The Metameric Echinoderm.

Animal phyla are distinguished by their body plans, the ways in which their bodies are organized. A distinction is made, for example, among phyla with bodies of many segments (metameric; e.g., annelids, arthropods, and chordates), others with completely unsegmented bodies (americ; e.g., flatworms and mollusks), and a few phyla with bodies of 2 or 3 regions (oligomeric; e.g., echinoderms and hemichordates). The conventional view of echinoderms as oligomeric coelomates adequately considers early development, but it fails to recognize the metameric body plan that develops in the juvenile rudiment and progresses during indeterminate adult growth. As in the 3 phyla traditionally viewed to be metameric (annelids, arthropods, and chordates), metamery, or metamerism, in echinoderms occurs by (1) subterminal budding of (2) serially repeated components of (3) mesodermal origin. A major difference in most echinoderms is that metamery is expressed along multiple body axes, usually 5. The view of a metameric echinoderm might invite new discussions of metazoan body plans and new approaches to the study of morphogenesis, particularly in comparative treatments with annelids, arthropods, and chordates.

Measuring cough-related quality of life and cough frequency in pulmonary TB.

BACKGROUND: Cough is the key symptom of pulmonary TB (PTB) and is associated with transmission. No tool for measuring the subjective impact of cough in PTB has been previously validated. We sought to measure patientreported cough in PTB and investigate any relationship to objectively quantified daily cough frequency.METHODS: The validity of the Leicester Cough Questionnaire (LCQ) was assessed in sequential patients newly diagnosed with PTB at a UK hospital. Resulting LCQ scores were compared to non-cough clinical variables, and to 24-h, ambulatory, objective cough frequency measured using the Leicester Cough Monitor.RESULTS: The LCQ in 30 patients with PTB was acceptable to users and had high internal reliability (Cronbach's α = 0.93), concurrent validity (correlation with visual analogue scale for cough severity, Spearman's ρ = ???0.69) and responsiveness (substantial median increase score after 2 weeks of TB treatment: 5.1 points, IQR 1.8???9.7; P = 0.003). There was only moderate correlation between patient-reported cough and objectively-measured 24-h cough frequency in PTB (ρ = ???0.48, P = 0.008).CONCLUSION: The LCQ is valid for use in PTB, with applications that include monitoring treatment of the disease. However, there was a mismatch between objective and subjective assessment of cough, which has important implications for delayed diagnosis and transmissibility.

Resveratrol differentially affects MMP-9 release from neurons and glia; implications for therapeutic efficacy.

Resveratrol, a naturally occurring polyphenol that activates sirtuin 1 (SIRT1), has been shown to reduce overall levels of matrix metalloprotease-9 (MMP-9) in cerebrospinal fluid (CSF) samples from patients with Alzheimer's dementia (AD). Depending on the site of release, however, MMP-9 has the potential to improve or impair cognition. In particular, its release from microglia or pericytes proximal to the blood brain barrier can damage the basement membrane, while neuronal activity-dependent release of this protease from glutamatergic neurons can instead promote dendritic spine expansion and long-term potentiation of synaptic plasticity. In the present study, we test the hypothesis that resveratrol reduces overall MMP-9 levels in CSF samples from patients with APOE4, an allele associated with increased glial inflammation. We also examine the possibility that resveratrol reduces inflammation-associated MMP release from cultured glia but spares neuronal activity-dependent release from cultured cortical neurons. We observe that resveratrol decreases overall levels of MMP-2 and MMP-9 in CSF samples from AD patients. Resveratrol also reduces CSF levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), glial-derived protein that restricts long-term potentiation of synaptic transmission, in individuals homozygous for APOE4. Consistent with these results, we observe that resveratrol reduces basal and lipopolysaccharide (LPS)-stimulated MMP and TIMP-1 release from cultured microglia and astrocytes. In contrast, however, resveratrol does not inhibit release of MMP-9 from cortical neurons. Overall, these results are consistent with the possibility that while resveratrol reduces potentially maladaptive MMP and TIMP-1 release from activated glia, neuroplasticity-promoting MMP release from neurons is spared. In contrast, resveratrol reduces release of neurocan and brevican, extracellular matrix components that restrict neuroplasticity, from both neurons and glia. These data underscore the diversity of resveratrol's actions with respect to affected cell types and molecular targets and also suggest that further studies may be warranted to determine if its effects on glial MMP release could make it a useful adjunct for AD- and/or anti-amyloid therapy-related damage to the blood brain barrier.

The global distribution of plants used by humans.

Plants sustain human life. Understanding geographic patterns of the diversity of species used by people is thus essential for the sustainable management of plant resources. Here, we investigate the global distribution of 35,687 utilized plant species spanning 10 use categories (e.g., food, medicine, material). Our findings indicate general concordance between utilized and total plant diversity, supporting the potential for simultaneously conserving species diversity and its contributions to people. Although Indigenous lands across Mesoamerica, the Horn of Africa, and Southern Asia harbor a disproportionate diversity of utilized plants, the incidence of protected areas is negatively correlated with utilized species richness. Finding mechanisms to preserve areas containing concentrations of utilized plants and traditional knowledge must become a priority for the implementation of the Kunming-Montreal Global Biodiversity Framework.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aß) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 µg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aß positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aß immunoglobulin G titers in 41/42 participants, slower rates of Aß plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aß active immunotherapies in individuals at risk for AD. HIGHLIGHTS: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease.

BACKGROUND: Monoclonal antibodies that target amyloid-beta (Aß) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aß IgG1 monoclonal antibody with highest affinity for aggregated Aß that has been tested for the treatment of Alzheimer's disease. METHODS: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aß42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort.

INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

Flower orientation and corolla length as reproductive barriers in the pollinator-driven divergence of Erica shannonea and Erica ampullacea.

A variety of reproductive barriers can enable reproductive isolation and stable coexistence of plant species. Differing floral traits might play an important role in reproductive isolation imposed by pollinators. Such shifts in pollinator use have been hypothesized to contribute to the radiation of Erica (Ericaceae) in the Cape Floristic Region, South Africa. The sister species Erica shannonea and Erica ampullacea co-occur and overlap in flowering phenology. Both have unscented long-tubed flowers consistent with adaptations for pollination by long-proboscid flies (LPFs), but differences in flower orientation and corolla tube length are indicative of a shift in pollinator species. We conducted controlled pollination experiments and pollinator observations to determine the breeding system and pollinators of the two species. Both species are self-incompatible and require pollinator visits for seed production, suggesting that pollinators could strongly influence flower evolution. The horizontally orientated flowers of E. shannonea were found to be pollinated by Philoliche rostrata (Tabanidae), which has a long, fixed forward-pointing proboscis, while the vertically upright orientated flowers of E. ampullacea were found to be pollinated by Prosoeca westermanni (Nemestrinidae), which has a shorter proboscis that can swivel downwards. The nemestrinid fly's proboscis is too short to access the nectar in the relative long-tubed flowers of E. shannonea and the tabanid fly's proboscis cannot swivel down to access the upright flowers of E. ampullacea. Consequently, these traits are likely to act as reproductive barriers between the two Erica species and thereby might have contributed to speciation and enable stable coexistence.

'We just need to find space for them to practice so that we can help to make a stronger society': Perceived barriers and facilitators to employing health psychologists in UK public health and clinical health settings.

INTRODUCTION: In recent years, health psychology has received significant attention within the health sector, due to its application to understanding influences on health and well-being and translation of health psychology into interventions to support behaviour change. The number of health psychologists in public health and healthcare settings is growing but remains limited, and is it unclear why. This study aimed to explore the views of potential and current employers of health psychologists, to elucidate barriers and facilitators of employing health psychologists in healthcare settings. METHODS: Semi-structured interviews were carried out to explore the experiences of working with and/or employing health psychologists. Opportunities and barriers were explored for increasing access to health psychology expertise in the NHS and public health. Interviews were analysed using inductive thematic analysis. RESULTS: Fifteen participants took part in interviews. Participants were mid-senior-level professionals working in varied healthcare settings and/or academic institutions. The majority had experience of health psychology/working with health psychologists, whilst others had limited experience but an interest in employing health psychologists. Three key themes were identified: (1) the organizational fit of health psychologists, (2) perception of competition for roles and (3) ideas for changing hearts, minds and processes. CONCLUSION: Barriers exist to employing health psychologists in healthcare settings. These barriers include misunderstandings of the role of health psychologists and the need to preserve other disciplines due to perceived competition. Recommendations for change included showcasing the benefits and skills of health psychologists and having transparent conversations with employees and multi-disciplinary colleagues about roles.

Estimating the aquatic risk from exposure to up to twenty-two pesticide active ingredients in waterways discharging to the Great Barrier Reef.

Pesticides decrease the quality of water reaching the Great Barrier Reef (GBR), Australia. Up to 86 pesticide active ingredients (PAIs) were monitored between July 2015 to end of June 2018 at 28 sites in waterways that discharge to the GBR. Twenty-two frequently detected PAIs were selected to calculate their combined risk when they co-occur in water samples. Species sensitivity distributions (SSDs) for the 22 PAIs to fresh and marine species were developed. The SSDs, the multi-substance potentially affected fraction (msPAF) method, Independent Action model of joint toxicity and a Multiple Imputation method were combined to convert measured PAI concentration data to estimates of the Total Pesticide Risk for the 22 PAIs (TPR22) expressed as the average percentage of species affected during the wet season (i.e., 182 days). The TPR22 and percent contribution of active ingredients of Photosystem II inhibiting herbicides, Other Herbicides, and Insecticides to the TPR22 were estimated. The TPR22 ranged from <1 % to 42 % of aquatic species being affected. Approximately 85 % of the TPR22 estimates were >1 % - meaning they did not meet the Reef 2050 Water Quality Improvement Plan's pesticide target for waters entering the GBR. There were marked spatial differences in TPR22 estimates - regions dominated by grazing had lower estimates while those with sugar cane tended to have higher estimates. On average, active ingredients of PSII herbicides contributed 39 % of the TPR22, the active ingredients of Other Herbicides contributed ~36 % and of Insecticides contributed ~24 %. Nine PAIs (diuron, imidacloprid, metolachlor, atrazine, MCPA, imazapic, metsulfuron, triclopyr and ametryn) were responsible for >97 % of TPR22 across all the monitored waterways.

Response adaptive salvage with KTd and ASCT for functional high-risk multiple myeloma-The Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial.

We evaluated re-induction incorporating carfilzomib-thalidomide-dexamethasone (KTd) and autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) refractory, or demonstrating a suboptimal response, to non-IMID bortezomib-based induction. KTd salvage consisted of thalidomide 100 mg daily and dexamethasone 20 mg orally combined with carfilzomib 56 mg/m2 days 1, 2, 8, 9, 15 and 16, of each 28-day cycle. Following four cycles, patients achieving a stringent complete response proceeded to ASCT whereas those who did not received a further two cycles then ASCT. Consolidation consisted of two cycles of KTd then Td to a total of 12 months post-ASCT therapy. Primary end-point was the overall response rate (ORR) with KTd prior to ASCT. Fifty patients were recruited. The ORR was 78% with EuroFlow MRD negativity of 34% in the intention-to-treat population and 65% in the evaluable population at 12 months post-ASCT. With follow-up >38 months median PFS and OS have not been reached with PFS and OS at 36 months of 64% and 80%, respectively. KTd was well tolerated with grade 3 and grade ≥4 adverse events rates of 32% and 10%, respectively. Response adaptive utilisation of KTd with ASCT is associated with both high-quality responses and durable disease control in functional high-risk NDMM.

Matrix disequilibrium in Alzheimer's disease and conditions that increase Alzheimer's disease risk.

Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

Legal Minors Who Inject: Differences in Socio-Demographics and Treatment Needs Compared to Adults in a Swedish National Sample of People with Injecting Drug Use.

BACKGROUND: Injection drug use among legal minors is under-researched. Although the population may be small in absolute terms, treatment needs may be greater than for those who began injecting as adults. Such knowledge may help tailor services more effectively. Previous research tends to use selective samples or focuses solely on medical indicators. The present study uses a larger sample drawn from national register data in Sweden over a 9-year period (2013-2021) to analyze differences in medical and social treatment needs between people who began injecting as legal minors and their older counterparts. METHOD: Data on first-time visitors to needle and syringe programmes (n = 8225, mean age 37.6, 26% women) were used. Historical socio-demographics and presenting treatment needs were compared between those with a debut injecting age under 18, and those who began injecting as adults. RESULTS: The prevalence of injecting before 18 years was 29%. This group had more negative social circumstances, such as leaving school early, worse health, and greater service consumption, compared to those who began injecting as adults. In particular, they had been subjected to a greater level of control measures, such as arrest and compulsory care. CONCLUSIONS: The present study shows that there are important health and social differences between those who inject prior to 18 and those who begin injecting as adults. This raises important questions for both child protection services and harm reduction approaches for legal minors who inject, who still qualify as 'children' in a legal and policy sense.

A Sister-Group Comparison of Branching and Pedicellariae in Brittlestars (Echinodermata: Ophiuroidea).

Branching of arms and presence of pedicellariae are characters among ophiuroids found only in the order Euryalida (snakestars and basketstars). Family Asteronychidae has neither character; family Euryalidae has 2 small clades with branched arms; and family Gorgonocephalidae has all species with pedicellariae and 3 or 4 clades with branched arms. Despite the rare occurrence of these characters in the Ophiuroidea, they might be key adaptations within the Euryalida that have led to relatively high diversification. Sister-group comparison of the distribution of these 2 characters among taxa indicates that neither character alone explains diversity patterns within the order. In particular, branching restricted to the tips of arms seems not strongly adaptive, probably for the lack of integration of basal forks with the disc. On the other hand, 2 clades of gorgonocephalids with basal branching exceed their snakestar sister groups in numbers of species, indicating an advantage of branching within the family. Unfortunately, the analysis cannot benefit from statistics, for at least 5 independent comparisons are required for a one-tailed sign test. Because branching and pedicellariae are probably not independent variables, future sister-group comparisons should be done only within the Gorgonocephalidae once clade structure is better clarified with increased taxon sampling (10 currently missing genera) and resolution of intra-generic inconsistencies in the most recent cladograms available. Branching might confer upon gorgonocephalid basketstars a more efficient use of pedicellariae for upstream capture of zooplankton over their snakestar relatives as well as over the Euryalidae, which retain ancestral downstream capture by mucus-laden podia.

GermanDie Verzweigung der Arme und das Vorhandensein von Pedicellarien sind Merkmale unter Ophiuroiden, die nur in der Ordnung Euryalida (Schlangensterne mit unverzweigten Armen und Korbsterne mit verzweigten Armen) vorkommen. Die Familie Asteronychidae hat kein Merkmal; die Familie Euryalidae hat zwei kleine Kladen mit verzweigten Armen; und die Familie Gorgonocephalidae hat alle Arten mit Pedicellarien und drei oder vier Kladen mit verzweigten Armen. Trotz des seltenen Vorkommens dieser Merkmale in den Ophiuroidea könnten sie Schlüsselanpassungen innerhalb der Euryalida sein, die zu einer relativ hohen Diversifizierung geführt haben. Eine Schwestergruppenanalyse der Verteilung dieser beiden Merkmale unter den Taxa zeigt, dass keines der Merkmale allein die Diversitätsmuster innerhalb der Ordnung erklärt. Insbesondere die auf die Armspitzen beschränkte Verzweigung scheint nicht stark adaptiv zu sein, wahrscheinlich wegen fehlender Integration von Basalgabeln in die Scheibe. Andererseits übertreffen zwei Kladen von Gorgonocephaliden mit basaler Verzweigung ihre Schlangenstern-Schwestergruppen in der Anzahl der Arten, was auf einen Vorteil der Verzweigung innerhalb der Familie hinweist. Leider kann die Analyse nicht von Statistiken profitieren, da für einen einseitigen Vorzeichentest mindestens fünf unabhängige Vergleiche erforderlich sind. Da Verzweigung und Pedicellariae wahrscheinlich keine unabhängigen Variablen sind, sollten zukünftige Schwestergruppenvergleiche nur innerhalb der Gorgonocephalidae durchgeführt werden, sobald die Klade-Struktur durch vermehrte Taxon-Stichproben (10 derzeit fehlende Gattungen) und durch Auflösung von Inkonsistenzen innerhalb der Gattungen in den neuesten verfügbaren Kladogrammen besser aufgeklärt ist. Die Verzweigung könnte gorgonocephaliden Korbsternen eine effizientere Nutzung von Pedicellarien für den stromaufwärts gelegenen Fang von Zooplankton gegenüber ihren Schlangenstern-Verwandten sowie gegenüber den Euryalidae verleihen, die den stromabwärts gelegenen Fang durch schleimbeladene Füsschen der Vorfahren beibehalten.

Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's disease.

Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDA-approved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild-moderate Alzheimer's disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice.

The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.

Total ammonia and coliform concentrations at the end of the Mississippi River from 1900 to 2019.

Total ammonia (TA) concentrations (NH3 + NH4+) at four locations at the terminal end of the Mississippi River, the largest river on the North American continent, were assembled to examine trends and relationships with point and non-point loadings from 1980 to 2019 and compared to values in 1900 to 1901. TA concentrations were lowest in 1900 to 1901, highest in 1980 and then declined, and then rose slightly in the last 2 decades. Variations in individual measurements and in situ temperature are indirectly related because of the influence temperature has on ammonia solubility and protein degradation rates. Importantly, the average annual concentrations of TA were directly related to both total coliform and fecal coliform densities. The highest measured average annual TA concentrations in the river (15.5 ± 1.5 SE µmol in 1985) were below the currently recommended toxicity thresholds for freshwater aquatic ecosystems. Sewerage loadings are implicated as controlling factors on TA concentrations, not nitrogen stabilizers added to fertilizers to reduce ammonia conversion to nitrate, nor the fertilizer loadings.

Disturbance legacies and shifting trajectories: Marsh soil strength and shoreline erosion a decade after the Deepwater Horizon oil spill.

Marsh resilience post disturbance is strongly dependent on the belowground dynamics affecting the emergent plants aboveground. We investigated the long-term impacts at the marsh-water interface in coastal wetlands of south Louisiana after the 2010 Deepwater Horizon oil spill with a combination of fieldwork (2010-2018) and spatial analysis (1998-2021). Data were collected on shoreline erosion rates, marsh platform elevation heights and cantilever overhang widths, and soil strength up to 1 m depth. Oil concentration in the top 5 cm of the marsh soil were determined using gas chromatography/mass spectrometry and were 1000 times higher than before the spill and remained 10 times higher eight years post-oiling. The oiling initially caused the marsh edge to subside, and chronic effects lowered soil strength, creating a faster erosion rate and deeper water within 150 cm of the shoreline. Soil strength declined by 50% throughout the 1 m soil profile after oiling and has not recovered. The mean erosion rate for 11 years post-spill was double that before oiling and there was an additive impact on erosion rates after Hurricane Isaac. Erosion appeared to have recovered to pre-spill rates by 2019, however from 2019 to 2021, the rate increased by 118% above the pre-spill rate. The continuing loss of soil strength indicates that the belowground biomass was seriously compromised by oiling. The perpetuation of oil in the remaining marsh may have set a new baseline for soil strength and subsequent storm induced erosional events. The remaining marsh soils retain chronic physical and biological legacies compromising recovery for more than a decade that may be evident in other marsh habitats subject to oiling and other stressors.

Social Determinants of Health and Body Mass Index in American Indian/Alaska Native Children.

Objective: To examine the associations between social determinants of health (SDOH) and prevalent overweight/obesity status and change in adiposity status among American Indian and Alaska Native (AI/AN) children. Methods: The study sample includes 23,950 AI/AN children 2-11 years of age, who used Indian Health Service (IHS) from 2010 to 2014. Multivariate generalized linear mixed models were used to examine the following: (1) cross-sectional associations between SDOH and prevalent overweight/obesity status and (2) longitudinal associations between SDOH and change in adiposity status over time. Results: Approximately 49% of children had prevalent overweight/obesity status; 18% had overweight status and 31% had obesity status. Prevalent severe obesity status was 20% in 6-11-year olds. In adjusted cross-sectional models, children living in counties with higher levels of poverty had 28% higher odds of prevalent overweight/obesity status. In adjusted longitudinal models, children 2-5 years old living in counties with more children eligible for free or reduced-priced lunch had 15% lower odds for transitioning from normal-weight status to overweight/obesity status. Conclusions: This work contributes to accumulating knowledge that economic instability, especially poverty, appears to play a large role in overweight/obesity status in AI/AN children. Research, clinical practice, and policy decisions should aim to address and eliminate economic instability in childhood.