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Abstract Background The effect of treating periodontal disease (PD) during pregnancy on adverse birth outcomes, such as preterm birth (PTB) and/or low birth weight (LBW), remains unclear. This is partially due to the fact that Randomized Controlled Trials (RCTs) have used different combinations of treatment approaches to test this hypothesis. In this meta-analysis of RCTs, we assessed the impact of treating PD during pregnancy with scaling and root planning (SRP) and mouthwash use on PTB and LBW. Methods A systematic review with meta-analysis was conducted following PRISMA guidelines. A comprehensive search strategy was employed across electronic databases, including PubMed/Medline, Embase, and Google Scholar. Quality assessment was performed using the Cochrane Risk of Bias 2 Tool. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effect models. Results Out of 133 initially identified reports, 9 RCTs involving 3,985 pregnant women met the inclusion criteria. Periodontal treatment with SRP and mouthwash use in pregnancy was associated with a lower risk of PTB and LBW in meta-analysis with random effects models (pooled RR for PTB = 0.44, 95% CI: 0.22–0.88) and (pooled RR for LBW = 0.33, 95% CI: 0.13–0.84). Substantial heterogeneity was observed among studies (I2 = 91% and 90% for PTB and LBW, respectively), with sensitivity analysis suggesting potential sources of heterogeneity. Funnel plot assessment for publication bias showed evidence of asymmetry. Conclusion SRP with mouthwash use during pregnancy were associated with significantly lower risks of PTB and LBW. Larger, well-conducted RCTs are warranted to address this issue, as existing trials are small and exhibit methodological and statistical heterogeneity.

A growing number of STEM doctorates pursue careers across the broader biomedical workforce, including industry, policy, and healthcare. Graduate and postdoctoral trainees need training to develop professional skills that prepare them for diverse workforce options. Through engagement with faculty and trainees, we determined that formal management skills are underdeveloped in trainees, particularly around managing projects in a way that is translatable to broader industries. At Georgetown University Medical Center, we adapted Kern's six-steps of curriculum design to develop the Academy for Transferable Management Skills (ATMS) program to help graduate and postdoctoral trainees develop linear experience in utilizing project management tools in their academic research contexts. ATMS includes a self-paced online CANVAS course with learning objectives and content modules that map to the project management cycle from initiation to closure, developed in consultation with PhD-level industry experts. From 2021–2024, 25 trainees have completed the ATMS program, including the capstone project and posttest evaluation. Trainees also complete brief quizzes after each module as a formative assessment of learning. The pre-test evaluation (n = 92) revealed a baseline of project management “pain points” regularly encountered by trainees (risk management, project charters, work breakdown structures, and managing project scope). Posttest data (n = 25) reveal a significant increase (p < 0.0001) in project management self-efficacy measures across the aforementioned pain point scales. Notably, 100% of trainees indicated that they may/would refer the program to colleagues. ATMS offers trainees the flexibility to pick frameworks that apply to their projects with trainees planning to use project schedules (84%), Work Break Down Structures (80%), lessons learned reports (68%), and communication plans (68%) in their work. This integrated experiential learning approach equips trainees to develop and execute their projects according to industry-informed project management principles, which allows them to perform their current research more efficiently and to utilize project management frameworks in a way that is directly transferable to broad careers.

Introduction The influence of implicit biases in virtual interviews must be addressed to ensure equity within the admissions process. ABATE is a mnemonic framework of five specific categories of implicit bias (affinity-based, backdrop-based, appearance-based, technology and media-based, and enunciation-based biases) that should be anticipated and mitigated for faculty, staff, health professionals, and medical students who conduct virtual interviews at medical schools. Methods A 60-minute workshop was developed to educate medical school admissions interviewers about the ABATE model and strategies to mitigate implicit bias during virtual interviews. Four workshops were held over 1 year totaling 217 individual attendees. The workshops were evaluated using a single-group, pre-post questionnaire designed with the Kirkpatrick evaluation model. Results Attendees reported that they found the ABATE workshop useful and relevant to improving their ability to minimize implicit bias during virtual interviews. Significant improvements were found in attendee reactions to the utility of implicit bias training (M pre = 2.6, M post = 3.1, p = .002). Significant changes were also reported in attendees’ attitudes about interviewing confidence (M pre = 3.0, M post = 3.2, p = .04), bias awareness (M pre = 3.0, M post = 3.4, p = .002), and identifying and applying bias mitigation solutions (M pre = 2.5, M post = 3.0, p = .003). Knowledge specific to backdrop-based biases also significantly increased (M pre = 3.2, M post = 3.4, p = .04). Discussion The ABATE workshop demonstrates promise in mitigating implicit bias in virtual medical school interviews.

Abstract Background The function of DNA methyltransferase genes of insects is a puzzle, because an association between gene expression and methylation is not universal for insects. If the genes normally involved in cytosine methylation are not influencing gene expression, what might be their role? We previously demonstrated that gametogenesis of Oncopeltus fasciatus is interrupted at meiosis following knockdown of DNA methyltransferase 1 (Dnmt1) and this is unrelated to changes in levels of cytosine methylation. Here, using transcriptomics, we tested the hypothesis that Dmnt1 is a part of the meiotic gene pathway. Testes, which almost exclusively contain gametes at varying stages of development, were sampled at 7 days and 14 days following knockdown of Dmnt1 using RNAi. Results Using microscopy, we found actively dividing spermatocysts were reduced at both timepoints. However, as with other studies, we saw Dnmt1 knockdown resulted in condensed nuclei after mitosis–meiosis transition, and then cellular arrest. We found limited support for a functional role for Dnmt1 in our predicted cell cycle and meiotic pathways. An examination of a priori Gene Ontology terms showed no enrichment for meiosis. We then used the full data set to reveal further candidate pathways influenced by Dnmt1 for further hypotheses. Very few genes were differentially expressed at 7 days, but nearly half of all transcribed genes were differentially expressed at 14 days. We found no strong candidate pathways for how Dnmt1 knockdown was achieving its effect through Gene Ontology term overrepresentation analysis. Conclusions We, therefore, suggest that Dmnt1 plays a role in chromosome dynamics based on our observations of condensed nuclei and cellular arrest with no specific molecular pathways disrupted.

Transcription of ribosomal RNA (rRNA) by RNA Polymerase (Pol) I in the nucleolus is necessary for ribosome biogenesis, which is intimately tied to cell growth and proliferation. Perturbation of ribosome biogenesis results in tissue specific disorders termed ribosomopathies in association with alterations in nucleolar structure. However, how rRNA transcription and ribosome biogenesis regulate nucleolar structure during normal development and in the pathogenesis of disease remains poorly understood. Here we show that homozygous null mutations in Pol I subunits required for rRNA transcription and ribosome biogenesis lead to preimplantation lethality. Moreover, we discovered that Polr1a-/-, Polr1b-/-, Polr1c-/- and Polr1d-/- mutants exhibit defects in the structure of their nucleoli, as evidenced by a decrease in number of nucleolar precursor bodies and a concomitant increase in nucleolar volume, which results in a single condensed nucleolus. Pharmacological inhibition of Pol I in preimplantation and midgestation embryos, as well as in hiPSCs, similarly results in a single condensed nucleolus or fragmented nucleoli. We find that when Pol I function and rRNA transcription is inhibited, the viscosity of the granular compartment of the nucleolus increases, which disrupts its phase separation properties, leading to a single condensed nucleolus. However, if a cell progresses through mitosis, the absence of rRNA transcription prevents reassembly of the nucleolus and manifests as fragmented nucleoli. Taken together, our data suggests that Pol I function and rRNA transcription are required for maintaining nucleolar structure and integrity during development and in the pathogenesis of disease.

A key component of parental care is avoiding killing and eating one's own offspring. Many organisms commit infanticide but switch to parental care when their own offspring are expected, known as temporal kin recognition. It is unclear why such types of indirect kin recognition are so common across taxa. One possibility is that temporal kin recognition may evolve through alteration of simple mechanisms, such as co-opting mechanisms that influence the regulation of timing and feeding in other contexts. Here, we determine whether takeout, a gene implicated in coordinating feeding, influences temporal kin recognition in Nicrophorus orbicollis. We found that takeout expression was not associated with non-parental feeding changes resulting from hunger, or a general transition to the full parental care repertoire. However, beetles that accepted and provided care to their offspring had a higher takeout expression than beetles that committed infanticide. Together, these data support the idea that the evolution of temporal kin recognition may be enabled by co-option of mechanisms that integrate feeding behaviour in other contexts.

Abstract DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.

Collective cell migration plays an essential role in vertebrate development, yet the extent to which dynamically changing microenvironments influence this phenomenon remains unclear. Observations of the distribution of the extracellular matrix (ECM) component fibronectin during the migration of loosely connected neural crest cells (NCCs) lead us to hypothesize that NCC remodeling of an initially punctate ECM creates a scaffold for trailing cells, enabling them to form robust and coherent stream patterns. We evaluate this idea in a theoretical setting by developing an individual-based computational model that incorporates reciprocal interactions between NCCs and their ECM. ECM remodeling, haptotaxis, contact guidance, and cell-cell repulsion are sufficient for cells to establish streams in silico, however, additional mechanisms, such as chemotaxis, are required to consistently guide cells along the correct target corridor. Further model investigations imply that contact guidance and differential cell-cell repulsion between leader and follower cells are key contributors to robust collective cell migration by preventing stream breakage. Global sensitivity analysis and simulated gain- and loss-of-function experiments suggest that long-distance migration without jamming is most likely to occur when leading cells specialize in creating ECM fibers, and trailing cells specialize in responding to environmental cues by upregulating mechanisms such as contact guidance.

Abstract Understanding the genetic influences of traits of nonmodel organisms is crucial to understanding how novel traits arise. Do new traits require new genes or are old genes repurposed? How predictable is this process? Here, we examine this question for gene expression influencing parenting behavior in a beetle, Nicrophorus vespilloides. Parental care, produced from many individual behaviors, should be influenced by changes of expression of multiple genes, and one suggestion is that the genes can be predicted based on knowledge of behavior expected to be precursors to parental care, such as aggression, resource defense, and mating on a resource. Thus, testing gene expression during parental care allows us to test expectations of this “precursor hypothesis” for multiple genes and traits. We tested for changes of the expression of serotonin, octopamine/tyramine, and dopamine receptors, as well as one glutamate receptor, predicting that these gene families would be differentially expressed during social interactions with offspring and associated resource defense. We found that serotonin receptors were strongly associated with social and aggression behavioral transitions. Octopamine receptors produced a complex picture of gene expression over a reproductive cycle. Dopamine was not associated with the behavioral transitions sampled here, while the glutamate receptor was most consistent with a behavioral change of resource defense/aggression. Our results generate new hypotheses, refine candidate lists for further studies, and inform the genetic mechanisms that are co‐opted during the evolution of parent–offspring interactions, a likely evolutionary path for many lineages that become fully social. The precursor hypothesis, while not perfect, does provide a starting point for identifying candidate genes.

Microtubule-associated protein 2 (MAP2) is the predominant cytoskeletal regulator within neuronal dendrites, abundant and specific enough to serve as a robust somatodendritic marker. It influences microtubule dynamics and microtubule/actin interactions to control neurite outgrowth and synaptic functions, similarly to the closely related MAP Tau. Though pathology of Tau has been well appreciated in the context of neurodegenerative disorders, the consequences of pathologically dysregulated MAP2 have been little explored, despite alterations in its immunoreactivity, expression, splicing and/or stability being observed in a variety of neurodegenerative and neuropsychiatric disorders including Huntington’s disease, prion disease, schizophrenia, autism, major depression and bipolar disorder. Here we review the understood structure and functions of MAP2, including in neurite outgrowth, synaptic plasticity, and regulation of protein folding/transport. We also describe known and potential mechanisms by which MAP2 can be regulated via post-translational modification. Then, we assess existing evidence of its dysregulation in various brain disorders, including from immunohistochemical and (phospho) proteomic data. We propose pathways by which MAP2 pathology could contribute to endophenotypes which characterize these disorders, giving rise to the concept of a “MAP2opathy”—a series of disorders characterized by alterations in MAP2 function.

Abstract Background The function of cytosine (DNA) methylation in insects remains inconclusive due to a lack of mutant and/or genetic studies. Results Here, we provide evidence for the functional role of the maintenance DNA methyltransferase 1 (Dnmt1) in an insect using experimental manipulation. Through RNA interference (RNAi), we successfully posttranscriptionally knocked down Dnmt1 in ovarian tissue of the hemipteran Oncopeltus fasciatus (the large milkweed bug). Individuals depleted for Dnmt1, and subsequently DNA methylation, failed to reproduce. Eggs were inviable and declined in number, and nuclei structure of follicular epithelium was aberrant. Erasure of DNA methylation from gene or transposon element bodies did not reveal a direct causal link to steady-state mRNA levels in somatic cells. These results reveal an important function of Dnmt1 seemingly not contingent on directly controlling gene expression. Conclusions This study provides direct experimental evidence for a functional role of Dnmt1 in egg production and embryo viability and uncovers a trivial role, if any, for DNA methylation in control of gene expression in O. fasciatus.

Given the importance of DNA methylation in protection of the genome against transposable elements and transcriptional regulation in other taxonomic groups, the diversity in both levels and patterns of DNA methylation in the insects raises questions about its function and evolution. We show that the maintenance DNA methyltransferase, DNMT1, affects meiosis and is essential to fertility in milkweed bugs, Oncopeltus fasciatus, while DNA methylation is not required in somatic cells. Our results support the hypothesis that Dnmt1 is required for the transition of germ cells to gametes in O. fasciatus and that this function is conserved in male and female gametogenesis. They further suggest that DNMT1 has a function independent of DNA methylation in germ cells. Our results raise thequestion as to how a gene that is so critical to fitness across multiple insect species is able to diverge widely across the insect tree of life.

There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages.

There is continued growth in the number of master's degrees awarded in the life sciences to address the evolving needs of the biomedical workforce. Academic medical centers leverage the expertise of their faculty and industry partners to develop one to two year intensive and multidisciplinary master's programs that equip students with advanced scientific skills and practical training experiences. However, there is little data published on the outcomes of these graduates to evaluate the effectiveness of these programs and to inform the return on investment of students. Here, the authors show the first five-year career outlook for master of science graduates from programs housed at an academic medical center. Georgetown University Biomedical Graduate Education researchers analyzed the placement outcomes of 1,204 graduates from 2014-2018, and the two-year outcomes of 412 graduates from 2016 and 2017. From the 15 M.S. programs analyzed, they found that 69% of graduates entered the workforce, while 28% entered an advanced degree program such as a Ph.D., allopathic or osteopathic medicine (M.D. or D.O.), or health professions degree. International students who pursue advanced degrees largely pursued Ph.D. degrees, while domestic students represent the majority of students entering into medical programs. Researchers found that a majority of the alumni that entered the workforce pursue research-based work, with 59% of graduates conducting research-based job functions across industries. Forty-nine percent of employed graduates analyzed from 2016 and 2017 changed employment positions, while 15% entered advanced degree programs. Alumni that changed positions changed companies in the same job function, changed to a position of increasing responsibility in the same or different organization, or changed to a different job function in the same or different company. Overall, standalone master's programs equip graduates with research skills, analytical prowess, and content expertise, strengthening the talent pipeline of the biomedical workforce.

DNA methylation is an important chromatin modification that can stably alter gene expression in cells and maintain genome integrity in plants and vertebrates. The function of DNA methylation outside of these well-studied systems, however, is unclear. Insects, in particular, represent an understudied group. Variation in the level of DNA methylation and gains and losses in the maintenance methyltransferase, DNMT1, across the insect tree of life suggests that there is much we don't understand about DMNT1 function and evolution. One constant across the studies examining patterns of Dnmt1 expression in insects is that expression is consistently high in reproductive tissues compared to somatic tissue. The explanation for this has been that DNMT1 is required in tissues that have high levels of cell division. Our previous study found that downregulation of Dnmt1 expression in the milkweed bug Oncopeltus fasciatus results in the expected reduction of DNA methylation, no global changes in gene expression reflecting changes in DNA methylation, and the loss of the ability to produce viable oocytes. Here, we show that females treated with ds-Dnmt1 RNA during larval development have a more extreme phenotype; they lack oocytes entirely but develop a normal somatic ovary. Our results indicate a specific role for DNMT1 in the formation of gametes and are consistent with data from other systems, including Tribolium castaneum, a species does not have DNA methylation. We propose that DNMT1 has multiple functional roles in addition to methylating DNA, which explains its complex patterns of evolution.

The Himalayas of South Asia are home to many glaciers that are retreating due to climate change and causing the formation of large glacial lakes in their absence. These lakes are held in place by naturally deposited moraine dams that are potentially unstable. Specifically, an impulse wave generated by an avalanche or landslide entering the lake can destabilize the moraine dam, thereby causing a catastrophic failure of the moraine and a glacial lake outburst flood (GLOF). Imja-Lhotse Shar Glacier is amongst the glaciers experiencing the highest rate of mass loss in the Mount Everest region, in part due to the expansion of Imja Tsho. A GLOF from this lake may have the potential to cause catastrophic damage to downstream villages, threatening both property and human life, which prompted the Nepali government to construct outlet works to lower the lake level. Therefore, it is essential to understand the processes that could trigger a flood and quantify the potential downstream impacts. The avalanche-induced GLOF process chain was modeled using the output of one component of the chain as input to the next. First, the volume and momentum of various avalanches entering the lake were calculated using Rapid Mass Movement Simulation (RAMMS). Next, the avalanche-induced waves were simulated using the Basic Simulation Environment for Computation of Environmental Flow and Natural Hazard Simulation (BASEMENT) model and validated with empirical equations to ensure the proper transfer of momentum from the avalanche to the lake. With BASEMENT, the ensuing moraine erosion and downstream flooding was modeled, which was used to generate hazard maps downstream. Moraine erosion was calculated for two geomorphologic models: one site-specific using field data and another worst-case based on past literature that is applicable to lakes in the greater region. Neither case resulted in flooding outside the river channel at downstream villages. The worst-case model resulted in some moraine erosion and increased channelization of the lake outlet, which yielded greater discharge downstream but no catastrophic collapse. The site-specific model generated similar results, but with very little erosion and a smaller downstream discharge. These results indicated that Imja Tsho is unlikely to produce a catastrophic GLOF due to an avalanche in the near future, although some hazard exists within the downstream river channel, necessitating continued monitoring of the lake. Furthermore, these models were designed for ease and flexibility such that local or national agency staff with reasonable training can apply them to model the GLOF process chain for other lakes in the region.

This paper studies the lake dynamics for avalanche-triggered glacial lake outburst floods (GLOFs) in the Cordillera Blanca mountain range in Ancash, Peru. As new glacial lakes emerge and existing lakes continue to grow, they pose an increasing threat of GLOFs that can be catastrophic to the communities living downstream. In this work, the dynamics of displacement waves produced from avalanches are studied through three-dimensional hydrodynamic simulations of Lake Palcacocha, Peru, with an emphasis on the sensitivity of the lake model to input parameters and boundary conditions. This type of avalanche-generated wave is an important link in the GLOF process chain because there is a high potential for overtopping and erosion of the lake-damming moraine. The lake model was evaluated for sensitivity to turbulence model and grid resolution, and the uncertainty due to these model parameters is significantly less than that due to avalanche boundary condition characteristics. Wave generation from avalanche impact was simulated using two different boundary condition methods. Representation of an avalanche as water flowing into the lake generally resulted in higher peak flows and overtopping volumes than simulating the avalanche impact as mass–momentum inflow at the lake boundary. Three different scenarios of avalanche size were simulated for the current lake conditions, and all resulted in significant overtopping of the lake-damming moraine. Although the lake model introduces significant uncertainty, the avalanche portion of the GLOF process chain is likely to be the greatest source of uncertainty. To aid in evaluation of hazard mitigation alternatives, two scenarios of lake lowering were investigated. While large avalanches produced significant overtopping waves for all lake-lowering scenarios, simulations suggest that it may be possible to contain waves generated from smaller avalanches if the surface of the lake is lowered.

With growing numbers of sequenced genomes, increasing numbers of duplicate genes are being uncovered. Here we examine Malvolio, a gene in the natural resistance-associated macrophage protein (Nramp) family, that has been duplicated in the subsocial beetle, Nicrophorus vespilloides, which exhibits advanced parental behavior. There is only one copy of Mvl in honey bees and Drosophila, whereas in vertebrates there are two copies that are subfunctionalized. We first compared amino acid sequences for Drosophila, beetles, mice, and humans. We found a high level of conservation between the different species, although there was greater variation in the C-terminal regions. A phylogenetic analysis across multiple insect orders suggested that Mvl has undergone several independent duplications. To examine the potential for different functions where it has been duplicated, we quantified expression levels of Mvl1 and Mvl2 in eight tissues in N. vespilloides. We found that while Mvl1 was expressed ubiquitously, albeit at varying levels, expression of Mvl2 was limited to brain and midgut. Because Mvl has been implicated in behavior, we examined expression during different behavioral states that reflected differences in opportunity for social interactions and expression of parental care behaviors. We found differing expression patterns for the two copies, with Mvl1 increasing in expression during resource preparation and feeding offspring, and Mvl2 decreasing in these same states. Given these patterns of expression, along with the protein analysis, we suggest that Mvl in N. vespilloides has experienced sub/neofunctionalization following its duplication, and may be evolving differing and tissue-specific roles in behavior and physiology.

Glacier outburst floods with origins from Lhotse Glacier, located in the Everest region of Nepal, occurred on 25 May 2015 and 12 June 2016. The most recent event was witnessed by investigators, which provided unique insights into the magnitude, source, and triggering mechanism of the flood. The field assessment and satellite imagery analysis following the event revealed that most of the flood water was stored englacially and that the flood was likely triggered by dam failure. The flood's peak discharge was estimated to be 210 m3 s−1.

Glacial lake outburst floods (GLOFs) pose a significant threat to downstream communities and infrastructure due to their potential to rapidly unleash stored lake water. The most common triggers of these GLOFs are mass movement entering the lake and/or the self-destruction of the terminal moraine due to hydrostatic pressures or a buried ice core. This study initially uses previous qualitative and quantitative assessments to understand the hazards associated with eight glacial lakes in the Nepal Himalaya that are widely considered to be highly dangerous. The previous assessments yield conflicting classifications with respect to each glacial lake, which spurred the development of a new holistic, reproducible, and objective approach based solely on remotely sensed data. This remote hazard assessment analyzes mass movement entering the lake, the stability of the moraine, and lake growth in conjunction with a geometric GLOF to determine the downstream impacts such that the present and future risk associated with each glacial lake may be quantified. The new approach is developed within a hazard, risk, and management action framework with the aim that this remote assessment may guide future field campaigns, modeling efforts, and ultimately risk-mitigation strategies. The remote assessment was found to provide valuable information regarding the hazards faced by each glacial lake and results were discussed within the context of the current state of knowledge to help guide future efforts.

One of the consequences of recent glacier recession in the Cordillera Blanca, Peru, is the risk of glacial lake outburst floods (GLOFs) from lakes that have formed at the base of retreating glaciers. GLOFs are often triggered by avalanches falling into glacial lakes, initiating a chain of processes that may culminate in significant inundation and destruction downstream. This paper presents simulations of all of the processes involved in a potential GLOF originating from Lake Palcacocha, the source of a previously catastrophic GLOF on 13 December 1941, killing about 1800 people in the city of Huaraz, Peru. The chain of processes simulated here includes (1) avalanches above the lake; (2) lake dynamics resulting from the avalanche impact, including wave generation, propagation, and run-up across lakes; (3) terminal moraine overtopping and dynamic moraine erosion simulations to determine the possibility of breaching; (4) flood propagation along downstream valleys; and (5) inundation of populated areas. The results of each process feed into simulations of subsequent processes in the chain, finally resulting in estimates of inundation in the city of Huaraz. The results of the inundation simulations were converted into flood intensity and preliminary hazard maps (based on an intensity-likelihood matrix) that may be useful for city planning and regulation. Three avalanche events with volumes ranging from 0.5 to 3 × 106 m3 were simulated, and two scenarios of 15 and 30 m lake lowering were simulated to assess the potential of mitigating the hazard level in Huaraz. For all three avalanche events, three-dimensional hydrodynamic models show large waves generated in the lake from the impact resulting in overtopping of the damming moraine. Despite very high discharge rates (up to 63.4 × 103 m3 s−1), the erosion from the overtopping wave did not result in failure of the damming moraine when simulated with a hydro-morphodynamic model using excessively conservative soil characteristics that provide very little erosion resistance. With the current lake level, all three avalanche events result in inundation in Huaraz due to wave overtopping, and the resulting preliminary hazard map shows a total affected area of 2.01 km2, most of which is in the high hazard category. Lowering the lake has the potential to reduce the affected area by up to 35 %, resulting in a smaller portion of the inundated area in the high hazard category.

Abstract The accelerated aging hypothesis of schizophrenia posits that physiological changes throughout the body that are associated with normal aging occur at an earlier age in individuals with schizophrenia. Testing this hypothesis has been limited by problems measuring biological age. Recently, a method using DNA methylation levels at 353 genomic sites to produce “DNA methylation age”, an estimate of tissue biological age, was described and validated. We used this method to test the hypothesis in the postmortem superior temporal gyrus of 22 non-psychiatric control and 22 schizophrenia subjects. DNA methylation age correlated with chronological age in both non-psychiatric control (r = 0.95, p

Debris thickness plays an important role in regulating ablation rates on debris-covered glaciers as well as controlling the likely size and location of supraglacial lakes. Despite its importance, lack of knowledge about debris properties and associated energy fluxes prevents the robust inclusion of the effects of a debris layer into most glacier surface energy balance models. This study combines fieldwork with a debris-covered glacier energy balance model to estimate debris temperatures and ablation rates on Imja–Lhotse Shar Glacier located in the Everest region of Nepal. The debris properties that significantly influence the energy balance model are the thermal conductivity, albedo, and surface roughness. Fieldwork was conducted to measure thermal conductivity and a method was developed using Structure from Motion to estimate surface roughness. Debris temperatures measured during the 2014 melt season were used to calibrate and validate a debris-covered glacier energy balance model by optimizing the albedo, thermal conductivity, and surface roughness at 10 debris-covered sites. Furthermore, three methods for estimating the latent heat flux were investigated. Model calibration and validation found the three methods had similar performance; however, comparison of modeled and measured ablation rates revealed that assuming the latent heat flux is zero may overestimate ablation. Results also suggest that where debris moisture is unknown, measurements of the relative humidity or precipitation may be used to estimate wet debris periods, i.e., when the latent heat flux is non-zero. The effect of temporal resolution on the model was also assessed and results showed that both 6 h data and daily average data slightly underestimate debris temperatures and ablation rates; thus these should only be used to estimate rough ablation rates when no other data are available.

Moraine dam collapse is one of the causes of glacial lake outburst floods. Available models seek to predict both moraine breach formation and lake outflow. The models depend on hydraulic, erosion, and geotechnical parameters that are mostly unknown or uncertain. This paper estimates the outflow hydrograph caused by a potential erosive collapse of the moraine dam of Lake Palcacocha in Peru and quantifies the uncertainty of the results. The overall aim is to provide a simple yet hydraulically robust approach for calculating the expected outflow hydrographs that is useful for risk assessment studies. To estimate the peak outflow and failure time of the hydrograph, we assessed several available empirical equations based on lake and moraine geometries; each equation has defined confidence intervals for peak flow predictions. Complete outflow hydrographs for each peak flow condition were modeled using a hydraulic simulation model calibrated to match the peak flows estimated with the empirical equations. Failure time and peak flow differences between the simulations, and the corresponding empirical equations were used as error parameters. Along with an expected hydrograph, lower and upper bound hydrographs were calculated for Lake Palcacocha, representing the confidence interval of the results. The approach has several advantages: first, it is simple and robust. Second, it evaluates the capability of empirical equations to reproduce the conditions of the lake and moraine dam. Third, this approach accounts for uncertainty in the hydrographs estimations, which makes it appropriate for risk management studies.

The DNA damage response (DDR) maintains genomic integrity through an elaborate network of signaling pathways that sense DNA damage and recruit effector factors to repair damaged DNA. DDR signaling pathways are usurped and manipulated by the replication programs of many viruses. Here, we review the papillomavirus (PV) life cycle, highlighting current knowledge of how PVs recruit and engage the DDR to facilitate productive infection.

Glacial-dominated areas pose unique challenges to downstream communities in adapting to recent and continuing global climate change, including increased threats of glacial lake outburst floods (GLOFs) that can increase risk due to flooding of downstream communities and cause substantial impacts on regional social, environmental and economic systems. The Imja glacial lake (or Imja Tsho) in Nepal, which has the potential to generate a GLOF, was studied using a two-dimensional debris-flow inundation model in order to evaluate the effectiveness of proposed measures to reduce possible flooding impacts to downstream communities by lowering the lake level. The results indicate that only minor flood impact reduction is achieved in the downstream community of Dingboche with modest (~3 m) lake lowering. Lowering the lake by 10 m shows a significant reduction in inundated area. However, lowering the lake by 20 m almost eliminates all flood impact at Dingboche. Further downstream at Phakding, the impact of the GLOF is significant and similar reductions in inundation are likely as a result of lake lowering.

Neural crest cells migrate throughout the embryo, but how cells move in a directed and collective manner has remained unclear. Here, we perform the first single-cell transcriptome analysis of cranial neural crest cell migration at three progressive stages in chick and identify and establish hierarchical relationships between cell position and time-specific transcriptional signatures. We determine a novel transcriptional signature of the most invasive neural crest Trailblazer cells that is consistent during migration and enriched for approximately 900 genes. Knockdown of several Trailblazer genes shows significant but modest changes to total distance migrated. However, in vivo expression analysis by RNAscope and immunohistochemistry reveals some salt and pepper patterns that include strong individual Trailblazer gene expression in cells within other subregions of the migratory stream. These data provide new insights into the molecular diversity and dynamics within a neural crest cell migratory stream that underlie complex directed and collective cell behaviors.

Imja Tsho, located in the Sagarmatha (Everest) National Park of Nepal, is one of the most studied and rapidly growing lakes in the Himalayan range. Compared with previous studies, the results of our sonar bathymetric survey conducted in September of 2012 suggest that its maximum depth has increased from 90.5 to 116.3 ± 5.2 m since 2002, and that its estimated volume has grown from 35.8 ± 0.7 to 61.7 ± 3.7 million m3. Most of the expansion of the lake in recent years has taken place in the glacier terminus–lake interface on the eastern end of the lake, with the glacier receding at about 52 m yr−1 and the lake expanding in area by 0.04 km2 yr−1. A ground penetrating radar survey of the Imja–Lhotse Shar glacier just behind the glacier terminus shows that the ice is over 200 m thick in the center of the glacier. The volume of water that could be released from the lake in the event of a breach in the damming moraine on the western end of the lake has increased to 34.1 ± 1.08 million m3 from the 21 million m3 estimated in 2002.

Debris thickness is an important characteristic of debris-covered glaciers in the Everest region of the Himalayas. The debris thickness controls the melt rates of the glaciers, which has large implications for hydrologic models, the glaciers' response to climate change, and the development of glacial lakes. Despite its importance, there is little knowledge of how the debris thickness varies over these glaciers. This paper uses an energy balance model in conjunction with Landsat7 Enhanced Thematic Mapper Plus (ETM+) satellite imagery to derive thermal resistances, which are the debris thickness divided by the thermal conductivity. Model results are reported in terms of debris thickness using an effective thermal conductivity derived from field data. The developed model accounts for the nonlinear temperature gradient in the debris cover to derive reasonable debris thicknesses. Fieldwork performed on Imja–Lhotse Shar Glacier in September 2013 was used to compare to the modeled debris thicknesses. Results indicate that accounting for the nonlinear temperature gradient is crucial. Furthermore, correcting the incoming shortwave radiation term for the effects of topography and resampling to the resolution of the thermal band's pixel is imperative to deriving reasonable debris thicknesses. Since the topographic correction is important, the model will improve with the quality of the digital elevation model (DEM). The main limitation of this work is the poor resolution (60 m) of the satellite's thermal band. The derived debris thicknesses are reasonable at this resolution, but trends related to slope and aspect are unable to be modeled on a finer scale. Nonetheless, the study finds this model derives reasonable debris thicknesses on this scale and was applied to other debris-covered glaciers in the Everest region.

ABSTRACT Human papillomaviruses (HPVs) replicate in the cutaneous and mucosal epithelia, and the infectious cycle is synchronous with the differentiation program of the host keratinocytes. The virus initially infects dividing cells in the lower layers of the epithelium, where it establishes a persistent infection. The viral genome is maintained as a low-copy-number, extrachromosomal element in these proliferating cells but switches to the late stage of the life cycle in differentiated cells. The cellular chromatin adaptor protein Brd4 is involved in several stages and processes of the viral life cycle. In concert with the viral transcriptional regulator E2, Brd4 can repress transcription from the early viral promoter. Brd4 and E2 form a complex with the viral genome that associates with host chromosomes to partition the viral genome in dividing cells; Brd4 also localizes to active sites of productive HPV DNA replication. However, because of the difficulties in producing HPV viral particles, the role of Brd4 in modulating viral transcription and replication at the initial stage of infection is unclear. In this study, we have used an HPV18 quasivirus-based genome delivery system to assess the role of Brd4 in the initial infectivity of primary human keratinocytes. We show that, upon infection of primary human keratinocytes with HPV18 quasivirus, Brd4 activates viral transcription and replication. Furthermore, this activation is independent of the functional interaction between Brd4 and the HPV18 E2 protein. IMPORTANCE HPVs lack encapsidated proteins and so rely exquisitely on host cellular factors to initiate their gene expression programs in newly infected cells. Brd4 is an important cellular chromatin adaptor molecule that normally activates host transcription initiation and elongation. In this study, we further optimize and utilize a quasivirus infection system to show that Brd4 activates HPV18 transcription at early stages of infection. HPVs are important human pathogens causing a wide range of cutaneous and tumorigenic morbidities. Therefore, specifically targeting this protein could provide a new target of therapeutic prevention of establishment of HPV infections.

The reprogramming of cellular memory in specific cell types, and in visceral adipocytes in particular, appears to be a fundamental aspect of obesity and its related negative health outcomes. We explored the hypothesis that adipose tissue contains epigenetically distinct subpopulations of adipocytes that are differentially potentiated to record cellular memories of their environment. Adipocytes are large, fragile, and technically difficult to efficiently isolate and fractionate. We developed fluorescence nuclear cytometry (FNC) and fluorescence activated nuclear sorting (FANS) of cellular nuclei from visceral adipose tissue (VAT) using the levels of the pan-adipocyte protein, peroxisome proliferator-activated receptor gamma-2 (PPARg2), to distinguish classes of PPARg2-Positive (PPARg2-Pos) adipocyte nuclei from PPARg2-Negative (PPARg2-Neg) leukocyte and endothelial cell nuclei. PPARg2-Pos nuclei were 10-fold enriched for most adipocyte marker transcripts relative to PPARg2-Neg nuclei. PPARg2-Pos nuclei showed 2- to 50-fold higher levels of transcripts encoding most of the chromatin-remodeling factors assayed, which regulate the methylation of histones and DNA cytosine (e.g., DNMT1, TET1, TET2, KDM4A, KMT2C, SETDB1, PAXIP1, ARID1A, JMJD6, CARM1, and PRMT5). PPARg2-Pos nuclei were large with decondensed chromatin. TAB-seq demonstrated 5-hydroxymethylcytosine (5hmC) levels were remarkably dynamic in gene bodies of various classes of VAT nuclei, dropping 3.8-fold from the highest quintile of expressed genes to the lowest. In short, VAT-derived adipocytes appear to be more actively remodeling their chromatin than non-adipocytes.