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Traditional vector control approaches such as source reduction and insecticide spraying have limited effect on reducing Aedes aegypti population. The endosymbiont Wolbachia is pointed as a promising tool to mitigate arbovirus transmission and has been deployed worldwide. Models predict a rapid increase on the frequency of Wolbachia-positive Ae. aegypti mosquitoes in local settings, supported by cytoplasmic incompatibility (CI) and high maternal transmission rate associated with the wMelBr strain. Wolbachia wMelBr strain was released for 20 consecutive weeks after receiving >87% approval of householders of the isolated community of Tubiacanga, Rio de Janeiro. wMelBr frequency plateued~40% during weeks 7-19, peaked 65% but dropped as releases stopped. A high (97.56%) maternal transmission was observed. Doubling releases and deploying mosquitoes with large wing length and low laboratory mortality produced no detectable effects on invasion trend. By investigating the lab colony maintenance procedures backwardly, pyrethroid resistant genotypes in wMelBr decreased from 68% to 3.5% after 17 generations. Therefore, we initially released susceptible mosquitoes in a local population highly resistant to pyrethroids which, associated with the over use of insecticides by householders, ended jeopardizing Wolbachia invasion. A new strain (wMelRio) was produced after backcrossing wMelBr females with males from field to introduce mostly pyrethroid resistance alleles. The new strain increased mosquito survival but produced relevant negative effects on Ae. aegypti fecundity traits, reducing egg clutche size and egg hatch. Despite the cost on fitness, wMelRio successful established where wMelBr failed, revealing that matching the local population genetics, especially insecticide resistance background, is critical to achieve invasion. Local householders support was constantly high, reaching 90% backing on the second release (wMelRio strain). Notwithstanding the drought summer, the harsh temperature recorded (daily average above 30°C) did not seem to affect the expression of maternal transmission of wMel on a Brazilian background. Wolbachia deployment should match the insecticide resistance profile of the wild population to achieve invasion. Considering pyrethroid-resistance is a widely distributed phenotype in natural Ae. aegypti populations, future Wolbachia deployments must pay special attention in maintaining insecticide resistance in lab colonies for releases.

The repair of high strength, high performance 7075 aluminum alloy is essential for a broad range of aerospace and defense applications. However, it is challenging to implement it using traditional fusion welding-based approaches, owing to hot cracking and void formation during solidification. Here, the use of an emerging solid-state additive manufacturing technology, additive friction stir deposition, is explored for the repair of volume damages such as through -holes and grooves in 7075 aluminum alloy. Three repair experiments have been conducted: double through-hole filling, single through-hole filling, and long, wide-groove filling. In all experiments, additive friction stir deposition proves to be effective at filling the entire volume. Additionally, sufficient mixing between the deposited material and the side wall of the feature is always observed in the upper portions of the repair. Poor mixing and inadequate repair quality have been observed in deeper portions of the filling in some scenarios. Based on these observations, the advantages and disadvantages of using additive friction stir deposition for repairing volume damages are discussed. High quality and highly flexible repairs are expected with systematic optimization work on process control and repair strategy development in the future.

Microtubule-disturbing drugs inhibit lysosomal trafficking and induce lysosomal membrane permeabilization followed by cathepsin-dependent cell death. To identify specific trafficking-related proteins that control cell survival and lysosomal stability, we screened a molecular motor siRNA library in human MCF7 breast cancer cells. SiRNAs targeting four kinesins (KIF11/Eg5, KIF20A, KIF21A, KIF25), myosin 1G (MYO1G), myosin heavy chain 1 (MYH1) and tropomyosin 2 (TPM2) were identified as effective inducers of non-apoptotic cell death. The cell death induced by KIF11, KIF21A, KIF25, MYH1 or TPM2 siRNAs was preceded by lysosomal membrane permeabilization, and all identified siRNAs induced several changes in the endo-lysosomal compartment, i.e. increased lysosomal volume (KIF11, KIF20A, KIF25, MYO1G, MYH1), increased cysteine cathepsin activity (KIF20A, KIF25), altered lysosomal localization (KIF25, MYH1, TPM2), increased dextran accumulation (KIF20A), or reduced autophagic flux (MYO1G, MYH1). Importantly, all seven siRNAs also killed human cervix cancer (HeLa) and osteosarcoma (U-2-OS) cells and sensitized cancer cells to other lysosome-destabilizing treatments, i.e. photo-oxidation, siramesine, etoposide or cisplatin. Similarly to KIF11 siRNA, the KIF11 inhibitor monastrol induced lysosomal membrane permeabilization and sensitized several cancer cell lines to siramesine. While KIF11 inhibitors are under clinical development as mitotic blockers, our data reveal a new function for KIF11 in controlling lysosomal stability and introduce six other molecular motors as putative cancer drug targets.

Osteopontin (OPN) is a multifunctional bioactive protein that is implicated in numerous biological processes such as bone remodeling, inhibition of ectopic calcification, and cellular adhesion and migration, as well as several immune functions. Osteopontin has cytokine-like properties and is a key factor in the initiation of T helper 1 immune responses. Osteopontin is present in most tissues and body fluids, with the highest concentrations being found in milk. In the present study, ELISA for human and bovine milk OPN were developed and OPN concentration in human breast milk, bovine milk, and infant formulas was measured and compared. The OPN concentration in human milk was measured to approximately 138 mg/L, which corresponds to 2.1% (wt/wt) of the total protein in human breast milk. This is considerably higher than the corresponding OPN concentrations in bovine milk (approximately 18 mg/L) and infant formulas (approximately 9 mg/L). Moreover, bovine milk OPN is shown to induce the expression of the T helper 1 cytokine IL-12 in cultured human lamina propria mononuclear cells isolated from intestinal biopsies. Finally, the OPN concentration in plasma samples from umbilical cords, 3-mo-old infants, and pregnant and nonpregnant adults was measured. The OPN level in plasma from 3-mo-old infants and umbilical cords was found to be 7 to 10 times higher than in adults. Thus, the high levels of OPN in milk and infant plasma suggest that OPN is important to infants and that ingested milk OPN is likely to induce cytokine production in neonate intestinal immune cells.

The current study assesses the feasibility and value of crushed cerebral blood flow (CBFcrushed) and arterial transit time (ATT) estimations for large clinical imaging studies in elderly with hypertension. Two pseudo-continuous arterial spin labeling (ASL) scans with (CBFcrushed) and without flow crushers (CBFnon-crushed) were performed in 186 elderly with hypertension, from which CBF and ATT maps were calculated. Standard flow territory maps were subdivided into proximal, intermediate and distal flow territories, based on the measured ATT. The coefficient of variation (CV) and physiological correlations with age and gender were compared between the three perfusion parameters. There was no difference in CV between CBFcrushed and CBFnon-crushed (15-24%, p>0.4) but the CV of ATT (4-9%) was much smaller. The total gray matter correlations with age and gender were most significant with ATT (p = .016 and p<.001 respectively), in between for CBFcrushed (p = .206 and p = .019) and least significant for CBFnon-crushed (p = .236 and p = .100). These data show the feasibility and added value of combined measurements of both crushed CBF and ATT for group analyses in elderly with hypertension. The obtained flow territories provide knowledge on vascular anatomy of elderly with hypertension and can be used in future studies to investigate regional vascular effects.

Previous research has found associations but not established mechanisms of developmental linkage between language ability and inattentive–hyperactive (I-H) behavior problems. The present study examined whether self-regulation mediates the effect of language ability on later I-H behavior problems among young children (N = 120) assessed at 30, 36, and 42 months of age. Cross-lagged panel models tested the direction of effect between language ability and self-regulation and longitudinal effects of language ability on later I-H problems mediated by self-regulation. Language ability was measured by children's scores on the receptive and expressive language subtests of the Differential Ability Scales. Self-regulation was measured by three behavioral tasks requiring inhibitory control. I-H problems were reported by parents and secondary caregivers. Language ability predicted later self-regulation as measured by all three tasks. There was no association, however, between self-regulation and later language ability, suggesting that the direction of effect was stronger from language ability to later self-regulation. Moreover, the effect of language ability on later I-H behavior problems was mediated by children's self-regulation in one of the tasks (for secondary caregivers' but not parents' ratings). Findings suggest that language deficits may explain later I-H behavior problems via their prediction of poorer self-regulatory skills.

Idiopathic duct-centric chronic pancreatitis (IDCP), also known as type 2 autoimmune pancreatitis (AIP), is an uncommon subtype of AIP. International Consensus Diagnostic Criteria for IDCP propose that the diagnosis requires pancreatic histology and/or concurrent IBD. We examined our experience with IDCP (type 2 AIP) to assess the appropriateness of these criteria, and identify unique characteristics in patients presenting with acute pancreatitis. We reviewed the Mayo Clinic AIP database through May 2014 to identify subjects with either definitive (n=31) or probable (n=12) IDCP. We compared demographic and clinical factors based on strength of diagnostic confidence (definitive versus probable), presence of IBD, and acute pancreatitis as the presenting manifestation. Relapse-free survival was determined using the Kaplan-Meier method. The clinical profiles were similar irrespective of the diagnostic criteria fulfilled. Common clinical presentations included acute pancreatitis (n=25, 58.1%, 12 of whom (27.9%) had recurrent pancreatitis) and pancreatic mass/obstructive jaundice (n=15, 34.9%). The cumulative relapse rate was 10.6% at 3 years (median follow-up 2.9 years). Relapse-free survival was similar for the different diagnostic categories, but was decreased in those initially presenting with acute pancreatitis (p=0.047) or treated with steroids (vs surgery, p=0.049). The current diagnostic classification of probable IDCP and the inclusion of IBD as a supportive criterion appear valid, because patients have similar clinical profiles and disease-related outcomes to those with definitive IDCP. Concurrent IBD, especially in young patients, may suggest when IDCP is the underlying cause of recurrent acute pancreatitis, but additional studies are needed for validation.

Fatigue occurs in the majority of multiple sclerosis patients and therapeutic possibilities are few. Fatigue, mood and quality of life were studied in patients with multiple sclerosis following progressive resistance training leading to improvement of muscular strength and functional capacity. Fatigue (Fatigue Severity Scale, FSS), mood (Major Depression Inventory, MDI) and quality of life (physical and mental component scores, PCS and MCS, of SF36) were scored at start, end and follow-up of a randomized controlled clinical trial of 12 weeks of progressive resistance training in moderately disabled (Expanded Disability Status Scale, EDSS: 3—5.5) multiple sclerosis patients including a Control group (n = 15) and an Exercise group (n = 16). Fatigue (FSS > 4) was present in all patients. Scores of FSS, MDI, PCS—SF36 and MCS—SF36 were comparable at start of study in the two groups. Fatigue improved during exercise by —0.6 (95% confidence interval (CI) —1.4 to 0.4) a.u. vs. 0.1 (95% CI —0.4 to 0.6) a.u. in controls (p = 0.04), mood improved by —2.4 (95% CI —4.1 to 0.7) a.u. vs. 1.1 (—1.2 to 3.4) a.u. in controls (p = 0.01) and quality of life (PCS—SF36) improved by 3.5 (95% CI 1.4—5.7) a.u. vs. —1.0 (95% CI —3.4—1.4) a.u. in controls (p = 0.01). The beneficial effect of progressive resistance training on all scores was maintained at follow-up after further 12 weeks. Fatigue, mood and quality of life all improved following progressive resistance training, the beneficial effect being maintained for at least 12 weeks after end of intervention.

Arabidopsis MAP kinase 4 (MPK4) functions as a regulator of pathogen defense responses, because it is required for both repression of salicylic acid (SA)‐dependent resistance and for activation of jasmonate (JA)‐dependent defense gene expression. To understand MPK4 signaling mechanisms, we used yeast two‐hybrid screening to identify the MPK4 substrate MKS1. Analyses of transgenic plants and genome‐wide transcript profiling indicated that MKS1 is required for full SA‐dependent resistance in mpk4 mutants, and that overexpression of MKS1 in wild‐type plants is sufficient to activate SA‐dependent resistance, but does not interfere with induction of a defense gene by JA. Further yeast two‐hybrid screening revealed that MKS1 interacts with the WRKY transcription factors WRKY25 and WRKY33. WRKY25 and WRKY33 were shown to be in vitro substrates of MPK4, and a wrky33 knockout mutant was found to exhibit increased expression of the SA‐related defense gene PR1 . MKS1 may therefore contribute to MPK4‐regulated defense activation by coupling the kinase to specific WRKY transcription factors.

Changes in the Earth's geomagnetic field induce geoelectric fields in the solid Earth. These electric fields drive Geomagnetically Induced Currents (GICs) in grounded, conducting infrastructure. These GICs can damage or degrade equipment if they are sufficiently intense—understanding and forecasting them is of critical importance. One of the key magnetospheric phenomena are Sudden Commencements (SCs). To examine the potential impact of SCs we evaluate the correlation between the measured maximum GICs and rate of change of the magnetic field (H′) in 75 power grid transformers across New Zealand between 2001 and 2020. The maximum observed H′ and GIC correlate well, with correlation coefficients (r2) around 0.7. We investigate the gradient of the relationship between H′ and GIC, finding a hot spot close to Dunedin: where a given H′ will drive the largest relative current (0.5 A nT−1 min). We observe strong intralocation variability, with the gradients varying by a factor of two or more at adjacent transformers. We find that GICs are (on average) greater if they are related to: (a) Storm Sudden Commencements (SSCs; 27% larger than Sudden Impulses, SIs); (b) SCs while New Zealand is on the dayside of the Earth (27% larger than the nightside); and (c) SCs with a predominantly East‐West magnetic field change (14% larger than North‐South equivalents). These results are attributed to the geology of New Zealand and the geometry of the power network. We extrapolate to find that transformers near Dunedin would see 2000 A or more during a theoretical extreme SC (H′ = 4000 nT min−1).