyl fumarate.

Inhibition of Endothelial Inflammatory Response by HT-C6, a Hydroxytyrosol Alkyl Ether Derivative.

Hydroxytyrosol (HT) is a bioactive phenolic compound naturally present in olives and extra virgin olive oil (EVOO) which is described as an antioxidant, antitumoral and antiangiogenic molecule. Previous studies of semi-synthetic HT-derivatives presented the hydroxytyrosyl alkyl ether HT-C6 as one of the most potent derivatives studied in the context of antioxidant, anti-platelet and antiangiogenic assays, but its direct effect on inflammation was not reported. In this work, we use RT-qPCR measure of gene expression, protein analysis by Western-blot and immunofluorescence techniques, adhesion and migration functional assays and single-cell monitoring of reactive oxygen species (ROS) in order to explore in vitro the ability of HT-C6 to interfere in the inflammatory response of endothelial cells (ECs). Our results showed that HT-C6 strongly reduces the TNF-α-induced expression of vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule 1 (ICAM1), E-selectin (SELE), C-C motif chemokine ligand 2 and 5 (CCL2 and CCL5) in HUVECs, impairing the chemotactic and adhesion potential of these cells towards THP-1 monocytes in vitro. In this work, we define a mechanism of action underlying the anti-inflammatory effect of HT-C6, which involves the abrogation of nuclear factor kappa B (NF-κB) pathway activation in ECs. These results, together with the ability of HT-C6 to reduce ROS formation in ECs, point to this compound as a promising HT-derivative to be tested in the treatment of atherosclerosis.

The time course of acclimation of critical thermal maxima is modulated by the magnitude of temperature change and thermal daily fluctuations.

Plasticity in the critical thermal maximum (CTmax) helps ectotherms survive in variable thermal conditions. Yet, little is known about the environmental mechanisms modulating its time course. We used the larvae of three neotropical anurans (Boana platanera, Engystomops pustulosus and Rhinella horribilis) to test whether the magnitude of temperature changes and the existence of fluctuations in the thermal environment affected both the amount of change in CTmax and its acclimation rate (i.e., its time course). For that, we transferred tadpoles from a pre-treatment temperature (23 °C, constant) to two different water temperatures: mean (28 °C) and hot (33 °C), crossed with constant and daily fluctuating thermal regimes, and recorded CTmax values, daily during six days. We modeled changes in CTmax as an asymptotic function of time, temperature, and the daily thermal fluctuation. The fitted function provided the asymptotic CTmax value (CTmax∞) and CTmax acclimation rate (k). Tadpoles achieved their CTmax∞ between one and three days. Transferring tadpoles to the hot treatment generated higher CTmax∞ at earlier times, inducing faster acclimation rates in tadpoles. In contrast, thermal fluctuations equally led to higher CTmax∞ values but tadpoles required longer times to achieve CTmax∞ (i.e., slower acclimation rates). These thermal treatments interacted differently with the studied species. In general, the thermal generalist Rhinella horribilis showed the most plastic acclimation rates whereas the ephemeral-pond breeder Engystomops pustulosus, more exposed to heat peaks during larval development, showed less plastic (i.e., canalized) acclimation rates. Further comparative studies of the time course of CTmax acclimation should help to disentangle the complex interplay between the thermal environment and species ecology, to understand how tadpoles acclimate to heat stress.

Ancient DNA suggests anaemia and low bone mineral density as the cause for porotic hyperostosis in ancient individuals.

Porotic hyperostosis (PH) is a disease that had high prevalence during the Neolithic. Several hypotheses have been suggested to explain the origin of the disease, such as an iron deficiency diet, low B12 intake, malaria caused by Plasmodium spp., low haemoglobin levels or low vitamin D levels. None of these hypotheses have been tested genetically. Here, I calculated different genetic scores to test each hypothesis. Additionally, I calculated a genetic score of bone mineral density as it is a phenotype that seems to be selected in ancient Europeans. I apply these genetic scores on 80 ancient samples, 33 with diagnosed PH. The results seem to suggest anaemia and low bone mineral density as the main cause for this disease. Additionally, Neolithic individuals show the lowest genetic risk score for bone mineral density of all other periods tested here, which may explain the highest prevalence of the porotic hyperostosis during this age.

Pregnant Women's Experiences During and After Hurricanes Irma and Maria, Pregnancy Risk Assessment Monitoring System, Puerto Rico, 2018.

OBJECTIVE: Exposure to natural disasters during and after pregnancy may increase adverse mental health outcomes. Hurricanes Irma and Maria struck Puerto Rico in September 2017. Our objectives were to understand hurricane-related experiences, maternal health concerns, and the impact of hurricane experiences on postpartum depressive symptoms (PDS). METHODS: We used data from the 2018 Pregnancy Risk Assessment Monitoring System to describe differences in maternal hurricane experiences among women who were pregnant during and after the 2017 hurricanes. We assessed maternal concerns and PDS. We estimated adjusted prevalence ratios (aPRs) and 95% CIs for the associations between hurricane experiences and PDS. RESULTS: The most frequently reported hurricane experiences were losing power for ≥1 week (97%) and feeling unsafe due to lack of order/security (70%). Almost 30% of women who were pregnant during the hurricanes reported missing prenatal care. PDS were reported by 13% of women. Most hurricane experiences were associated with an increased prevalence of PDS. Feeling unsafe (aPR = 2.4; 95% CI, 1.2-4.9) and having difficulty getting food (aPR = 2.1; 95% CI, 1.1-4.1) had the strongest associations. CONCLUSIONS: Most women who were pregnant during or after hurricanes Irma and Maria struck Puerto Rico reported negative hurricane experiences, and most experiences were associated with an increased prevalence of PDS. Understanding the experiences of pregnant women during and after disasters and identifying risks for adverse mental health outcomes after pregnancy are important to inform emergency preparedness and prenatal and postpartum care.

Infant Receipt of Health Care Services during the 2016-2017 Zika Virus Outbreak in Puerto Rico.

OBJECTIVE: To assess the receipt of health care services among live-born infants of women with and without evidence of Zika virus (ZIKV) infection while pregnant during the 2016-2017 ZIKV outbreak in Puerto Rico. METHODS: We used data from the Pregnancy Risk Assessment Monitoring System-Zika Postpartum Emergency Response study telephone surveys to examine maternal reports of the receipt of health care services by infants born in Puerto Rico from August through December 2016 and November through December 2017. Evidence of ZIKV infection was ascertained from the infant's birth certificate or was self-reported in the survey. RESULTS: Fourteen percent of women in 2016 and 9% in 2017 had evidence of ZIKV infection during pregnancy. Most infants of women with evidence of ZIKV received the recommended health care services in 2016 and 2017, respectively, including a hearing test (91% vs. 92%), developmental assessment (90% vs. 92%), and an eye exam (74% vs. 70%); fewer received a head scan (45% vs. 36%) and evaluation for physical therapy (17% vs. 10%). From 2016 to 2017, the proportion of infants having a personal doctor increased for all infants; for infants of women without evidence of ZIKV infection, receiving hearing, developmental, and eye assessments increased. CONCLUSION: Most infants of women with evidence of ZIKV infection during pregnancy received the recommended hearing and developmental assessments during the ZIKV outbreak. Experiences with increasing service capacity during the ZIKV outbreak can be evaluated to inform the response to future emergencies that affect maternal and child health.

The Sponge-Derived Brominated Compound Aeroplysinin-1 Impairs the Endothelial Inflammatory Response through Inhibition of the NF-κB Pathway.

(+)-Aeroplysinin-1 (Apl-1) is a brominated compound isolated from the marine sponge Aplysina aerophoba that exhibits pleiotropic bioactive effects, impairing cell growth in cancer cells, inhibiting angiogenesis in vitro and in vivo and modulating the redox status of different cell types, among other reported activities. In addition to the aforementioned effects, the anti-inflammatory potential of this natural compound was explored in previous work of our laboratory, but the mechanism of action underlying this effect was not described. In this work, we delve into the anti-inflammatory effect of Apl-1 in the context of vascular endothelial cells in vitro, providing new data regarding the molecular mechanism underlying this activity. The characterization of the mechanism of action points to an inhibitory effect of Apl-1 on the NF-κB pathway, one of the main axes involved in endothelial response during inflammatory events. Our results show that Apl-1 can inhibit the expression of pro-inflammatory genes in tumor necrosis factor alpha (TNF-α)- and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), targeting the nuclear factor kappa B subunit (NF-κB) pathway through a mechanism of action involving the inhibition of I kappa B kinase (IKK) complex phosphorylation and RelA/p65 nuclear import. In addition, Apl-1 prevented the phosphorylation of Akt induced by TNF-α in HUVECs, probably supporting the inhibitory effect of this compound in the NF-κB pathway. Experimental evidence reported in this work opens the door to the potential pharmacological use of this compound as an anti-inflammatory agent in diseases that course with a pathological endothelial response to inflammation, such as atherosclerosis.

Look-alike humans identified by facial recognition algorithms show genetic similarities.

The human face is one of the most visible features of our unique identity as individuals. Interestingly, monozygotic twins share almost identical facial traits and the same DNA sequence but could exhibit differences in other biometrical parameters. The expansion of the world wide web and the possibility to exchange pictures of humans across the planet has increased the number of people identified online as virtual twins or doubles that are not family related. Herein, we have characterized in detail a set of "look-alike" humans, defined by facial recognition algorithms, for their multiomics landscape. We report that these individuals share similar genotypes and differ in their DNA methylation and microbiome landscape. These results not only provide insights about the genetics that determine our face but also might have implications for the establishment of other human anthropometric properties and even personality characteristics.

The effect of thermal microenvironment in upper thermal tolerance plasticity in tropical tadpoles. Implications for vulnerability to climate warming.

Current climate change is generating accelerated increase in extreme heat events and organismal plastic adjustments in upper thermal tolerances, (critical thermal maximum -CTmax ) are recognized as the quicker mitigating mechanisms. However, current research casts doubt on the actual mitigating role of thermal acclimation to face heat impacts, due to its low magnitude and weak environmental signal. Here, we examined these drawbacks by first estimating maximum extent of thermal acclimation by examining known sources of variation affecting CTmax expression, such as daily thermal fluctuation and heating rates. Second, we examined whether the magnitude and pattern of CTmax plasticity is dependent of the thermal environment by comparing the acclimation responses of six species of tropical amphibian tadpoles inhabiting thermally contrasting open and shade habitats and, finally, estimating their warming tolerances (WT = CTmax - maximum temperatures) as estimator of heating risk. We found that plastic CTmax responses are improved in tadpoles exposed to fluctuating daily regimens. Slow heating rates implying longer duration assays determined a contrasting pattern in CTmax plastic expression, depending on species environment. Shade habitat species suffer a decline in CTmax whereas open habitat tadpoles greatly increase it, suggesting an adaptive differential ability of hot exposed species to quick hardening adjustments. Open habitat tadpoles although overall acclimate more than shade habitat species, cannot capitalize this beneficial increase in CTmax, because the maximum ambient temperatures are very close to their critical limits, and this increase may not be large enough to reduce acute heat stress under the ongoing global warming.

Rapid Population-Based Surveillance of Prenatal and Postpartum Experiences During Public Health Emergencies, Puerto Rico, 2016‒2018.

The Pregnancy Risk Assessment Monitoring System-Zika Postpartum Emergency Response study, implemented in Puerto Rico during the Zika virus outbreak (2016-2017) and after Hurricanes Irma and María (2017-2018), collected pregnancy-related data using postpartum hospital-based surveys and telephone follow-up surveys. Response rates of 75% or more were observed across five study surveys. The study informed programs, increased the Puerto Rico Department of Health's capacity to conduct maternal‒infant health surveillance, and demonstrated the effectiveness of this methodology for collecting data during public health emergencies. (Am J Public Health. 2022;112(4):574-578. https://doi.org/10.2105/AJPH.2021.306687).

Phenotypic and genomic diversification with isolation by environment along elevational gradients in a neotropical treefrog.

Understanding how geographic and environmental heterogeneity drive local patterns of genetic variation is a major goal of ecological genomics and a key question in evolutionary biology. The tropical Andes and inter-Andean valleys are shaped by markedly heterogeneous landscapes, where species experience strong selective processes. We examined genome-wide SNP data together with behavioural and ecological traits (mating calls and body size) known to contribute to genetic isolation in anurans in the banana tree-dwelling frog, Boana platanera, distributed across an environmental gradient in Central Colombia (northern South America). Here, we analysed the relationships between environmentally (temperature and precipitation) associated genetic and phenotypic differentiation and the potential drivers of isolation by environment along an elevation gradient. We identified candidate SNPs associated with temperature and body size, which follow a clinal pattern of genome-wide differentiation tightly coupled with phenotypic variation: as elevation increases, B. platanera exhibits larger body size and longer call duration with more pulses but lower pulse rate and frequency. Thus, the environmental landscape has rendered a scenario where isolation by environment and candidate loci show concordance with phenotypic divergence in this tropical frog along an elevation gradient in the Colombian Andes. Our study sets the basis for evaluating the role of temperature in the genetic structure and local adaptation in tropical treefrogs and its putative effect on life cycle (embryos, tadpoles, adults) along elevation gradients.

Opportunities to Address Men's Health During the Perinatal Period - Puerto Rico, 2017.

Decreased use of health care services (1), increased exposure to occupational hazards, and higher rates of substance use (2) might contribute to men's poorer health outcomes when compared with such outcomes for women (3). During the transition to fatherhood, paternal health and involvement during pregnancy might have an impact on maternal and infant outcomes (4-6). To assess men's health-related behaviors and participation in fatherhood-related activities surrounding pregnancy, the Puerto Rico Department of Health and CDC analyzed data from the paternal survey of the Pregnancy Risk Assessment Monitoring System-Zika Postpartum Emergency Response (PRAMS-ZPER)* study. Fewer than one half (48.3%) of men attended a health care visit for themselves in the 12 months before their newborn's birth. However, most fathers attended one or more prenatal care visits (87.2%), were present at the birth (83.1%), and helped prepare for the newborn's arrival (e.g., by preparing the home [92.4%] or purchasing supplies [93.9%]). These findings suggest that opportunities are available for public health messaging directed toward fathers during the perinatal period to increase attention to their own health and health behaviors, and to emphasize the role they can play in supporting their families' overall health and well-being.

Preventing Vector-Borne Transmission of Zika Virus Infection During Pregnancy, Puerto Rico, USA, 2016-20171.

We examined pregnant women's use of personal protective measures to prevent mosquito bites during the 2016-2017 Zika outbreak in Puerto Rico. Healthcare provider counseling on recommended measures was associated with increased use of insect repellent among pregnant women but not with wearing protective clothing.

The advertisement call of the Colombian endemic glassfrog Rulyrana susatamai (Anura: Centrolenidae).

Anuran calls are conspicuous, diverse and subject to sexual selection. Many types of calls are described, but the most commonly studied is the advertisement call (Wells 2007; Toledo et al. 2014). Advertisement calls in anurans are emitted by males and some females (Toledo et al. 2014), and have the function of attracting conspecific mates and repelling male competitors. Because the advertisement calls of many species differ by such a magnitude that they serve as premating species (Heyer et al. 1996), it has been demonstrated that advertisement calls play an important role in species recognition, reproductive isolation, and may reflect evolutionary relations among taxa (Wells 2007; Escalona et al. 2018).

Toxinological characterization of venom from Leptodeira annulata (Banded cat-eyed snake; Dipsadidae, Imantodini).

We investigated the histology of Duvernoy's venom gland and the biochemical and biological activities of Leptodeira annulata snake venom. The venom gland had a lobular organization, with secretory tubules formed by serous epithelial cells surrounding each lobular duct. The latter drained into a common lobular duct and subsequently into a central cistern. In contrast, the supralabial gland was mucous in nature. SDS-PAGE revealed a profile of venom components that differed from pitviper (Bothrops spp.) venoms. RP-HPLC also revealed greater complexity of this venom compared to Bothrops venoms. The venom had no esterase, l-amino acid oxidase or thrombin-like activity, but was proteolytic towards elastin-Congo red, fibrin, fibrinogen, gelatin and hide powder azure. The venom showed strong α-fibrinogenase and fibrinolytic activities and reduced the rate and extent of plasma recalcification. The proteolytic activity was inhibited by EDTA and 1,10-phenanthroline (metalloproteinase inhibitors) but not by AEBSF and PMSF (serine proteinase inhibitors). The venom had phospholipase A2 (PLA2) activity that was inhibited by varespladib. The venom cross-reacted with antivenoms to lancehead (Bothrops spp.), coralsnake (Micrurus spp.) and rattlesnake (Crotalus durissus terrificus) venoms. The venom did not aggregate rat platelets or inhibit collagen-induced aggregation, but partially inhibited thrombin-induced aggregation. The venom was hemorrhagic (inhibited by EDTA) and increased the vascular permeability (inhibited by varespladib) in rat dorsal skin. In gastrocnemius muscle, the venom caused myonecrosis and increased serum creatine kinase concentrations. In conclusion, L. annulata venom has various enzymatic and biological activities, with the local effects being mediated primarily by metalloproteinases and PLA2.

Mapping co-ancestry connections between the genome of a Medieval individual and modern Europeans.

Historical genetic links among similar populations can be difficult to establish. Identity by descent (IBD) analyses find genomic blocks that represent direct genealogical relationships among individuals. However, this method has rarely been applied to ancient genomes because IBD stretches are progressively fragmented by recombination and thus not recognizable after few tens of generations. To explore such genealogical relationships, we estimated long IBD blocks among modern Europeans, generating networks to uncover the genetic structures. We found that Basques, Sardinians, Icelanders and Orcadians form, each of them, highly intraconnected sub-clusters in a European network, indicating dense genealogical links within small, isolated populations. We also exposed individual genealogical links -such as the connection between one Basque and one Icelandic individual- that cannot be uncovered with other, widely used population genetics methods such as PCA or ADMIXTURE. Moreover, using ancient DNA technology we sequenced a Late Medieval individual (Barcelona, Spain) to high genomic coverage and identified IBD blocks shared between her and modern Europeans. The Medieval IBD blocks are statistically overrepresented only in modern Spaniards, which is the geographically closest population. This approach can be used to produce a fine-scale reflection of shared ancestry across different populations of the world, offering a direct genetic link from the past to the present.

Differential DNA methylation of vocal and facial anatomy genes in modern humans.

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-associated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.