New Technologies for Monitoring Coastal Ecosystem Dynamics.

In recent years, our view of coastal ecosystems has expanded and come into greater focus. We are currently making more types of observations over larger areas and at higher frequencies than ever before. These advances are timely, as coastal ecosystems are facing increasing pressures from climate change and anthropogenic stressors. This article synthesizes recent literature on emerging technologies for coastal ecosystem monitoring, including satellite monitoring, aerial and underwater drones, in situ sensor networks, fiber optic systems, and community science observatories. We also describe how advances in artificial intelligence and deep learning underpin all these technologies by enabling insights to be drawn from increasingly large data volumes. Even with these recent advances, there are still major gaps in coastal ecosystem monitoring that must be addressed to manage coastal ecosystems during a period of accelerating global change.

Brain region-specific alterations in gene expression trajectories in the offspring born from influenza A virus infected mice.

Influenza A virus (IAV) infection during pregnancy can increase the risk for neurodevelopmental disorders in the offspring, however, the underlying neurobiological mechanisms are largely unknown. To recapitulate viral infection, preclinical studies have traditionally focused on using synthetic viral mimetics, rather than live IAV, to examine consequences of maternal immune activation (MIA)-dependent processes on offspring. In contrast, few studies have used live IAV to assess effects on global gene expression, and none to date have addressed whether moderate IAV, mimicking seasonal influenza disease, alters normal gene expression trajectories in different brain regions across different stages of development. Herein, we show that moderate IAV infection during pregnancy, which causes mild maternal disease and no overt foetal complications in utero, induces lasting effects on the offspring into adulthood. We observed behavioural changes in adult offspring, including disrupted prepulse inhibition, dopaminergic hyper-responsiveness, and spatial recognition memory deficits. Gene profiling in the offspring brain from neonate to adolescence revealed persistent alterations to normal gene expression trajectories in the prefronal cortex, hippocampus, hypothalamus and cerebellum. Alterations were found in genes involved in inflammation and neurogenesis, which were predominately dysregulated in neonatal and early adolescent offspring. Notably, late adolescent offspring born from IAV infected mice displayed altered microglial morphology in the hippocampus. In conclusion, we show that moderate IAV during pregnancy perturbs neurodevelopmental trajectories in the offspring, including alterations in the neuroinflammatory gene expression profile and microglial number and morphology in the hippocampus, resulting in behavioural changes in adult offspring. Such early perturbations may underlie the vulnerability in human offspring for the later development of neurodevelopmental disorders, including schizophrenia. Our work highlights the importance of using live IAV in developing novel preclinical models that better recapitulate the real-world impact of inflammatory insults during pregnancy on offspring neurodevelopmental trajectories and disease susceptibility later in life.

Physics of the Seasonal Sea Ice Zone.

The seasonal sea ice zone encompasses the region between the winter maximum and summer minimum sea ice extent. In both the Arctic and Antarctic, the majority of the ice cover can now be classified as seasonal. Here, we review the sea ice physics that governs the evolution of seasonal sea ice in the Arctic and Antarctic, spanning sea ice growth, melt, and dynamics and including interactions with ocean surface waves as well as other coupled processes. The advent of coupled wave-ice modeling and discrete-element modeling, together with improved and expanded satellite observations and field campaigns, has yielded advances in process understanding. Many topics remain in need of further investigation, including rheologies appropriate for seasonal sea ice, wave-induced sea ice fracture, welding for sea ice freeze-up, and the distribution of snow on seasonal sea ice. Future research should aim to redress biases (such as disparities in focus between the Arctic and Antarctic and between summer and winter processes) and connect observations to modeling across spatial scales.

INHIBITION OF INTEGRIN VLA-3 AND TETRASPANIN CD151 PROTECTS AGAINST NEUTROPHIL-MEDIATED ENDOTHELIAL DAMAGE.

ABSTRACT: Background: The recruitment of neutrophils to sites of localized injury or infection is initiated by changes on the surface of endothelial cells located in proximity to tissue damage. Inflammatory mediators, such as TNF-α, increase surface expression of adhesive ligands and receptors on the endothelial surface to which neutrophils tether and adhere. Neutrophils then transit through the activated endothelium to reach sites of tissue injury with little lasting vascular injury. However, in cases of sepsis, the interaction of endothelial cells with highly activated neutrophils can cause damage vascular damage. The identification of molecules that are essential for neutrophil diapedesis may reveal targets of therapeutic opportunity for preservation of endothelial function in the presence of critical illness. We tested the hypothesis that inhibition of neutrophil ß1 integrin very late antigen-3 (VLA-3; α3ß1) and/or inhibition of the tetraspanin (TM4) family member CD151 would protect against neutrophil-mediated loss of endothelial function. Methods: Blood was obtained from septic patients or healthy donors. Neutrophils were purified, and aliquots were treated with/without proinflammatory molecules. Confluent human umbilical vascular endothelial cells were activated with TNF-α. Electric cell impedance sensing was used to determine monolayer resistance over time after the addition of neutrophils that were treated with blocking antibodies against VLA-3 and/or CD151 or isotype controls. Groups (depending on relevancy) were analyzed by Mann-Whitney U test, Wilcoxon test, or repeated-measures one-way ANOVA. Results: Neutrophils from septic patients and neutrophils activated ex vivo reduced endothelial monolayer resistance to a greater extent than neutrophils from healthy donors. Antibody blockade of VLA-3 and/or CD151 significantly reduced activation-associated endothelial damage. Similar findings were demonstrated on fibronectin, collagen I, collagen IV, and laminin, suggesting that neutrophil surface VLA-3 and CD151 are responsible for endothelial damage regardless of substrata and are likely to be operative in all bodily tissues. Conclusion: This report identifies VLA-3 and CD151 on the activated human neutrophil, which are responsible for damage to endothelial function. Targeting these molecules in vivo may demonstrate preservation of organ function during critical illness.

Low dose aspirin prevents endothelial dysfunction in the aorta and foetal loss in pregnant mice infected with influenza A virus.

Influenza A virus (IAV) infection in pregnancy resembles a preeclamptic phenotype characterised by vascular dysfunction and foetal growth retardation. Given that low dose aspirin (ASA) is safe in pregnancy and is used to prevent preeclampsia, we investigated whether ASA or NO-conjugated aspirin, NCX4016, resolve vascular inflammation and function to improve offspring outcomes following IAV infection in pregnant mice. Pregnant mice were intranasally infected with a mouse adapted IAV strain (Hkx31; 104 plaque forming units) and received daily treatments with either 200µg/kg ASA or NCX4016 via oral gavage. Mice were then culled and the maternal lungs and aortas collected for qPCR analysis, and wire myography was performed on aortic rings to assess endothelial and vascular smooth muscle functionality. Pup and placentas were weighed and pup growth rates and survival assessed. IAV infected mice had an impaired endothelial dependent relaxation response to ACh in the aorta, which was prevented by ASA and NCX4016 treatment. ASA and NCX4016 treatment prevented IAV dissemination and inflammation of the aorta as well as improving the pup placental ratios in utero, survival and growth rates at post-natal day 5. Low dose ASA is safe to use during pregnancy for preeclampsia and this study demonstrates that ASA may prove a promising treatment for averting the significant vascular complications associated with influenza infection during pregnancy.

Building on a theme: The redox hierarchy of pyridine nucleotide-disulfide oxidoreductases.

Flavin disulfide reductases (FDRs) are FAD-dependent enzymes that transmit electrons from NAD(P)H to reduce specific oxidant substrate disulfides. These enzymes have been studied extensively, most particularly the paradigm examples: glutathione reductase and thioredoxin reductase. The common, though not universal, traits of the family include a tyrosine- or phenylalanine-gated binding pocket for NAD(P) nicotinamides adjacent to the FAD isoalloxazine re-face, and a disulfide stacked against the si-face of the isoalloxazine whose dithiol form is activated for subsequent exchange reactions by a nearby histidine acting as a base. This arrangement promotes transduction of the reducing equivalents for disulfide exchange relay reactions. From an observational standpoint the proximal parallel stacking of three redox moieties induces up to three opportunities for unique charge transfer interactions (NAD(P)H FAD, NAD(P)+•FADH2, and FAD•thiolate). In transient state, the charge transfer transitions provide discrete signals to assign reaction sequences. This review summarizes the lineage of observations for the FDR enzymes that have been extensively studied. Where applicable and in order to chart a consistent interpretation of the record, only data derived from studies that used anaerobic methods are cited. These data reveal a recurring theme for catalysis that is elaborated with specific additional functionalities for each oxidant substrate.

Dyadic Moderators of the Minority Stress-HIV Risk Association in Male Couples.

Minority stressors have been linked to HIV risk behaviors among gay, bisexual, queer, and other men who have sex with men (MSM). Committed partnerships are a key context for new HIV infections and coping with minority stress among MSM, but very little work has tested the minority stress-HIV risk link among male couples, and little is known about how processes within one's relationship may exacerbate or buffer this association. The present study examined links between minority stress (i.e., internalized stigma, microaggressions) and HIV transmission risk behaviors (i.e., condomless anal sex with outside partners, breaks in relationship agreements) among male couples, as well as relationship-based moderators (i.e., social support, dyadic coping) of these associations. An analytic sample of male couples from a large cohort study (analytic N = 410 individuals, 205 dyads) completed self-report measures of minority stress, relationship-based moderators, and HIV transmission risk behaviors which were submitted to moderated actor-partner interdependence models (APIMs). In many cases, coping with stress with one's partner buffered the minority stress-HIV transmission link risk. However, findings also suggested situations in which partners may overburden one another with coping, thus exacerbating HIV-related risk behaviors.

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices.

Inborn errors of immunity (IEIs) encompass a diverse spectrum of genetic disorders that disrupt the intricate mechanisms of the immune system, leading to a variety of clinical manifestations. Traditionally associated with an increased susceptibility to recurrent infections, IEIs have unveiled a broader clinical landscape, encompassing immune dysregulation disorders characterized by autoimmunity, severe allergy, lymphoproliferation, and even malignancy. This review delves into the intricate interplay between IEIs and the JAK-STAT signaling pathway, a critical regulator of immune homeostasis. Mutations within this pathway can lead to a wide array of clinical presentations, even within the same gene. This heterogeneity poses a significant challenge, necessitating individually tailored therapeutic approaches to effectively manage the diverse manifestations of these disorders. Additionally, JAK-STAT pathway defects can lead to simultaneous susceptibility to both infection and immune dysregulation. JAK inhibitors, with their ability to suppress JAK-STAT signaling, have emerged as powerful tools in controlling immune dysregulation. However, questions remain regarding the optimal selection and dosing regimens for each specific condition. Hematopoietic stem cell transplantation (HSCT) holds promise as a curative therapy for many JAK-STAT pathway disorders, but this procedure carries significant risks. The use of JAK inhibitors as a bridge to HSCT has been proposed as a potential strategy to mitigate these risks.

Shining the Spotlight on Multiple Daily Insulin Therapy: Real-World Evidence of the InPen Smart Insulin Pen.

Objective: Connected insulin pens are creating opportunities for the millions of individuals with diabetes using multiple daily injections (MDI) therapy across the globe. Continuous glucose monitoring (CGM) data from connected insulin pens are revealing gaps and opportunities to significantly improve care for this population. In this article, we report real-world findings of the InPen™ smart insulin pen paired with CGM (InPen system), used by persons with type 1 diabetes (T1D) and type 2 diabetes (T2D). Methods: A retrospective cohort analysis was conducted with the real-world data collected from the InPen system of individuals (N = 3793 with T1D, N = 552 with T2D, and N = 808 unidentified) who used the system from January 01, 2020, to December 31, 2021. Diabetes management (e.g., missed and mistimed insulin dosing, mismatched food intake, and correction dose delivery) and glycemic outcomes were assessed. Results: In the overall and T1D populations, a dosing frequency of ≥3 doses per day and a missed dose frequency of <20% was associated with improved glycemia. In adults with T2D, missing <20% of doses was the significant factor determining improved glycemia. Conclusion: This analysis, integrating data from a smart insulin pen and CGM, provides insights into the impact of dosing behavior on glycemic outcomes and informs counseling strategies for the diabetes care team, through technologically advanced insulin management for those using MDI therapy.

Assigning function to active site residues of Schistosoma mansoni thioredoxin/glutathione reductase from analysis of transient state reductive half-reactions with variant forms of the enzyme.

Thioredoxin/glutathione reductase (TGR) from the platyhelminthic parasitic worms has recently been identified as a drug target for the treatment of schistosomiasis. Schistosomes lack catalase, and so are heavily reliant on the regeneration of reduced thioredoxin (Trx) and glutathione (GSH) to reduce peroxiredoxins that ameliorate oxidative damage from hydrogen peroxide generated by the host immune response. This study focuses on the characterization of the catalytic mechanism of Schistosoma mansoni TGR (SmTGR). Variant forms of SmTGR were studied to assign the function of residues that participate in the electron distribution chain within the enzyme. Using anaerobic transient state spectrophotometric methods, redox changes for the FAD and NADPH were observed and the function of specific residues was defined from observation of charge transfer absorption transitions that are indicative of specific complexations and redox states. The C159S variant prevented distribution of electrons beyond the flavin and as such did not accumulate thiolate-FAD charge transfer absorption. The lack of this absorption facilitated observation of a new charge transfer absorption consistent with proximity of NADPH and FAD. The C159S variant was used to confine electrons from NADPH at the flavin, and it was shown that NADPH and FAD exchange hydride in both directions and come to an equilibrium that yields only fractional FAD reduction, suggesting that both have similar reduction potentials. Mutation of U597 to serine resulted in sustained thiolate-FAD charge transfer absorption and loss of the ability to reduce Trx, indicating that the C596-U597 disulfide functions in the catalytic sequence to receive electrons from the C154 C159 pair and distribute them to Trx. No kinetic evidence for a loss or change in function associated with the distal C28-C31 disulfide was observed when the C31S variant reductive half-reaction was observed. The Y296A variant was shown to slow the rate of but increase extent of reduction of the flavin, and the dissociation of NADP+. The H571 residue was confirmed to be the residue responsible for the deprotonation of the C159 thiol, increasing its reactivity and generating the prominent thiolate-FAD charge transfer absorption that accumulates with oxidation of the flavin.

TLR7 promotes chronic airway disease in RSV-infected mice.

Respiratory syncytial virus (RSV) commonly infects the upper respiratory tract (URT) of humans, manifesting with mild cold or flu-like symptoms. However, in infants and the elderly, severe disease of the lower respiratory tract (LRT) often occurs and can develop into chronic airway disease. A better understanding of how an acute RSV infection transitions to a LRT chronic inflammatory disease is critically important to improve patient care and long-term health outcomes. To model acute and chronic phases of the disease, we infected wild-type C57BL/6 and toll-like receptor 7 knockout (TLR7 KO) mice with RSV and temporally assessed nasal, airway and lung inflammation for up to 42 days post-infection. We show that TLR7 reduced viral titers in the URT during acute infection but promoted pronounced pathogenic and chronic airway inflammation and hyperreactivity in the LRT. This study defines a hitherto unappreciated molecular mechanism of lower respiratory pathogenesis to RSV, highlighting the potential of TLR7 modulation to constrain RSV pathology to the URT.

Substance Use and Relationship Functioning Among Young Male Couples.

Research shows that, for different sex couples, individual levels of substance use are deleterious for relationship quality (e.g., satisfaction, intimate partner aggression), whereas dyadic concordance is usually protective. However, there has been no research on these effects among male couples, even though they show increased risk for substance use and certain indices of relationship distress (e.g., intimate partner aggression) compared to different sex couples. Male partners also display distinct similarity patterns and norms surrounding substance use, suggesting that there might be unique effects of substance use on relationship quality among this population. We conducted actor-partner interdependence models of substance use on relationship quality (intimate partner aggression, satisfaction) among a large sample of male dyads (N = 934 individuals, N = 467 dyads). Results suggested that there are novel actor, partner, and similarity effects that imply unique pathways to relationship well-being for male couples. These results are discussed in light of future clinical and empirical efforts. [NCT03186534 - 6/12/2017; NCT03284541 - 6/23/2017].

A Database of Snow on Sea Ice in the Central Arctic Collected during the MOSAiC expedition.

Snow plays an essential role in the Arctic as the interface between the sea ice and the atmosphere. Optical properties, thermal conductivity and mass distribution are critical to understanding the complex Arctic sea ice system's energy balance and mass distribution. By conducting measurements from October 2019 to September 2020 on the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition, we have produced a dataset capturing the year-long evolution of the physical properties of the snow and surface scattering layer, a highly porous surface layer on Arctic sea ice that evolves due to preferential melt at the ice grain boundaries. The dataset includes measurements of snow during MOSAiC. Measurements included profiles of depth, density, temperature, snow water equivalent, penetration resistance, stable water isotope, salinity and microcomputer tomography samples. Most snowpit sites were visited and measured weekly to capture the temporal evolution of the physical properties of snow. The compiled dataset includes 576 snowpits and describes snow conditions during the MOSAiC expedition.

The unusual chemical sequences of mammalian dihydropyrimidine dehydrogenase revealed by transient-state analysis.

Dihydropyrimidine dehydrogenase (DPD) catalyzes the reduction of the 5,6-vinylic bond of uracil and thymine with electrons from NADPH. The complexity of the enzyme belies the simplicity of the reaction catalyzed. To accomplish this chemistry DPD has two active sites that are ∼60Šapart, both of which house flavin cofactors, FAD and FMN. The FAD site interacts with NADPH, while the FMN site with pyrimidines. The distance between the flavins is spanned by four Fe4S4 centers. Though DPD has been studied for nearly 50years, it is only recently that the novel apects of its mechanism have been described. The primary reason for this is that the chemistry of DPD is not portrayed adequately by known descriptive steady-state mechanism categories. The highly chromophoric nature of the enzyme has recently been exploited in transient-state to document unexpected reaction sequences. Specifically, DPD undergoes reductive activation prior to catalytic turnover. Two electrons are taken up from NADPH and transmitted via the FAD and Fe4S4 centers to form the FAD•4(Fe4S4)•FMNH2 form of the enzyme. This form of the enzyme will only reduce pyrimidine substrates in the presence NADPH, establishing that hydride transfer to the pyrimidine precedes reductive reactivation that reinstates the active form of the enzyme. DPD is therefore the first flavoprotein dehydrogenase known to complete the oxidative half-reaction prior to the reductive half-reaction. Here we describe the methods and deduction that led to this mechanistic assignment.

Risky Sexual Behaviors as a Transaction of Individual Differences and Situational Context.

Risky sexual behaviors (RSBs) incur large societal and personal costs. Despite widespread prevention efforts, RSBs and associated consequences (e.g., sexually transmitted infections) continue to rise. A proliferation of research has emerged on situational (e.g., alcohol use) and individual difference (e.g., impulsivity) factors to explain this rise, but these approaches assume an unrealistically static mechanism underlying RSB. Because this prior research has resulted in few compelling effects, we sought to innovate by examining the interaction of situation and individual differences in explaining RSBs. A large sample (N = 105) completed baseline reports of psychopathology and 30 daily diary reports of RSBs and associated contexts. These data were submitted to multilevel models including cross-level interactions to test a person-by-situation conceptualization of RSBs. Results suggested that RSBs are most strongly predicted from interactions of person- and situation-level factors in both protective and facilitative directions. These interactions outnumbered main effects and commonly included partner commitment as a central mechanism. These results point to theoretical and clinical gaps in preventing RSB and urge a departure from prior ways of conceptualizing sexual risk as a static outcome.

Descriptive Analysis of Transient-State Observations for Thioredoxin/Glutathione Reductase (Sec597Cys) from Schistosoma mansoni.

Thioredoxin/glutathione reductase from Schistosoma mansoni (SmTGR) catalyzes the reduction of both oxidized thioredoxin and glutathione with electrons from reduced nicotinamide adenine dinucleotide phosphate (NADPH). SmTGR is a drug target for the treatment of Schistosomiasis, an infection caused by Schistosoma platyhelminths residing in the blood vessels of the host. Schistosoma spp. are reliant on TGR enzymes as they lack catalase and so use reduced thioredoxin and glutathione to regenerate peroxiredoxins consumed in the detoxification of reactive oxygen species. SmTGR is a flavin adenine dinucleotide (FAD)-dependent enzyme, and we have used the flavin as a spectrophotometric reporter to observe the movement of electrons within the enzyme. The data show that NADPH fractionally reduces the active site flavin with an observed rate constant estimated in this study to be ∼3000 s-1. The flavin then reoxidizes by passing electrons at a similar rate to the proximal Cys159-Cys154 disulfide pair. The dissociation of NADP+ occurs with a rate of ∼180 s-1, which induces the deprotonation of Cys159, and this coincides with the accumulation of an intense FAD-thiolate charge transfer band. It is proposed that the electrons then pass to the Cys596-Cys597 disulfide pair of the associated subunit in the dimer with a net rate constant of ∼2 s-1. (Note: Cys597 is Sec597 in wild-type (WT) SmTGR.) From this position, the electrons can be passed to oxidized thioredoxin or further into the protein to reduce the Cys28-Cys31 disulfide pair of the originating subunit of the dimer. From the Cys28-Cys31 center, electrons can then pass to oxidized glutathione that has a binding site directly adjacent.

Inhibition of oxidative stress by apocynin attenuated chronic obstructive pulmonary disease progression and vascular injury by cigarette smoke exposure.

BACKGROUND AND PURPOSE: Cardiovascular disease affects up to half of the patients with chronic obstructive pulmonary disease (COPD), exerting deleterious impact on health outcomes and survivability. Vascular endothelial dysfunction marks the onset of cardiovascular disease. The present study examined the effect of a potent NADPH Oxidase (NOX) inhibitor and free-radical scavenger, apocynin, on COPD-related cardiovascular disease. EXPERIMENTAL APPROACH: Male BALB/c mice were exposed to either room air (Sham) or cigarette smoke (CS) generated from 9 cigarettes·day-1 , 5 days a week for up to 24 weeks with or without apocynin treatment (5 mg·kg-1 ·day-1 , intraperitoneal injection). KEY RESULTS: Eight-weeks of apocynin treatment reduced airway neutrophil infiltration (by 42%) and completely preserved endothelial function and endothelial nitric oxide synthase (eNOS) availability against the oxidative insults of cigarette smoke exposure. These preservative effects were maintained up until the 24-week time point. 24-week of apocynin treatment markedly reduced airway inflammation (reduced infiltration of macrophage, neutrophil and lymphocyte), lung function decline (hyperinflation) and prevented airway collagen deposition by cigarette smoke exposure. CONCLUSION AND IMPLICATIONS: Limiting NOX activity may slow COPD progression and lower cardiovascular disease risk, particularly when signs of oxidative stress become evident.

LINCs Are Vulnerable to Epileptic Insult and Fail to Provide Seizure Control via On-Demand Activation.

Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. Long-range inhibitory neuronal nitric oxide synthase-expressing cells (LINCs), a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA-mediated and GABAB-mediated postsynaptic inhibition. We therefore hypothesized that LINCs could be an effective target for seizure control. LINCs were optogenetically activated for on-demand seizure intervention in the intrahippocampal kainate (KA) mouse model of chronic TLE. Unexpectedly, LINC activation at 1 month post-KA did not substantially reduce seizure duration in either male or female mice. We tested two different sets of stimulation parameters, both previously found to be effective with on-demand optogenetic approaches, but neither was successful. Quantification of LINCs following intervention revealed a substantial reduction of LINC numbers compared with saline-injected controls. We also observed a decreased number of LINCs when the site of initial insult (i.e., KA injection) was moved to the amygdala [basolateral amygdala (BLA)-KA], and correspondingly, no effect of light delivery on BLA-KA seizures. This indicates that LINCs may be a vulnerable population in TLE, regardless of the site of initial insult. To determine whether long-term circuitry changes could influence outcomes, we continued testing once a month for up to 6 months post-KA. However, at no time point did LINC activation provide meaningful seizure suppression. Altogether, our results suggest that LINCs are not a promising target for seizure inhibition in TLE.