Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.

The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-ß signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.

Individual Optimization of Reproductive Investment and the Cost of Incubation in a Wild Songbird.

AbstractDespite avid interest in life history trade-offs and the costs of reproduction, evidence that increased parental allocation reduces subsequent breeding productivity is mixed. This uncertainty may be attributable to environmental heterogeneity in space and time, necessitating experiments across a range of ecological contexts. Over three breeding seasons, we cross-fostered clutches between nests to manipulate incubation duration in a wild population of Carolina wrens, a species in which only females incubate, to test for a cost of incubation on current and future reproduction. Prolonged incubation affected maternal productivity in a manner dependent on the current environment and initial investment in eggs, suggesting that incubation is optimized according to other components of reproduction and individual quality. Effects of incubation duration on foster nestling condition varied between years, being costly in one, beneficial in another, and neutral in the third. The proportion of young fledged, females' probability of breeding again within seasons, and subsequent clutch sizes all declined with increasing incubation effort-effects that became more pronounced as seasons progressed. Therefore, costs of incubation were almost entirely dependent on maternal quality and environmental variation, illustrating the importance of conducting experiments across a range of environmental settings for understanding the costs of reproduction and evolution of life histories.

The effects of palladium coordination complex speciation and concentration upon the ubiquitous bacterial species Pseudomonas aeruginosa.

The toxicity of three different palladium (Pd) species to Pseudomonas aeruginosa, an environmentally ubiquitous bacterial species, is reported. Palladium was added to chemically-defined minimal media as three complex ion salts, namely sodium tetrachloropalladate (Na2[PdCl4]), tetraamminepalladium(II) chloride ([Pd(NH3)4]Cl2), and potassium hexachloropalladate(IV) (K2[PdCl6]), inoculated with log-phase cultures and incubated for 24 h at 25 °C. Toxicity was tested for Pd concentrations ranging from 6.55 µg/L (0.06 µM Pd) to 250 µg/L (2.33 µM Pd). Minimum inhibitory concentrations (MICs) were determined and growth tracked via optical absorption at 600 nm. Viability and minimum bactericidal concentrations (MBCs) were measured in parallel with dilution, plating and colony forming unit (CFU) counting. MICs for all forms of Pd were 62.5 µg Pd/L, approximately 1000 times lower than previously reported values. The MBCs for PdCl42- and Pd(NH3)42+ were 62.5 µg Pd/L and 125 µg Pd/L for PdCl62-. Pd(NH3)42+ and PdCl62- culture viability at 7.8-31.3 µg Pd/L was not different from controls. However, PdCl42- culture viability was different from the other additives, with decreasing viability at sub-MBC concentrations down to 6.55 µg Pd/L. To understand the possible effect of speciation upon toxicity, the equilibrium speciation of Pd was modeled for all solutions using PHREEQC and found to be dominated by Pd(NH3)3Cl+ (65.6 % of total Pd) and Pd(NH3)42+ (34.2 % total Pd). The juxtaposition of the equilibrium calculations and the toxicity results indicates that the kinetics of ligand exchange between the palladium complexes and the growth medium could influence bacterial response.

Genome evolution in the allotetraploid frog Xenopus laevis.

To explore the origins and consequences of tetraploidy in the African clawed frog, we sequenced the Xenopus laevis genome and compared it to the related diploid X. tropicalis genome. We characterize the allotetraploid origin of X. laevis by partitioning its genome into two homoeologous subgenomes, marked by distinct families of 'fossil' transposable elements. On the basis of the activity of these elements and the age of hundreds of unitary pseudogenes, we estimate that the two diploid progenitor species diverged around 34 million years ago (Ma) and combined to form an allotetraploid around 17-18 Ma. More than 56% of all genes were retained in two homoeologous copies. Protein function, gene expression, and the amount of conserved flanking sequence all correlate with retention rates. The subgenomes have evolved asymmetrically, with one chromosome set more often preserving the ancestral state and the other experiencing more gene loss, deletion, rearrangement, and reduced gene expression.

Measuring actual learning versus feeling of learning in response to being actively engaged in the classroom.

We compared students' self-reported perception of learning with their actual learning under controlled conditions in large-enrollment introductory college physics courses taught using 1) active instruction (following best practices in the discipline) and 2) passive instruction (lectures by experienced and highly rated instructors). Both groups received identical class content and handouts, students were randomly assigned, and the instructor made no effort to persuade students of the benefit of either method. Students in active classrooms learned more (as would be expected based on prior research), but their perception of learning, while positive, was lower than that of their peers in passive environments. This suggests that attempts to evaluate instruction based on students' perceptions of learning could inadvertently promote inferior (passive) pedagogical methods. For instance, a superstar lecturer could create such a positive feeling of learning that students would choose those lectures over active learning. Most importantly, these results suggest that when students experience the increased cognitive effort associated with active learning, they initially take that effort to signify poorer learning. That disconnect may have a detrimental effect on students' motivation, engagement, and ability to self-regulate their own learning. Although students can, on their own, discover the increased value of being actively engaged during a semester-long course, their learning may be impaired during the initial part of the course. We discuss strategies that instructors can use, early in the semester, to improve students' response to being actively engaged in the classroom.

Parental favoritism in a wild bird population.

In most taxa with altricial young, offspring solicit food from their parents using a combination of visual and acoustic stimuli, but exactly what these young are communicating, and how selection shapes parental responses, remains unresolved. Theory posits that parents' interpretation and response to begging should vary with the likelihood of a return on their investment. We tested this in a wild population of prothonotary warblers (Protonotaria citrea), predicting that parents bias food non-randomly toward certain individuals within their broods depending on both the size and number of offspring. We observed parent-offspring interactions and detected strong dependence between brood size and nestling size in shaping parental responses to begging. Larger siblings were less likely to solicit food during feeding events than their smaller siblings, but they received a disproportionate share from parents in nests containing fewer-than-average young, whereas the smaller-than-average nestlings were disproportionately fed in broods containing a greater-than-average number of young. These findings suggest that parents respond to begging signals according to multiple social cues, favoring the stronger siblings with greater survival prospects when few copies of their genes are present, but overtly favoring runts to ensure whole-brood survival when capable of fledging more young. Future experimental studies may shed light on the contributions of parental decision-making and memory, how young nestlings learn in parent-offspring communication systems, and the adaptive significance of these behaviors.

Augmented intelligence to predict 30-day mortality in patients with cancer.

Aim: An augmented intelligence tool to predict short-term mortality risk among patients with cancer could help identify those in need of actionable interventions or palliative care services. Patients & methods: An algorithm to predict 30-day mortality risk was developed using socioeconomic and clinical data from patients in a large community hematology/oncology practice. Patients were scored weekly; algorithm performance was assessed using dates of death in patients' electronic health records. Results: For patients scored as highest risk for 30-day mortality, the event rate was 4.9% (vs 0.7% in patients scored as low risk; a 7.4-times greater risk). Conclusion: The development and validation of a decision tool to accurately identify patients with cancer who are at risk for short-term mortality is feasible.

The power of amphibians to elucidate mechanisms of size control and scaling.

Size is a fundamental feature of biology that affects physiology at all levels, from the organism to organs and tissues to cells and subcellular structures. How size is determined at these different levels, and how biological structures scale to fit together and function properly are important open questions. Historically, amphibian systems have been extremely valuable to describe scaling phenomena, as they occupy some of the extremes in biological size and are amenable to manipulations that alter genome and cell size. More recently, the application of biochemical, biophysical, and embryological techniques to amphibians has provided insight into the molecular mechanisms underlying scaling of subcellular structures to cell size, as well as how perturbation of normal size scaling impacts other aspects of cell and organism physiology.

Multispecialty Enterprise Imaging Workgroup Consensus on Interactive Multimedia Reporting Current State and Road to the Future: HIMSS-SIIM Collaborative White Paper.

Diagnostic and evidential static image, video clip, and sound multimedia are captured during routine clinical care in cardiology, dermatology, ophthalmology, pathology, physiatry, radiation oncology, radiology, endoscopic procedural specialties, and other medical disciplines. Providers typically describe the multimedia findings in contemporaneous electronic health record clinical notes or associate a textual interpretative report. Visual communication aids commonly used to connect, synthesize, and supplement multimedia and descriptive text outside medicine remain technically challenging to integrate into patient care. Such beneficial interactive elements may include hyperlinks between text, multimedia elements, alphanumeric and geometric annotations, tables, graphs, timelines, diagrams, anatomic maps, and hyperlinks to external educational references that patients or provider consumers may find valuable. This HIMSS-SIIM Enterprise Imaging Community workgroup white paper outlines the current and desired clinical future state of interactive multimedia reporting (IMR). The workgroup adopted a consensus definition of IMR as "interactive medical documentation that combines clinical images, videos, sound, imaging metadata, and/or image annotations with text, typographic emphases, tables, graphs, event timelines, anatomic maps, hyperlinks, and/or educational resources to optimize communication between medical professionals, and between medical professionals and their patients." This white paper also serves as a precursor for future efforts toward solving technical issues impeding routine interactive multimedia report creation and ingestion into electronic health records.

Engineering 4-coumaroyl-CoA derived polyketide production in Yarrowia lipolytica through a ß-oxidation mediated strategy.

Polyketides are a diverse class of molecules sought after for their valuable properties, including as potential pharmaceuticals. Previously, we demonstrated that the oleaginous yeast Yarrowia lipolytica is an optimal host for production of the simple polyketide, triacetic acid lactone (TAL). We here expand the capacities of this host by overcoming previous media challenges and enabling production of more complex polyketides. Specifically, we employ a ß-oxidation related strategy to improve polyketide production directly from defined media. Beyond TAL production, we establish biosynthesis of the 4-coumaroyl-CoA derived polyketides: naringenin, resveratrol, and bisdemethoxycurcumin, as well as the diketide intermediate, (E)-5-(4-hydroxyphenyl)-3-oxopent-4-enoic acid. In this background, we enable high-level de novo production of naringenin through import of both a heterologous pathway and a mutant Y. lipolytica allele. In doing so, we generated an averaged maximum titer of 898 mg/L naringenin, the highest titer reported to date in any host. These results demonstrate that Y. lipolytica is an ideal polyketide production host for more complex 4-coumaroyl-CoA derived products.

Condition-Dependent Begging Elicits Increased Parental Investment in a Wild Bird Population.

The coevolution of parental supply and offspring demand has long been thought to involve offspring need driving begging and parental care, leaving other hypotheses underexplored. In a population of wild birds, we experimentally tested whether begging serves as a negatively condition-dependent signal of need or a positively condition-dependent signal of quality. Across multiple years, we supplemented nestling house wrens with food shortly after hatching and simultaneously manipulated corticosterone levels to simulate the hunger-induced increase in glucocorticoids thought to mediate begging. This allowed us to also test whether begging is simply a proximate signal of hunger. Days after supplementation ended, food-supplemented nestlings were in better condition than nonsupplemented nestlings and begged for food at an increased rate; their parents, in turn, increased provisioning to a greater extent than parents of nonsupplemented young, as begging positively predicted provisioning. Food-supplemented nestlings therefore attained above-average condition, which predicted their recruitment as breeding adults in the local population. Glucocorticoids increased begging in the short term, but this transient effect depended on satiety. Thus, glucocorticoids promoted begging as a proximate response to hunger, whereas the longer-term changes in nestling condition, begging, and food provisioning suggest that begging ultimately signals offspring quality to elicit increased investment, thereby enhancing offspring survival.

Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer's disease patient brain samples.

Identification of multiple immune-related genetic risk factors for sporadic AD (sAD) have put the immune system center stage in mechanisms underlying this disorder. Comprehensive analysis of microglia in different stages of AD in human brains revealed microglia activation to follow the progression of AD neuropathological changes and requiring the co-occurrence of beta-Amyloid (Aß) and tau pathology. Carriers of AD-associated risk variants in TREM2 (Triggering receptor expressed on myeloid cells 2) showed a reduction of plaque-associated microglia and a substantial increase in dystrophic neurites and overall pathological tau compared with age and disease stage matched AD patients without TREM2 risk variants. These findings were substantiated by digital spatial profiling of the plaque microenvironment and targeted gene expression profiling on the NanoString nCounter system, which revealed striking brain region dependent differences in immune response patterns within individual cases. The demonstration of profound brain region and risk-variant specific differences in immune activation in human AD brains impacts the applicability of immune-therapeutic approaches for sAD and related neurodegenerative diseases.

Yarrowia lipolytica: more than an oleaginous workhorse.

Microbial production of fuels and chemicals offers a means by which sustainable product manufacture can be achieved. In this regard, Yarrowia lipolytica is a unique microorganism suitable for a diverse array of biotechnological applications. As a robust oleaginous yeast, it has been well studied for production of fuels and chemicals derived from fatty acids. However, thanks in part to newfound genetic tools and metabolic understanding, Y. lipolytica has been explored for high-level production of a variety of non-lipid products. This mini-review will discuss some of the recent research surrounding the ability of Y. lipolytica to support bio-based chemical production outside the realm of fatty acid metabolism including polyketides, terpenes, carotenoids, pentose phosphate-derived products, polymers, and nanoparticles.

Identification of interactions among host and bacterial proteins and evaluation of their role early during Shigella flexneri infection.

Shigella species cause diarrhoea by invading and spreading through the epithelial layer of the human colon. The infection triggers innate immune responses in the host that the bacterium combats by translocating into the host cell cytosol via a type 3 secretion system bacterial effector proteins that interfere with host processes. We previously demonstrated that interaction of the Shigella type 3 secreted effector protein IcsB with the host protein Toca-1 inhibits the innate immune response microtubule-associated protein light-chain 3 (LC3)-associated phagocytosis, and that IcsB interaction with Toca-1 is required for inhibition of this host response. Here, we show that Toca-1 in vitro precipitated not only IcsB, but also the type 3 secreted proteins OspC3, IpgD and IpaB. OspC3 and IpgD precipitation with Toca-1 was dependent on IcsB. Early during infection, most of these proteins localized near intracellular Shigella. We examined whether interactions among these proteins restrict innate host cell responses other than LC3-associated phagocytosis. In infected cells, OspC3 blocks production and secretion of the mature pro-inflammatory cytokine IL-18; however, we found that interaction of OspC3 with IcsB, either directly or indirectly via Toca-1, was not required for OspC3-mediated restriction of IL-18 production. These results indicate that interactions of the host protein Toca-1 with a subset of type 3 effector proteins contribute to the established function of some, but not all involved, effector proteins.

Early burst in body size evolution is uncoupled from species diversification in diving beetles (Dytiscidae).

Changes in morphology are often thought to be linked to changes in species diversification, which is expected to leave a signal of early burst (EB) in phenotypic traits. However, such signal is rarely recovered in empirical phylogenies, even for groups with well-known adaptive radiation. Using a comprehensive phylogenetic approach in Dytiscidae, which harbours ~4,300 species with as much as 50-fold variation in body size among them, we ask whether pattern of species diversification correlates with morphological evolution. Additionally, we test whether the large variation in body size is linked to habitat preference and whether the latter influences species turnover. We found, in sharp contrast to most animal groups, that Dytiscidae body size evolution follows an early-burst model with subsequent high phylogenetic conservatism. However, we found no evidence for associated shifts in species diversification, which point to an uncoupled evolution of morphology and species diversification. We recovered the ancestral habitat of Dytiscidae as lentic (standing water), with many transitions to lotic habitat (running water) that are concomitant to a decrease in body size. Finally, we found no evidence for difference in net diversification rates between habitats nor difference in turnover in lentic and lotic species. This result, together with recent findings in dragonflies, contrasts with some theoretical expectations of the habitat stability hypothesis. Thus, a thorough reassessment of the impact of dispersal, gene flow and range size on the speciation process is needed to fully encompass the evolutionary consequences of the lentic-lotic divide for freshwater fauna.

Verbal Learning and Memory After Cochlear Implantation in Postlingually Deaf Adults: Some New Findings with the CVLT-II.

OBJECTIVES: Despite the importance of verbal learning and memory in speech and language processing, this domain of cognitive functioning has been virtually ignored in clinical studies of hearing loss and cochlear implants in both adults and children. In this article, we report the results of two studies that used a newly developed visually based version of the California Verbal Learning Test-Second Edition (CVLT-II), a well-known normed neuropsychological measure of verbal learning and memory. DESIGN: The first study established the validity and feasibility of a computer-controlled visual version of the CVLT-II, which eliminates the effects of audibility of spoken stimuli, in groups of young normal-hearing and older normal-hearing (ONH) adults. A second study was then carried out using the visual CVLT-II format with a group of older postlingually deaf experienced cochlear implant (ECI) users (N = 25) and a group of ONH controls (N = 25) who were matched to ECI users for age, socioeconomic status, and nonverbal IQ. In addition to the visual CVLT-II, subjects provided data on demographics, hearing history, nonverbal IQ, reading fluency, vocabulary, and short-term memory span for visually presented digits. ECI participants were also tested for speech recognition in quiet. RESULTS: The ECI and ONH groups did not differ on most measures of verbal learning and memory obtained with the visual CVLT-II, but deficits were identified in ECI participants that were related to recency recall, the buildup of proactive interference, and retrieval-induced forgetting. Within the ECI group, nonverbal fluid IQ, reading fluency, and resistance to the buildup of proactive interference from the CVLT-II consistently predicted better speech recognition outcomes. CONCLUSIONS: Results from this study suggest that several underlying foundational neurocognitive abilities are related to core speech perception outcomes after implantation in older adults. Implications of these findings for explaining individual differences and variability and predicting speech recognition outcomes after implantation are discussed.

Parent-Child Attunement Moderates the Prospective Link between Parental Overcontrol and Adolescent Adjustment.

Parental overcontrol (OC), behavior that intrusively or dominantly restricts child autonomy, has been identified as a transdiagnostic risk factor for youth. However, it is as yet unknown whether the association between parental OC and child maladjustment remains even when OC is exerted infrequently or by attuned parents. Rather, the selective use of OC might steer children away from danger. Taking a developmental psychopathology approach, this study focuses on the larger parent-child relationship context, testing whether either the dose at which parents demonstrate OC or the degree to which children perceive their parents as attuned determines whether OC is risky or protective for adolescents' adjustment. Among a community sample of 114 families of children followed from the ages of 12-18, we examine whether OC, behaviorally coded from triadic mother-father-child discussions in middle childhood, is associated with later risky behavior and anxiety symptoms in adolescence. Overcontrol exerted by either mothers or fathers had a curvilinear effect on adolescent risky behaviors, and this effect was moderated by children's perceived attunement. Although OC generally was associated with increased risky behaviors, low doses of OC or OC exerted by highly attuned parents protected against engagement in risky behaviors. No main effect of OC was observed on adolescent anxiety; however, mothers' OC interacted with perceived parental attunement, such that OC exerted by less attuned parents predicted greater anxiety. Results underscore that the effect of parenting behaviors depends on the larger parent-child relationship context.

Molecular phylogeny of the aquatic beetle family Noteridae (Coleoptera: Adephaga) with an emphasis on data partitioning strategies.

The first molecular phylogenetic hypothesis for the aquatic beetle family Noteridae is inferred using DNA sequence data from five gene fragments (mitochondrial and nuclear): COI, H3, 16S, 18S, and 28S. Our analysis is the most comprehensive phylogenetic reconstruction of Noteridae to date, and includes 53 species representing all subfamilies, tribes and 16 of the 17 genera within the family. We examine the impact of data partitioning on phylogenetic inference by comparing two different algorithm-based partitioning strategies: one using predefined subsets of the dataset, and another recently introduced method, which uses the k-means algorithm to iteratively divide the dataset into clusters of sites evolving at similar rates across sampled loci. We conducted both maximum likelihood and Bayesian inference analyses using these different partitioning schemes. Resulting trees are strongly incongruent with prior classifications of Noteridae. We recover variant tree topologies and support values among the implemented partitioning schemes. Bayes factors calculated with marginal likelihoods of Bayesian analyses support a priori partitioning over k-means and unpartitioned data strategies. Our study substantiates the importance of data partitioning in phylogenetic inference, and underscores the use of comparative analyses to determine optimal analytical strategies. Our analyses recover Noterini Thomson to be paraphyletic with respect to three other tribes. The genera Suphisellus Crotch and Hydrocanthus Say are also recovered as paraphyletic. Following the results of the preferred partitioning scheme, we here propose a revised classification of Noteridae, comprising two subfamilies, three tribes and 18 genera. The following taxonomic changes are made: Notomicrinae sensu n. (= Phreatodytinae syn. n.) is expanded to include the tribe Phreatodytini; Noterini sensu n. (= Neohydrocoptini syn. n., Pronoterini syn. n., Tonerini syn. n.) is expanded to include all genera of the Noterinae; The genus Suphisellus Crotch is expanded to include species of Pronoterus Sharp syn. n.; and the former subgenus Sternocanthus Guignot stat. rev. is resurrected from synonymy and elevated to genus rank.

The unique paradigm of spirochete motility and chemotaxis.

Spirochete motility is enigmatic: It differs from the motility of most other bacteria in that the entire bacterium is involved in translocation in the absence of external appendages. Using the Lyme disease spirochete Borrelia burgdorferi (Bb) as a model system, we explore the current research on spirochete motility and chemotaxis. Bb has periplasmic flagella (PFs) subterminally attached to each end of the protoplasmic cell cylinder, and surrounding the cell is an outer membrane. These internal helix-shaped PFs allow the spirochete to swim by generating backward-moving waves by rotation. Exciting advances using cryoelectron tomography are presented with respect to in situ analysis of cell, PF, and motor structure. In addition, advances in the dynamics of motility, chemotaxis, gene regulation, and the role of motility and chemotaxis in the life cycle of Bb are summarized. The results indicate that the motility paradigms of flagellated bacteria do not apply to these unique bacteria.