Bedraggled, a putative transporter, influences the tissue polarity complex during the R3/R4 fate decision in the Drosophila eye

The tissue polarity pathway is required for the establishment of epithelial polarity in a variety of vertebrate and invertebrate organs. Core tissue polarity proteins act in a dynamically regulated complex to direct the polarization of the Drosophila eye. We report the identification and characterization of bedraggled (bdg), a novel gene that regulates one output of the tissue polarity pathway--the establishment of the R3/R4 photoreceptor fates. bdg encodes a novel, putative transporter protein and interacts genetically with all of the core polarity genes to influence the specification of the R3 and R4 cell fates. Finally, bdg is required for both viability and the initial stages of imaginal disc development.     

Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies

Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.     

Mutation in a flexible linker modulates binding affinity for modular complexes

Tandem beta zippers are modular complexes formed between repeated linear motifs and tandemly arrayed domains of partner proteins in which β-strands form upon binding. Studies of such complexes, formed by LIM domain proteins and linear motifs in their intrinsically disordered partners, revealed spacer regions between the linear motifs that are relatively flexible but may affect the overall orientation of the binding modules. We demonstrate that mutation of a solvent exposed side chain in the spacer region of an LHX4–ISL2 complex has no significant effect on the structure of the complex, but decreases binding affinity, apparently by increasing flexibility of the linker.     

Tree identity and diversity directly affect soil moisture and temperature but not soil carbon ten years after planting

1. Soil C is the largest C pool in forest ecosystems that contributes to C sequestration and mitigates climate change. Tree diversity enhances forest productivity, so diversifying the tree species composition, notably in managed forests, could increase the quantity of organic matter being transferred to soils and alter other soil properties relevant to the C cycle.
2. A ten‐year‐old tree diversity experiment was used to study the effects of tree identity and diversity (functional and taxonomic) on soils. Surface (0–10 cm) mineral soil was repeatedly measured for soil C concentration, C:N ratio, pH, moisture, and temperature in twenty‐four tree species mixtures and twelve corresponding monocultures (replicated in four blocks).
3. Soil pH, moisture, and temperature responded to tree diversity and identity. Greater productivity in above‐ and below‐ground tree components did not increase soil C concentration. Soil pH increased and soil moisture decreased with functional diversity, more specifically, when species had different growth strategies and shade tolerances. Functional identity affected soil moisture and temperature, such that tree communities with more slow‐growing and shade‐tolerant species had greater soil moisture and temperature. Higher temperature was measured in communities with broadleaf‐deciduous species compared to communities with coniferous‐evergreen species.
4. We conclude that long‐term soil C cycling in forest plantations will likely respond to changes in soil pH, moisture, and temperature that is mediated by tree species composition, since tree species affect these soil properties through their litter quality, water uptake, and physical control of soil microclimates.

     

Functional insight into LOAD-associated microglial response genes

Alzheimer''s disease (AD) is characterized by the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), neuronal and synaptic loss and inflammation of the central nervous system (CNS). The majority of AD research has been dedicated to the understanding of two major AD hallmarks (i.e. Aβ and NFTs); however, recent genome-wide association studies (GWAS) data indicate neuroinflammation as having a critical role in late-onset AD (LOAD) development, thus unveiling a novel avenue for AD therapeutics. Recent evidence has provided much support to the innate immune system''s involvement with AD progression; however, much remains to be uncovered regarding the role of glial cells, specifically microglia, in AD. Moreover, numerous variants in immune and/or microglia-related genes have been identified in whole-genome sequencing and GWAS analyses, including such genes as TREM2, CD33, APOE, API1, MS4A, ABCA7, BIN1, CLU, CR1, INPP5D, PICALM and PLCG2. In this review, we aim to provide an insight into the function of the major LOAD-associated microglia response genes.     

Seroepidemiology of Crimean-Congo Haemorrhagic Fever among cattle in Cameroon: Implications from a One Health perspective

BackgroundCrimean-Congo Haemorrhagic Fever (CCHF) is a tick-borne viral zoonotic disease distributed across several continents and recognized as an ongoing health threat. In humans, the infection can progress to a severe disease with high fatality, raising public health concerns due to the limited prophylactic and therapeutic options available. Animal species, clinically unaffected by the virus, serve as viral reservoirs and amplifier hosts, and can be a valuable tool for surveillance. Little is known about the occurrence and prevalence of Crimean-Congo Haemorrhagic Fever Virus (CCHFV) in Cameroon. Knowledge on CCHFV exposure and the factors associated with its presence in sentinel species are a valuable resource to better understand transmission dynamics and assess local risks for zoonotic disease emergence.Methods and findingsWe conducted a CCHFV serological survey and risk factor analysis for animal level seropositivity in pastoral and dairy cattle in the North West Region (NWR) and the Vina Division (VD) of the Adamawa Region in Cameroon. Seroprevalence estimates were adjusted for sampling design-effects and test performance. In addition, explanatory multivariable logistic regression mixed-effects models were fit to estimate the effect of animal characteristics, husbandry practices, risk contacts and ecological features on the serological status of pastoral cattle. The overall seroprevalence was 56.0% (95% CI 53.5–58.6) and 6.7% (95% CI 2.6–16.1) among pastoral and dairy cattle, respectively. Animals going on transhumance had twice the odds of being seropositive (OR 2.0, 95% CI 1.1–3.8), indicating that animal movements could be implicated in disease expansion. From an ecological perspective, absolute humidity (OR 0.6, 95% CI 0.4–0.9) and shrub density (OR 2.1, 95% CI 1.4–3.2) were associated with seropositivity, which suggests an underlying viral dynamic connecting vertebrate host and ticks in a complex transmission network.ConclusionsThis study demonstrated high seroprevalence levels of CCHFV antibodies in cattle in Cameroon indicating a potential risk to human populations. However, current understanding of the underlying dynamics of CCHFV locally and the real risk for human populations is incomplete. Further studies designed using a One Health approach are required to improve local knowledge of the disease, host interactions and environmental risk factors. This information is crucial to better project the risks for human populations located in CCHFV-suitable ecological niches.     

Maitotoxin and P2Z/P2X7 purinergic receptor stimulation activate a common cytolytic pore

The effects ofmaitotoxin (MTX) on plasmalemma permeability are similar to thosecaused by stimulation of P2Z/P2X₇ionotropic receptors, suggesting that1) MTX directly activatesP2Z/P2X₇ receptors or2) MTX andP2Z/P2X₇ receptor stimulationactivate a common cytolytic pore. To distinguish between these twopossibilities, the effect of MTX was examined in1) THP-1 monocytic cells before andafter treatment with lipopolysaccharide and interferon-, a maneuverknown to upregulate P2Z/P2X₇receptor, 2) wild-type HEK cells andHEK cells stably expressing theP2Z/P2X₇ receptor, and3) BW5147.3 lymphoma cells, a cellline that expresses functional P2Z/P2X₇ channels that are poorlylinked to pore formation. In control THP-1 monocytes, addition of MTXproduced a biphasic increase in the cytosolic freeCa²⁺ concentration([Ca²⁺]_i);the initial increase reflects MTX-inducedCa²⁺ influx, whereas the secondphase correlates in time with the appearance of large pores and theuptake of ethidium. MTX produced comparable increases in[Ca²⁺]_iand ethidium uptake in THP-1 monocytes overexpressing theP2Z/P2X₇ receptor. In bothwild-type HEK and HEK cells stably expressing theP2Z/P2X₇ receptor, MTX-inducedincreases in[Ca²⁺]_iand ethidium uptake were virtually identical. The response of BW5147.3cells to concentrations of MTX that produced large increases in[Ca²⁺]_ihad no effect on ethidium uptake. In both THP-1 and HEK cells, MTX- andBz-ATP-induced pores activate with similar kinetics and exhibit similarsize exclusion. Last, MTX-induced pore formation, but not channelactivation, is greatly attenuated by reducing the temperature to22°C, a characteristic shared by theP2Z/P2X₇-induced pore. Together,the results demonstrate that, although MTX activates channels that aredistinct from those activated byP2Z/P2X₇ receptor stimulation, thecytolytic/oncotic pores activated by MTX- and Bz-ATP are indistinguishable.

     

Local polynomial regression modeling of human plasma melatonin levels

Accurate characterization of features of the melatonin production curve is important for research in chronobiology. Local polynomial regression is used to model the plasma melatonin concentration curve and obtain consistent and asymptotically normally distributed estimates of synthesis onset and offset times, duration, peak concentration, and area under the curve. A simple production-clearance model for melatonin kinetics provides the connection between plasma concentrations and the melatonin production curve. This model identifies onset and offset times with critical points of derivatives of the concentration curve. The method proposed has the advantage of flexibility and ease of implementation. Local polynomial regression can be shown to produce consistent estimates of the regression curve and parameters of interest. Furthermore, the method can be implemented in any software package with weighted least squares routines.