A Preliminary Investigation of Prenatal Anxiety Sensitivity and Postpartum Distress.

INTRODUCTION: Distress during pregnancy and postpartum is common and contributes to poor infant and maternal outcomes, such as developmental delays and mental health disorders, respectively. Anxiety sensitivity, or fear of the symptoms of anxiety (eg, palpitations, confusion), is a risk factor known to increase distress across psychological and health-related conditions. Given the physiologic and emotional changes that occur during the perinatal period, anxiety sensitivity may be a salient risk factor for maternal distress. In this pilot study, we aimed to understand the unique role of prenatal anxiety sensitivity in postpartum psychological and parenting distress. METHODS: Twenty-eight pregnant women (mean age, 30.86 years) were recruited from the community in a Southeastern metropolitan area of the United States. Participants completed self-report measures during their third trimester of pregnancy and again within 10 weeks postpartum. The Depression Anxiety and Stress Scales-21 and the Parenting Distress subscale of the Parenting Stress Index-4-Short Form were the primary postpartum outcome measures. RESULTS: Prenatal anxiety sensitivity was elevated in this sample relative to convenience samples. Prenatal anxiety sensitivity uniquely contributed to postpartum psychological (b, 1.01; P < .001) and parenting distress (b, 0.62; P = .008), after accounting for age, gravidity, and gestation. DISCUSSION: Albeit preliminary, results suggest prenatal anxiety sensitivity may be an important and malleable risk factor associated with several mental health concerns common in the perinatal period. Anxiety sensitivity may be targeted with brief interventions to prevent or reduce postpartum distress. Reducing prenatal anxiety sensitivity has the potential prevent the onset or worsening of psychological disorders among women and, in turn, may improve infant and child outcomes. Future studies should replicate these findings in a larger sample.

S9.6-based hybrid capture immunoassay for pathogen detection.

The detection of pathogens is critical for clinical diagnosis and public health surveillance. Detection is usually done with nucleic acid-based tests (NATs) and rapid antigen tests (e.g., lateral flow assays [LFAs]). Although NATs are more sensitive and specific, their use is often limited in resource-poor settings due to specialized requirements. To address this limitation, we developed a rapid DNA-RNA Hybrid Capture immunoassay (HC) that specifically detects RNA from pathogens. This assay utilizes a unique monoclonal antibody, S9.6, which binds DNA-RNA hybrids. Biotinylated single-stranded DNA probes are hybridized to target RNAs, followed by hybrid capture on streptavidin and detection with S9.6. The HC-ELISA assay can detect as few as 104 RNA molecules that are 2.2 kb in length. We also adapted this assay into a LFA format, where captured Bacillus anthracis rpoB RNA of 3.5 kb length was detectable from a bacterial load equivalent to 107 CFU per 100 mg of mouse tissue using either HC-ELISA or HC-LFA. Importantly, we also demonstrated the versatility of HC by detecting other pathogens, including SARS-CoV-2 and Toxoplasma gondii, showing its potential for broad pathogen detection. Notably, HC does not require amplification of the target nucleic acid and utilizes economical formats like ELISA and LFA, making it suitable for use in sentinel labs for pathogen detection or as a molecular tool in basic research laboratories. Our study highlights the potential of HC as a sensitive and versatile method for RNA-based pathogen detection.

Isolation and Immunodetection of Enzymatic DNA-Protein Crosslinks by RADAR Assay.

DNA-protein crosslinks (DPCs) are steric hindrances to DNA metabolic processes and the removal and repair of DPCs is a rapidly evolving area of research. A critical component of deciphering this repair pathway is developing techniques that detect and quantify specific types of DPCs in cells. Here we describe a protocol for direct detection of enzymatic DPCs from mammalian cells-the RADAR assay. The method involves isolating genomic DNA and DPCs from cells and binding them to nitrocellulose membrane with a vacuum slot blot manifold. DPCs are detected using antibodies raised against the protein of interest and quantified by normalizing to a DNA loading control. The RADAR assay allows for the detection of specific types of DPCs and the sensitive analysis of the DNA-protein crosslinking activity of various drugs, is adaptable across different cell types and conditions, and requires little specialized equipment.

USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma.

In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most EWS, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress. The mechanism by which EWS cells override activation of apoptosis or cellular senescence in response to increased replication stress is not known. We show that USP1 is overexpressed in EWS and EWS::FLI1 regulates USP1 transcript levels. USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. Mechanistically, USP1 regulates Survivin (BIRC5/API4) protein stability and the activation of caspase-9 and caspase-3/7 in response to endogenous replication stress. Notably, USP1 inhibition sensitizes cells to doxorubicin and etoposide treatment. Together, our study demonstrates that USP1 is regulated by EWS::FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes cells to standard of care chemotherapy. IMPLICATIONS: High USP1 and replication stress levels driven by EWS::FLI1 transcription factor in EWS are vulnerabilities that can be exploited to improve existing treatment avenues and overcome drug resistance.

S9.6 Antibody-Enzyme Conjugates for the Detection of DNA-RNA Hybrids.

Diagnosis of infectious agents is increasingly done by the detection of unique nucleic acid sequences, typically using methods such as PCR that specifically amplify these sequences. A largely neglected alternative approach is to use antibodies that recognize nucleic acids. The unique monoclonal antibody S9.6 recognizes DNA-RNA hybrids in a largely sequence-independent manner. S9.6 has been used in several cases for the analysis of nucleic acids. Extending our recent determination of the structure of S9.6 Fab bound to a DNA-RNA hybrid, we have developed reagents and methods for the sensitive detection of specific DNA and RNA sequences. To facilitate the use in diagnostics, we conjugated the S9.6 Fab to the highly active and well-characterized reporter enzyme human-secreted embryonic alkaline phosphatase (SEAP). Two approaches were utilized for conjugation. The first used sortase A (SrtA), which generates a covalent peptide bond between short amino acid sequences added to recombinantly produced S9.6 Fab and SEAP. The second approach was to genetically fuse the S9.6 Fab and SEAP so that the two are produced as a single molecule. Using these two antibody-SEAP proteins, we developed a simplified ELISA format for the identification of synthetic DNA-RNA hybrids, which can be optimized for detecting nucleic acids of pathogens, as well as for other applications. We successfully used this immunosorbent assay, HC-S, to identify DNA-RNA hybrids in solution with high specificity and sensitivity.

Climate change, human health, and resilience in the Holocene.

Climate change is an indisputable threat to human health, especially for societies already confronted with rising social inequality, political and economic uncertainty, and a cascade of concurrent environmental challenges. Archaeological data about past climate and environment provide an important source of evidence about the potential challenges humans face and the long-term outcomes of alternative short-term adaptive strategies. Evidence from well-dated archaeological human skeletons and mummified remains speaks directly to patterns of human health over time through changing circumstances. Here, we describe variation in human epidemiological patterns in the context of past rapid climate change (RCC) events and other periods of past environmental change. Case studies confirm that human communities responded to environmental changes in diverse ways depending on historical, sociocultural, and biological contingencies. Certain factors, such as social inequality and disproportionate access to resources in large, complex societies may influence the probability of major sociopolitical disruptions and reorganizations-commonly known as "collapse." This survey of Holocene human-environmental relations demonstrates how flexibility, variation, and maintenance of Indigenous knowledge can be mitigating factors in the face of environmental challenges. Although contemporary climate change is more rapid and of greater magnitude than the RCC events and other environmental changes we discuss here, these lessons from the past provide clarity about potential priorities for equitable, sustainable development and the constraints of modernity we must address.

Compounding vulnerabilities: Syndemics and the social determinants of disease in the past.

OBJECTIVE: This article explores the theory and utility of a syndemic approach for the study of disease in the past. Syndemic principles are examined alongside other theoretical developments within bioarchaeology. Two case studies are provided to illustrate the efficacy of this approach: Tuberculosis and vitamin D deficiency in 18th and 19th century England, and malaria and helminth infections in Early Medieval England. MATERIALS: Public health studies of present syndemics, in addition to published bioarchaeological, clinical and social information relating to the chosen case studies. METHODS: The data from these two historical examples are revisited within a syndemic framework to draw deeper conclusions about disease clustering and heterogeneity in the past. RESULTS: A syndemic framework can be applied to past contexts using clinical studies of diseases in a modern context and relevant paleopathological, archaeological, and historical data. CONCLUSIONS: This approach provides a means for providing a deeper, contextualised understanding ancient diseases, and integrates well with extant theoretical tools in bioarchaeology SIGNIFICANCE: Syndemics provides scholars a deep-time perspective on diseases that still impact modern populations. LIMITATIONS: Many of the variables essential for a truly syndemic approach cannot be obtained from current archaeological, bioarchaeological, or historical methods. SUGGESTIONS FOR FURTHER RESEARCH: More detailed and in-depth analysis of specific disease clusters within the past and the present, which draws on a comprehensive analysis of the social determinants of health.

Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease.

DNA-protein crosslinks (DPCs) are deleterious DNA lesions that occur when proteins are covalently crosslinked to the DNA by the action of variety of agents like reactive oxygen species, aldehydes and metabolites, radiation, and chemotherapeutic drugs. Unrepaired DPCs are blockades to all DNA metabolic processes. Specifically, during DNA replication, replication forks stall at DPCs and are vulnerable to fork collapse, causing DNA breakage leading to genome instability and cancer. Replication-coupled DPC repair involves DPC degradation by proteases such as SPRTN or the proteasome and the subsequent removal of DNA-peptide adducts by nucleases and canonical DNA repair pathways. SPRTN is a DNA-dependent metalloprotease that cleaves DPC substrates in a sequence-independent manner and is also required for translesion DNA synthesis following DPC degradation. Biallelic mutations in SPRTN cause Ruijs-Aalfs (RJALS) syndrome, characterized by hepatocellular carcinoma and segmental progeria, indicating the critical role for SPRTN and DPC repair pathway in genome maintenance. In this review, we will discuss the mechanism of replication-coupled DPC repair, regulation of SPRTN function and its implications in human disease and cancer.

Differential diagnosis of metabolic disease in a commingled sample from 19th century Hisban, Jordan.

OBJECTIVE: This research attempts a differential diagnosis of skeletal lesions in a commingled sample from Hisban, Jordan, focusing on non-adults in the assemblage. MATERIALS: 2,883 well-preserved skeletal elements and 9 relatively complete skulls representing an MNI of 32 non-adults (<18 years old). METHODS: All skeletal elements were observed macroscopically and pathophysiological processes underlying any lesions or other anomalies were assessed, followed by a comparative approach to rule out potential diagnoses. RESULTS: The skeletal lesions observed were caused by inflammation due to chronic hemorrhaging, marrow hyperplasia due to an increase in hemopoiesis, rapid bone growth, and the impact of biomechanical strain on poorly mineralized elements. Rickets, scurvy, and acquired anemias best fit this pattern of lesions, although inflammation from other sources such as trauma or infection could not be definitively ruled out. CONCLUSIONS: The in utero and postnatal environments at Hisban were conducive to the development of vitamin C and D deficiencies from birth until 2 years of age. The analysis of commingled remains requires an ontological shift in the importance of the individual to the population in paleopathology. SIGNIFICANCE: This investigation demonstrates the efficacy of a combined biological and comparative approach in differential diagnosis in complicated commingled collections. In addition, it emphasizes the importance of the mother-infant dyad in understanding metabolic disease. LIMITATIONS: Histological and radiographic analyses were not included in this diagnostic study due to COVID-19 travel restrictions. SUGGESTIONS FOR FURTHER RESEARCH: Isotopic analysis to investigate childhood diet and histological and radiographic analyses to assess survival of deficiencies.

Emotion Regulation Difficulties and Depression Among Individuals With Dermatological and Body Dysmorphic Concerns.

ABSTRACT: Existing literature demonstrates strong links between emotion regulation (ER) difficulties and depression. Although high rates of depression are observed among individuals with body dysmorphic disorder and skin disease, little is known about these co-occurring syndromes. To advance our understanding of a vulnerable population, this study examined facets of ER difficulties in relation to depression among adults with skin disease symptoms and body dysmorphic concerns (N = 97). Participants were recruited online and completed self-report measures. The overall hierarchical regression model accounted for 61.6% of the variance in depression. After controlling for anxiety and stress, ER difficulties added 9.9% unique variance. In particular, limited access to ER strategies was the only ER dimension significantly associated with depression. This study integrates divergent literatures and suggests the important role of ER difficulties in depression in this unique sample, thereby highlighting directions for future investigation.

USP11 mediates repair of DNA-protein cross-links by deubiquitinating SPRTN metalloprotease.

DNA-protein cross-links (DPCs) are toxic DNA lesions that interfere with DNA metabolic processes such as replication, transcription, and recombination. USP11 deubiquitinase participates in DNA repair, but the role of USP11 in DPC repair is not known. SPRTN is a replication-coupled DNA-dependent metalloprotease that cleaves proteins cross-linked to DNA to promote DPC repair. SPRTN function is tightly regulated by a monoubiquitin switch that controls SPRTN auto-proteolysis and chromatin accessibility during DPC repair. Previously, VCPIP1 and USP7 deubiquitinases have been shown to regulate SPRTN. Here, we identify USP11 as an SPRTN deubiquitinase. USP11 interacts with SPRTN and cleaves monoubiquitinated SPRTN in cells and in vitro. USP11 depletion impairs SPRTN deubiquitination and promotes SPRTN auto-proteolysis in response to formaldehyde-induced DPCs. Loss of USP11 causes an accumulation of unrepaired DPCs and cellular hypersensitivity to treatment with DPC-inducing agents. Our findings show that USP11 regulates SPRTN auto-proteolysis and SPRTN-mediated DPC repair to maintain genome stability.

Mapping and enumerating houses and households to support malaria control interventions on Bioko Island.

BACKGROUND: Housing mapping and household enumeration are essential for the planning, implementation, targeting, and monitoring of malaria control interventions. In many malaria endemic countries, control efforts are hindered by incomplete or non-existent housing cartography and household enumeration. This paper describes the development of a comprehensive mapping and enumeration system to support the Bioko Island Malaria Control Project (BIMCP). RESULTS: A highly detailed database was developed to include every housing unit on Bioko Island and uniquely enumerate the associated households residing in these houses. First, the island was divided into a virtual, geo-dereferenced grid of 1 × 1 km sequentially numbered map-areas, each of which was in turn subdivided into one hundred, 100 × 100 m sequentially numbered map-sectors. Second, high-resolution satellite imagery was used to sequentially and uniquely identify all housing units within each map-sector. Third, where satellite imagery was not available, global positioning systems (GPS) were used as the basis for uniquely identifying and mapping housing units in a sequential manner. A total of 97,048 housing units were mapped by 2018, 56% of which were concentrated in just 5.2% of Bioko Island's total mapped area. Of these housing units, 70.7% were occupied, thus representing uniquely identified households. CONCLUSIONS: The housing unit mapping and household enumeration system developed for Bioko Island enabled the BIMCP to more effectively plan, implement, target, and monitor malaria control interventions. Since 2014, the BIMCP has used the unique household identifiers to monitor all household-level interventions, including indoor residual spraying, long-lasting insecticide-treated nets distribution, and annual malaria indicator surveys. The coding system used to create the unique housing unit and household identifiers is highly intuitive and allows quick location of any house within the grid without a GPS. Its flexibility has permitted the BIMCP to easily take into account the rapid and substantial changes in housing infrastructure. Importantly, by utilizing this coding system, an unprecedented quantity and diversity of detailed, geo-referenced demographic and health data have been assembled that have proved highly relevant for informing decision-making both for malaria control and potentially for the wider public health agenda on Bioko Island.

Human mobility patterns and malaria importation on Bioko Island.

Malaria burden on Bioko Island has decreased significantly over the past 15 years. The impact of interventions on malaria prevalence, however, has recently stalled. Here, we use data from island-wide, annual malaria indicator surveys to investigate human movement patterns and their relationship to Plasmodium falciparum prevalence. Using geostatistical and mathematical modelling, we find that off-island travel is more prevalent in and around the capital, Malabo. The odds of malaria infection among off-island travelers are significantly higher than the rest of the population. We estimate that malaria importation rates are high enough to explain malaria prevalence in much of Malabo and its surroundings, and that local transmission is highest along the West Coast of the island. Despite uncertainty, these estimates of residual transmission and importation serve as a basis for evaluating progress towards elimination and for efficiently allocating resources as Bioko makes the transition from control to elimination.

Scurvy: Dietary Discretion in a Developed Country.

Although the causes have changed, scurvy (vitamin C deficiency) is still diagnosed in developed countries. We report a case of an 18-year-old female who presented to our emergency department with thrombocytopenia, sinus tachycardia, hypotension, fatigue, gingival hyperplasia, knee effusion, petechiae and ecchymosis in lower extremities. The differential diagnosis included hematologic abnormalities, infectious etiologies, vasculitis and vitamin deficiency. A brief dietary history was performed revealing poor fruit and vegetable intake, thus increasing our suspicion for vitamin C deficiency. This experience illustrates the importance of a dietary history and reminds us to keep scurvy in the differential diagnosis.

Combined administration of MK-801 and cycloheximide produces a delayed potentiation of fear discrimination memory extinction.

Mixed evidence exists regarding the role of N-methyl-D-aspartate (NMDA) receptors in memory reconsolidation. We provide no evidence that NMDA receptors are involved with memory reconsolidation, but instead demonstrate that prereactivation systemic MK-801 injection, combined with postreactivation intrabasolateral amygdala (BLA) cycloheximide infusion, produces a delayed potentiation of extinction learning. These data suggest that an interaction between NMDA antagonism and protein synthesis inhibition may enhance extinction by exerting effects outside of the intended reconsolidation manipulation window. The present work demonstrates a novel pharmacological enhancement of extinction, and underscores the importance of employing proper control procedures in reconsolidation research. (PsycINFO Database Record

Estimating Suicide Rates in Developing Nations: A Low-Cost Newspaper Capture-Recapture Approach in Cambodia.

This study tested a low-cost method for estimating suicide rates in developing nations that lack adequate statistics. Data comprised reported suicides from Cambodia's 2 largest newspapers. Capture-recapture modeling estimated a suicide rate of 3.8/100 000 (95% CI = 2.5-6.7) for 2012. That compares to World Health Organization estimates of 1.3 to 9.4/100 000 and a Cambodian government estimate of 3.5/100 000. Suicide rates of males were twice that of females, and rates of those <40 years were twice that of those ≥40 years. Capture-recapture modeling with newspaper reports proved a reasonable method for estimating suicide rates for countries with inadequate official data. These methods are low-cost and can be applied to regions with at least 2 newspapers with overlapping reports. Means to further improve this approach are discussed. These methods are applicable to both recent and historical data, which can benefit epidemiological work, and may also be applicable to homicides and other statistics.

Characterization of covalently bonded proteins on poly(methyl methacrylate) by X-ray photoelectron spectroscopy.

X-ray photoelectron spectroscopy (XPS) has been used to characterize a poly(methyl methacrylate) (PMMA) surface with covalently attached proteins. The PMMA surfaces were first aminated using hexamethyldiamine; the resulting -NH(2) sites were reacted with the hetero-bifunctional cross-linker Sulfo-EMCS to form a maleimide-terminated surface. The N-hydroxysuccinimide ester terminal and maleimide terminal groups of Sulfo-EMCS reacts with amine and sulfhydryl groups, respectively, exposed on the surface of the proteins. This study characterizes Thermotoga maritima beta-glucosidase 1 (TmGH1), which belongs to a family of proteins that facilitate hydrolysis of glucose-related monomers with retention of conformation. The surfaces were characterized by XPS to monitor surface composition, and to elucidate protein orientation on the surface. Results suggest that a covalently bonded surface of TmGH1 on PMMA has been obtained. These results demonstrate the feasibility of using XPS to study protein surface chemistry and demonstrate a useful method to anchor cysteine-terminated proteins for the purposes of creating biosensors or platforms for mechanical force experiments to investigate protein structure.

An isotopic perspective on the transport of Byzantine mining camp laborers into southwestern Jordan.

The Byzantine Empire managed a complex administrative network that controlled the mining and processing of natural resources from within its boundaries. Scholars relying upon archeological and textual evidence debate the level of imperial involvement in these ventures, particularly in the provinces. Ancient sources note that many mining camps, for instance, purportedly contained criminal laborers and elite administrators transported from distant locales, indicating significant organization and expenditures by the imperial administration to run the mines. This analysis explores the presence of these nonlocal individuals in a cemetery associated with the third to seventh century A.D. mining camp of Phaeno (Faynan), located in modern Jordan. Strontium isotope analysis of 31 burials indicates that most spent their childhood in a similar geological region as Phaeno, implying that they were locally born. The delta(18)O results mirror the homogeneous (87)Sr/(86)Sr values, confirming a local origin for most of the sample. Isotopic evidence therefore suggests that the Phaeno mining camp was largely a local operation, contrary to the picture presented in textual sources, although the profits surely padded imperial coffers.

Social capital and health care experiences among low-income individuals.

OBJECTIVES: We examined relationships between social capital and health service measures among low-income individuals and assessed the psychometric properties of a theory-based measure of social capital. METHODS: We conducted a statewide telephone survey of 1216 low-income New Mexico residents. Respondents reported on barriers to health care access, use of health care services, satisfaction with care, and quality of provider communication and answered questions focusing on social capital. RESULTS: The social capital measure demonstrated strong psychometric properties. Regression analyses showed that some but not all components of social capital were related to measures of health services; for example, social support was inversely related to barriers to care (odds ratio=0.73; 95% confidence interval=0.59, 0.92). CONCLUSIONS: Social capital is a complex concept, with some elements appearing to be related to individuals' experiences with health services. More research is needed to refine social capital theory and to clarify the contributions of social capital versus structural factors (e.g., insurance coverage and income) to health care experiences.