BACKGROUND:Discovering determinants of cardiomyocyte maturity is critical for deeply understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration, but elucidation of endogenous developmental regulators of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. MBNL1 (muscleblind-like 1) regulates fibroblast, thymocyte, and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation.METHODS:MBNL1 gain- and loss-of-function mouse models were studied at several developmental time points and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro assays to determine the mechanisms through which MBNL1 exerts its effects.RESULTS:MBNL1 is coexpressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deficiency was insufficient to promote regeneration in the adult heart because of cell cycle checkpoint activation.CONCLUSIONS:Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Targeting loss of cardiomyocyte maturity and downregulation of cell cycle inhibitors through MBNL1 deletion was not sufficient to promote adult regeneration.

Purpose: Single lung transplantation (SLT) for interstitial lung disease (ILD) has dramatically declined globally due to reported inferior long-term outcomes compared to bilateral lung transplantation. However, the impact of this approach on overall population-level waiting list mortality and net transplant benefit is unknown. This study aimed to model potential UK allocation policies with and without prioritising SLT for ILD using a discrete event simulation engine to compare impacts of this approach.

The Indian Ocean is a frequent site for the initiation of the Madden-Julian oscillation (MJO). The evolu-tion of convection during MJO initiation is intimately linked to the subcloud atmospheric mixed layer (ML). Much of the air entering developing cumulus clouds passes through the cloud base; hence, the properties of the ML are critical in deter-mining the nature of cloud development. The properties and depth of the ML are influenced by horizontal advection, precipitation-driven cold pools, and vertical motion. To address ML behavior during the initiation of the MJO, data from the 2011/12 Dynamics of the MJO Experiment (DYNAMO) are utilized. Observations from the research vessel Revelle are used to document the ML and its modification during the time leading up to the onset phase of the October MJO. The mixed layer depth increased from -500 to -700 m during the 1-12 October suppressed period, allowing a greater propor-tion of boundary layer thermals to reach the lifting condensation level and hence promote cloud growth. The ML heat bud-get defines an equilibrium mixed layer depth that accurately diagnoses the mixed layer depth over the DYNAMO convectively suppressed period, provided that horizontal advection is included. The advection at the Revelle is significantly influenced by low-level convective outflows from the southern ITCZ. The findings also demonstrate a connection between cirrus clouds and their remote impact on ML depth and convective development through a reduction in the ML radiative cooling rate. The emergent behavior of the equilibrium mixed layer has implications for simulating the MJO with models with parameterized cloud and turbulent-scale motions.

The Dynamics of the Madden-Julian Oscillation (MJO) (DYNAMO) field campaign over the central Indian Ocean captured three strong MJO events during October-December 2011. Using the conventional budget approach of Yanai et al. surface rainfall P-0 is computed as a residual from the vertically integrated form of the moisture budget equation. This budget-derived P-0 is spatially averaged over the Gan Island NCAR S-PolKa radar domain and compared with rainfall estimates from the radar itself. To isolate the MJO signal, these rainfall time series are low-pass (LP) filtered and a three-MJO composite is created based on the time of maximum LP-filtered S-PolKa rainfall for each event. A comparison of the two composite rainfall estimates shows that the budget rainfall overestimates the radar rainfall by similar to 15% in the MJO buildup stage and underestimates radar rainfall by similar to 8% in the MJO decay stage. These rainfall differences suggest that hydrometeor (clouds and rain) storage and advection effects, which are neglected in the budget approach, are likely significant. Satellite and ground-based observations are used to investigate these hydrometeor storage and advection effects. While the findings are qualitatively consistent with expectations from theory, they fall short of explaining their full magnitude, suggesting even more refined experimental designs and measurements will be needed to adequately address this issue.

Systemic and oral health are interconnected via bacteria and their byproducts which can circulate throughout the body which are found in the oral biofilm. Oral biofilm and its associated periodontal health have not been frequently addressed in patients with systemic health issues. This is especially true for those patients who do not respond to medical treatment via their physician for systemic issues. The periodontal sulcus in the absence of clinical presence of periodontal disease (bleeding on probing, gingival inflammation) may have oral biofilm present. Periodontal reaction is dependent on the patient’s immune response to the associated bacteria and their byproducts present in the oral biofilm. Increasing evidence has emerged in recent years that are connecting oral biofilms with systemic conditions, either by initiating them or by complicating those medical conditions. Patient health needs to be considered as a whole-body system with connections that may originate in the oral cavity and have distant effects throughout the body. In order to maximize the patient’s total health, healthcare needs to be a coordination between the physician and dentist to eliminate the oral biofilm and aid in the prevention of systemic disease or minimize these effects to improve the overall patient health and their quality of life. Various systemic health areas have been associated with the bacteria in oral biofilms and their byproducts. Those include cardiovascular disease, chronic kidney disease, diabetes, pulmonary disease, prostate cancer, colon cancer, pancreatic cancer, pre-term pregnancy, erectile dysfunction, Alzheimer’s disease, and rheumatoid arthritis. This article will discuss oral biofilm, its systemic effects, and review the medical conditions associated with the oral systemic connection with an extensive review of the literature to aid in demonstrating the total body connection.

Chemotherapy has remained the mainstay for the treatment of multiple types of cancers. In particular, topical use of chemotherapy has been used for skin cancers. Though effective, topical chemotherapy has been limited due to adverse effects such as local and even systemic toxicities. Given our ongoing studies that exposure to pro-oxidative stressors, including therapeutic agents induces the generation of extracellular vesicles known as microvesicle particles (MVP) which are dependent on activation of the Platelet-activating factor-receptor (PAFR), a G-protein coupled receptor present on various cell types, and acid sphingomyelinase (ASMase), an enzyme required for MVP biogenesis. Based upon this premise, we tested the hypothesis whether topical application of gemcitabine will induce MVP generation in human skin. Our ex vivo studies using human skin explants demonstrate that gemcitabine treatment results in MVP generation in a dose-dependent manner in a process blocked by PAFR antagonist and ASMase inhibitor. To confirm the mechanisms, we employed PAFR-expressing and deficient (Ptafr-/-) mouse models as well as mouse deficient in ASMase enzyme (Smpd-1-/-). Similar to the findings using human skin explants, our studies demonstrate that gemcitabine-induced MVP release in WT mice was blunted in Ptafr-/- and Smpd-1-/- mice. These findings demonstrate a possible mechanism by which local chemotherapy can signal systemically, in a process that is dependent upon the PAFR-ASMase pathway. Future studies can test the abilities of blocking MVP release on the effectiveness and tolerability of topical chemotherapy.

Frequently, periodontal health and it's associated oral biofilm has not been addressed in those patients who have systemic health issues, especially those who are not responding to medical treatment via their physician. Oral biofilm may be present in the periodontal sulcus in the absence of clinical disease of periodontal disease (bleeding on probing, gingival inflammation) and periodontal reaction is dependent on the patient's immune response to the associated bacterial and their byproducts. Increasing evidence has been emerging the past decade connecting oral biofilm with systemic conditions, either initiating them or complicating those medical conditions. The patient's health needs to be thought of as a whole-body system with connections that may originate in the oral cavity and have distant affects throughout the body. To maximize total health, a coordination in healthcare needs to be a symbiosis between the physician and dentist to eliminate the oral biofilm and aid in prevention of systemic disease or minimize those effects to improve the patient's overall health and quality of life. Various areas of systemic health have been associated with the bacteria and their byproducts in the oral biofilm. Those include cardiovascular disease, chronic kidney disease, diabetes, pulmonary disease, prostate cancer, colon cancer, pancreatic cancer, pre-term pregnancy, erectile dysfunction Alzheimer's disease and Rheumatoid arthritis. This article will discuss oral biofilm, its affects systemically and review the medical conditions associated with the oral systemic connection with an extensive review of the literature.

The Asian citrus psyllid (Diaphorina citri) is a pest of citrus and the primary insect vector of the bacterial pathogen, ‘Candidatus Liberibacter asiaticus’ (CLas), which is associated with citrus greening disease. The citrus relative Murraya paniculata (orange jasmine) is a host plant of D. citri but is more resistant to CLas compared with all tested Citrus genotypes. The effect of host switching of D. citri between Citrus medica (citron) and M. paniculata plants on the acquisition and transmission of CLas was investigated. The psyllid CLas titer and the proportion of CLas-infected psyllids decreased in the generations after transfer from CLas-infected citron to healthy M. paniculata plants. Furthermore, after several generations of feeding on M. paniculata, pathogen acquisition (20 to 40% reduction) and transmission rates (15 to 20% reduction) in psyllids transferred to CLas-infected citron were reduced compared with psyllids continually maintained on infected citron. Top-down (difference gel electrophoresis) and bottom-up (shotgun MS/MS) proteomics methods were used to identify changes in D. citri protein expression resulting from host plant switching between Citrus macrophylla and M. paniculata. Changes in expression of insect metabolism, immunity, and cytoskeleton proteins were associated with host plant switching. Both transient and sustained feeding on M. paniculata induced distinct patterns of protein expression in D. citri compared with psyllids reared on C. macrophylla. The results point to complex interactions that affect vector competence and may lead to strategies to control the spread of citrus greening disease.

Fine et al. (2016, hereafter F16) investigated the potential role of Sumatra Island, as well as the Malay Peninsula and Java, in creating terrain-induced circulations over the Indian Ocean (IO) that subsequently develop into tropical cyclones (TCs). Applying sophisticated vortex tracking software to 2.5 yrs of model analyses, F16 found four regions downstream of topographic features in the Maritime Continent to be prolific generators of low-level cyclonic vortices (123/yr). This present study extends the limited analyses of F16 by applying a similar approach to 10 yrs (2008-2017) of ERA5 analyses. While the 2.5-yr period which F16 studied was slightly (8%) more active in terms of vortex production than the 10-yr period, in general the findings of F16 are representative of the longer-term record with 80% of all shed vortices occurring with easterly low-level (925 hPa) flow over the hotspot regions. Additional analysis of the 10-yr record found that vortex counts are highest near MJO phase 1 when low-level easterlies are strongest over the maritime continent region. A secondary peak in vortex counts occurs during MJO phase 4 when low-level westerlies were present near the equator west of Sumatra. This suggests that low-level westerly surges on the equator impinging on Sumatra associated with the MJO contribute to an increase in wake vortex development. While the frequency of vortex genesis over the four hotspot regions is strongly tied to the annual cycle of winds, periods with anomalous zonal flow are shown to impact vortex counts. This is most apparent in the region off the southern tip of Sumatra where vortex counts were 4 times higher during periods of anomalous easterlies compared to periods with anomalous westerlies. In this region positive (negative) ENSO and Indian-Ocean Dipole conditions drive anomalous easterlies (westerlies) which impact vortex formation rates.

Analyses of atmospheric heat and moisture budgets serve as an effective tool to study convective characteristics over a region and to provide large‐scale forcing fields for various modeling applications. This paper examines two popular methods for computing large‐scale atmospheric budgets: the conventional budget method (CBM) using objectively gridded analyses based primarily on radiosonde data and the constrained variational analysis (CVA) approach which supplements vertical profiles of atmospheric fields with measurements at the top of the atmosphere and at the surface to conserve mass, water, energy, and momentum. Successful budget computations are dependent on accurate sampling and analyses of the thermodynamic state of the atmosphere and the divergence field associated with convection and the large‐scale circulation that influences it. Utilizing analyses generated from data taken during Dynamics of the Madden‐Julian Oscillation (DYNAMO) field campaign conducted over the central Indian Ocean from October to December 2011, we evaluate the merits of these budget approaches and examine their limitations. While many of the shortcomings of the CBM, in particular effects of sampling errors in sounding data, are effectively minimized with CVA, accurate large‐scale diagnostics in CVA are dependent on reliable background fields and rainfall constraints. For the DYNAMO analyses examined, the operational model fields used as the CVA background state provided wind fields that accurately resolved the vertical structure of convection in the vicinity of Gan Island. However, biases in the model thermodynamic fields were somewhat amplified in CVA resulting in a convective environment much weaker than observed.

During the Dynamics of the MJO (DYNAMO) field campaign, radiosonde launches were regularly conducted from three small islands/atolls (Malé and Gan, Maldives, and Diego Garcia, British Indian Ocean Territory) as part of a large-scale sounding network. Comparison of island upsondes with nearby and near-contemporaneous dropsondes over the ocean provides evidence for the magnitude and scope of the islands’ influence on the surrounding atmosphere and on the island upsonde profiles. The island’s impact on the upsonde data is most prominent in the lowest 200 m. Noting that the vertical gradients of temperature, moisture, and winds over the ocean are generally constant in the lowest 0.5 km of dropsondes, a simple procedure was constructed to adjust the upsonde profiles in the lowest few hundred meters to resemble the atmospheric structures over the open ocean. This procedure was applied to the soundings from the three islands mentioned above for the October–December 2011 period of DYNAMO. As a result of this procedure, the adjusted diurnal cycle amplitude of surface temperature is reduced fivefold, resembling that over the ocean, and low-level wind speeds are increased in ~90% of the island soundings. Examination of the impact of these sounding adjustments shows that dynamical and budget fields are primarily affected by adjustments to the wind field, whereas convective parameters are sensitive to the adjustments in thermodynamic fields. Although the impact of the adjustments is generally small (on the order of a few percent), intraseasonal wind regime changes result in some systematic variations in divergence and vertical motion over the sounding arrays.

Huanglongbing (HLB) is a deadly, incurable citrus disease putatively caused by the unculturable bacterium, 'CandidatusLiberibacter asiaticus' (CLas), and transmitted byDiaphorina citri. Prior studies suggestD.citritransmits CLas in a circulative and propagative manner; however, the precise interactions necessary for CLas transmission remain unknown, and the impact of insect sex onD.citri-CLas interactions is poorly understood despite reports of sex-dependent susceptibilities to CLas. We analyzed the transcriptome, proteome, metabolome, and microbiome of male and female adultD.citrireared on healthy or CLas-infectedCitrus medicato determine shared and sex-specific responses ofD.citriand its endosymbionts to CLas exposure. More sex-specific than sharedD.citriresponses to CLas were observed, despite there being no difference between males and females in CLas density or relative abundance. CLas exposure altered the abundance of proteins involved in immunity and cellular and oxidative stress in a sex-dependent manner. CLas exposure impacted cuticular proteins and enzymes involved in chitin degradation, as well as energy metabolism and abundance of the endosymbiont 'CandidatusProfftella armatura' in both sexes similarly. Notably, diaphorin, a toxic Profftella-derived metabolite, was more abundant in both sexes with CLas exposure. The responses reported here resulted from a combination of CLas colonization ofD.citrias well as the effect of CLas infection onC.medica. Elucidating these impacts onD.citriand their endosymbionts contributes to our understanding of the HLB pathosystem and identifies the responses potentially critical to limiting or promoting CLas acquisition and propagation in both sexes.

Spanning across the equator with a northwest–southeast orientation, the island of Sumatra can exert significant influences on low-level flow. Under northeasterly flow, in particular, lee vortices can form and some of them may subsequently develop into tropical cyclones (TCs) in the Indian Ocean (IO). Building upon the recent work of Fine et al., this study investigates the roles of the Sumatra topography and other common features on the formation of selected cases for analysis and numerical experiments. Four cases in northern IO were selected for analysis and two of them [Nisha (2008) and Ward 2009)] for simulation at a grid size of 4 km. Sensitivity tests without the Sumatra topography were also performed. Our results indicate that during the lee stage, most pre-TC vortices tend to be stronger with a clearer circulation when the topography is present. However, the island’s terrain is a helpful but not a deciding factor in TC formation. Specifically, the vortices in the no-terrain tests also reach TC status, but just at a later time. Some common ingredients contributing to a favorable environment for TC genesis are identified. They include northeasterly winds near northern Sumatra, westerly wind bursts along the equator, and migratory disturbances (TC remnants or Borneo vortices) to provide additional vorticity/moisture from the South China Sea. These factors also appear in most of the 22 vortices in northern IO during October–December in 2008 and 2009. For the sole case (Cleo) examined in southern IO, the deflection of equatorial westerlies into northwesterlies by Sumatra (on the windward side) is also helpful to TC formation.

Background & Aim Enumerating circulating white blood cells in peripheral blood using flow cytometry is a popular method for tracking changes in the immune system. We have developed a methodology using quantitative flow cytometry to study 100+ phenotypes in combination with bioinformatic approaches to identify characteristic immune profiles or combinations of similarly expressed leukocytes among patient groups. Currently, aside from survival and degree of disease progression or treatment benefit there is a lack of methods for identifying active changes to the immune system and good markers for identify cause of adverse events, all problems which could be solved with the use of immune monitoring. Currently, the Mayo clinic has utilized this method in over 30% of their MSC, DC, and CAR-T clinical trials with the intent of monitoring all trials using this methodology. Thus far we have applied this analysis to disease patient groups such as amyotrophic lateral sclerosis, thyroid cancer, liver cancer, glioblastoma multiforme, and chronic lymphocytic leukemia. Methods, Results & Conclusion These analyses uncovered previously unidentified subgroups of ALS patients that predicted survival, biomarkers in diseased patients, and changes in the immune systems of those in clinical trials. When clustered with healthy volunteers, we found two distinct profiles of ALS patients, one that more closely resembled a healthy immune system and one that did not. Patients that profiled separately from healthy volunteers had unique phenotypic characteristics such as increased absolute counts of CD3+CD56+ (p>0.001), CD3+CD8+CD28+ (p>0.001), CD3+CD4+PD-1+ T cells, increased survival (p=0.012), and were more likely to have familial ALS rather than sporadic (p=0.011). Additionally, we have tested our system on a cohort of 130 healthy volunteers to see which immune parameters contribute most to clustering of non-diseased individuals. Thus, we believe that profiling patients based on their immune systems can aid in predicting which immune modulating therapies will be most effective and in the future help in tailoring immune therapies specific to the patient. Based on our work we have confidence that immune monitoring it is key in unlocking complex mechanisms between the various components of the immune system that are critical to wound repair, healing and regenerative medicine as well as an essential tool for clinical trials. Enumerating circulating white blood cells in peripheral blood using flow cytometry is a popular method for tracking changes in the immune system. We have developed a methodology using quantitative flow cytometry to study 100+ phenotypes in combination with bioinformatic approaches to identify characteristic immune profiles or combinations of similarly expressed leukocytes among patient groups. Currently, aside from survival and degree of disease progression or treatment benefit there is a lack of methods for identifying active changes to the immune system and good markers for identify cause of adverse events, all problems which could be solved with the use of immune monitoring. Currently, the Mayo clinic has utilized this method in over 30% of their MSC, DC, and CAR-T clinical trials with the intent of monitoring all trials using this methodology. Thus far we have applied this analysis to disease patient groups such as amyotrophic lateral sclerosis, thyroid cancer, liver cancer, glioblastoma multiforme, and chronic lymphocytic leukemia. These analyses uncovered previously unidentified subgroups of ALS patients that predicted survival, biomarkers in diseased patients, and changes in the immune systems of those in clinical trials. When clustered with healthy volunteers, we found two distinct profiles of ALS patients, one that more closely resembled a healthy immune system and one that did not. Patients that profiled separately from healthy volunteers had unique phenotypic characteristics such as increased absolute counts of CD3+CD56+ (p>0.001), CD3+CD8+CD28+ (p>0.001), CD3+CD4+PD-1+ T cells, increased survival (p=0.012), and were more likely to have familial ALS rather than sporadic (p=0.011). Additionally, we have tested our system on a cohort of 130 healthy volunteers to see which immune parameters contribute most to clustering of non-diseased individuals. Thus, we believe that profiling patients based on their immune systems can aid in predicting which immune modulating therapies will be most effective and in the future help in tailoring immune therapies specific to the patient. Based on our work we have confidence that immune monitoring it is key in unlocking complex mechanisms between the various components of the immune system that are critical to wound repair, healing and regenerative medicine as well as an essential tool for clinical trials.

The West African summer monsoon features multiple, complex interactions between African easterly waves (AEWs), moist convection, variable land surface properties, dust aerosols, and the diurnal cycle. One aspect of these interactions, the coupling between convection and AEWs, is explored using observations obtained during the 2006 African Monsoon Multidisciplinary Analyses (AMMA) field campaign. During AMMA, a research weather radar operated at Niamey, Niger, where it surveilled 28 squall-line systems characterized by leading convective lines and trailing stratiform regions. Nieto Ferreira et al. found that the squall lines were linked with the passage of AEWs and classified them into two tracks, northerly and southerly, based on the position of the African easterly jet (AEJ). Using AMMA sounding data, we create a composite of northerly squall lines that tracked on the cyclonic shear side of the AEJ. Latent heating within the trailing stratiform regions produced a midtropospheric positive potential vorticity (PV) anomaly centered at the melting level, as commonly observed in such systems. However, a unique aspect of these PV anomalies is that they combined with a 400-500-hPa positive PV anomaly extending southward from the Sahara. The latter feature is a consequence of the deep convective boundary layer over the hot Saharan Desert. Results provide evidence of a coupling and merging of two PV sources-one associated with the Saharan heat low and another with latent heating-that ends up creating a prominent midtropospheric positive PV maximum to the rear of West African squall lines.