Search

MERTK tyrosine kinase expression is upregulated upon monocyte to macrophage differentiation. This receptor tyrosine kinase enables macrophages to efficiently clear apoptotic cells to maintain tissue homeostasis. Activation of MERTK in macrophages during efferocytosis promotes an immunosuppressive phenotype, which is hijacked by tumors to inhibit anti-tumor immunity. Further, this immunosuppressive phenotype in MERTK expressing macrophages in the tumor microenvironment is reversed using MERTK selective inhibitors, suggesting that inhibiting MERTK expression or activity in the tumor microenvironment may be of therapeutic benefit in the treatment of cancer. In an attempt to further understand the mechanism of MERTK upregulation in macrophages, we treated the monocytic leukemia cell line THP1 with PMA to differentiate the cells from a monocytic morphology to an adherent macrophage-like morphology. Following differentiation of the THP-1 cells, MERTK upregulation was confirmed by western blot and flow cytometry. In a similar fashion, treatment with of murine bone marrow derived monocytic cells with PMA induced MERTK expression. Proteomics cytokine array analysis also revealed increased levels of multiple chemokines including MCP-1 and RANTES. Treatment of THP-1 cells with a pan STAT inhibitor in the presence of PMA abrogated the induction of MERTK expression, suggesting a critical role for STAT pathways in the regulation of MERTK expression during monocyte differentiation to macrophages. Specifically, the STAT3 pathway was found to be important in MERTK regulation, as treatment with a STAT3 selective inhibitor was sufficient to abrogate MERTK expression in the presence of PMA treatment. Single cell sequencing of the immune cells in the bone marrow demonstrated Stat3 expression in monocytic lineage cells. Furthermore, both CD11C+Ly6c+CD45+ population and MERTK+CD11C+Ly6c+CD45+ populations were lower in Stat3 -/- bone marrow cells treated with PMA relative to the untreated cells. Collectively, these data suggest that MERTK expression during macrophage maturation may be mediated by STAT3 activation. Previously published data have also demonstrated that STAT3 can be activated downstream of MERTK activation. Thus, we propose that MERTK and STAT3 form a positive feedback loop during macrophage maturation. Treatment with either a MERTK and/or STAT3 inhibitor may interfere with this feedback pathway, potentially reversing an immunosuppressive phenotype in the macrophages in the tumor microenvironment. Citation Format: Dan Yan, Justus M. Huelse, Swati Sharma Bhasin, Manoj Bhasin, Deborah DeRyckere, Douglas K. Graham. Targeting a positive feedback loop of MERTK and STAT3 during macrophage differentiation may provide anti-tumor immune function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2335.

This study sought to establish Business Process Reengineering (BPR) strategies used by telecommunication companies in Kenya to enhance their service delivery to gain competitive advantage, and to explore the influence of BPR strategies in the telecommunication companies in Kenya. The study was anchored on the following theories, Resource-Based, the Open Systems and Stakeholder. The study used a descriptive cross sectional research design targeting thirty five telecommunication firms in Kenya. Data was collected through structured questionnaires. Data analysis was done by use of descriptive and inferential statistics. The study established that most of Telecommunication companies have used various BPR strategies such as Teleconferencing technologies, computerized performance measurement and reporting system, shared Information Technology infrastructure and computerized procurement system. Findings show that after BPR implementation the telecommunications firms were able to increase efficiency of customer service, quality of products and workforce, elimination of non-value adding process, reduction in inspection time, moving time and waiting/queuing time. The study recommends that Telecommunication companies should fully automate their operations besides replacing obsolete technology equipment with modern ones. BPR efforts should be implemented in the most effective manner through sound management and leadership; this is because top management commitment, support, championship, sponsorship, and effective management of risks are the most noticeable managerial practices that seem to directly influence the success of BPR execution. The study recommends that most companies should be cautious when re-engineering in order to avoid downsizing without figuring out how to reduce the workload. Key words: Business Process Reengineering, Telecommunication companies, management support, employee commitment, ITinfrastructure.

System of rice intensification (SRI) is a novel technological approach aimed at improving rice productivity using environmental-friendly and cost-effective agronomic practices. Although its utility has been demonstrated in several settings in sub-Saharan Africa, its implementation is still considerably low. This study explored the challenges faced and coping strategies used by Kenyan smallholder farmers who contribute substantially to domestic rice production, in the uptake of SRI practices in rural setting in the western part of the country where it was previously been introduced. The study involved a survey of 101 smallholder rice farmers in Oluch Irrigation Scheme in Homabay County, to understand the challenges and coping strategies to the uptake of the system of rice intensification practices. Descriptive and inferential statistical analysis was done to guide in summarising the results using the SPSS package. The findings revealed that a host of challenges impede the acceptance of SRI in Oluch irrigation scheme, mainly insufficient knowledge, shortage and high costs of labour, weak stakeholder networks in the rice value chain; pests and diseases; and high cost of agricultural inputs to facilitate SRI. Notably, none of these challenges were overwhelmingly prevalent across majority of farmers, but that they were accosted by multiple complex and competing challenges limiting their opportunities for uptake of different SRI practices. It was observed that the nature and manifestation of these challenges necessitated the involvement of multiple actors in the rice value chain to address them. This formed the basis for a multi-stakeholder approach to address challenges that limited the implementation of new agricultural technologies, especially the utility of innovative approaches such as innovation platform to promote the uptake of SRI.

As acquiring bigger data becomes easier in experimental brain science, computational and statistical brain science must achieve similar advances to fully capitalize on these data. Tackling these problems will benefit from a more explicit and concerted effort to work together. Specifically, brain science can be further democratized by harnessing the power of community-driven tools, which both are built by and benefit from many different people with different backgrounds and expertise. This perspective can be applied across modalities and scales and enables collaborations across previously siloed communities.

Significance When an animal forms a memory, synapses in specific brain pathways change their strength. Pinpointing which synapses and pathways are modulated in any given learning paradigm, however, is technically challenging and needs to be performed one candidate connection at a time. Here we present SYNPLA, a tool to quickly detect strengthened synapses in genetically or anatomically defined pathways across the brain. To do so, we exploit the temporary translocation of AMPA receptor GluA1 into newly strengthened synapses. Using an assay that can identify proteins less than 40 nm away, we label only synapses that contain both GluA1 and a presynaptic protein exogenously expressed in a specific pathway. SYNPLA thus provides a pathway- and synapse-specific screening tool for memory formation.

INTRODUCTION: Sleep destabilization is strongly associated with aging and cognitive function decline. Despite sleep fragmentation being central to the most prevalent complaints of sleep problems in elderly populations, the mechanistic underpinnings of sleep instability remain elusive. Fragmented sleep during aging has been observed across species, indicating conserved underlying mechanisms across the phylogenetic tree. Therefore, understanding why the aging brain fails to consolidate sleep may shed light on translational applications for improving the sleep quality of aged individuals. RATIONALE: We hypothesized that the decline in sleep quality could be due to malfunction of the neural circuits associated with sleep/wake control. It has been established that hypocretin/orexin (Hcrt/OX) neuronal activity is tightly associated with wakefulness and initiates and maintains the wake state. In this study, we investigated whether the intrinsic excitability of Hcrt neurons is altered, leading to a destabilized control of sleep/wake states during aging. RESULTS: Aged mice exhibited sleep fragmentation and a significant loss of Hcrt neurons. Hcrt neurons manifested a more frequent firing pattern, driving wake bouts and disrupting sleep continuity in aged mice. Aged Hcrt neurons were capable of eliciting more prolonged wake bouts upon optogenetic stimulations. These results suggested that hyperexcitability of Hcrt neurons emerges with age. Patch clamp recording in genetically identified Hcrt neurons revealed distinct intrinsic properties between the young and aged groups. Aged Hcrt neurons were hyperexcitable with depolarized membrane potentials (RMPs) and a smaller difference between RMP and the firing threshold. Aged Hcrt neurons expressing ChR2-eYFP were more sensitive to optogenetic stimulations, with a smaller-amplitude attenuation upon repetitive light pulse stimulations. More spikelets were generated in aged Hcrt neurons upon current injections. Recording from non-Hcrt neurons postsynaptic to Hcrt neurons revealed that optogenetic stimulation of Hcrt neurons expressing ChR2-eYFP reliably evoked time-locked postsynaptic currents (PSCs) after optogenetic stimulation more often in the aged group. Aged Hcrt neurons were characterized with a functional impairment of repolarizing M-current mediated by KCNQ2/3 channels and an anatomical loss of KCNQ2, revealed with array tomography at ultrastructural resolution. Single-nucleus RNA-sequencing (snRNA-seq) revealed molecular adaptions, including up-regulated prepro-Hcrt mRNA expression and a smaller fraction of Kcnq family subtypes Kcnq1/2/3/5 in aged Hcrt neurons. CRISPR/SaCas9–mediated disruption of Kcnq2/3 genes selectively in Hcrt neurons was sufficient to recapitulate the aging-associated sleep fragmentation trait in young mice. Pharmacological augmentation of M-current repolarized the RMP, suppressed spontaneous firing activity in aged Hcrt neurons, and consolidated sleep stability in aged mice. Sleep fragmentation in a narcolepsy mouse model with genetic ablation of Hcrt neurons at young ages manifested a mechanism other than hyperexcitable arousal-promoting Hcrt neurons that drives sleep fragmentation during healthy aging. CONCLUSION: Our data indicate that emerging hyperexcitability of arousal-promoting Hcrt neurons is strongly associated with fragmented sleep in aged mice, which display a lowered sleep-to-wake transition threshold defined for Hcrt neuronal activity. We have demonstrated that the down-regulation of KCNQ2/3 channels compromising repolarization drives Hcrt neuronal hyperexcitability, which leads to sleep instability during aging. Pharmacological remedy of sleep continuity through targeting KCNQ2/3 channels in aged mice confers a potential translational therapy strategy for improving sleep quality in aged individuals.

Comparative transcriptomics could reveal patterns of cell type evolution in the tetrapod brain

Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1–6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7–9. Although ICPN are anatomically diverse10–14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ( $$\vec{{\rm{M}}}$$ ) ICPN compared with secondary somatosensory cortex-projecting ( $$\vec{{\rm{S}}2}$$ ) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in $$\vec{{\rm{M}}}$$ versus $$\vec{{\rm{S}}2}$$ ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons. Combined analysis of the connectome and transcriptome in the mouse cortex indicates that dynamic differences in expression levels of largely generic sets of genes regulate differential targeting within neuronal subtypes.

The TAM family receptor tyrosine kinases TYRO3, AXL and MERTK are potential therapeutic targets in a variety of cancers. In our previous studies, MERTK inhibition in the leukemia microenvironment significantly prolonged survival in a syngeneic B-cell acute leukemia (B-ALL) model, implicating MERTK as a promising immuno-oncology target. Strikingly, Mertk-/- mice were almost completely protected against leukemia. Here, we probed the mechanisms of anti-leukemia immunity mediated by MERTK inhibition and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Single cell RNA sequencing and flow cytometry studies revealed an increase in CD8α+ dendritic cells (DCs) with enhanced antigen-presentation capacity in naïve and leukemia-bearing Mertk-/- mice. These cells were also increased in leukemic wild type (WT) mice treated with the MERTK inhibitor MRX-2843 (currently in phase I/Ib clinical trials). Additionally, CD8+ T cells expressing high levels of the T cell exhaustion marker Tox were decreased in mice treated with MRX-2843, implicating a CD8α+ DC – T cell axis in the anti-leukemia immune response stimulated by MERTK inhibition. Indeed, combined depletion of CD8+ T cells and CD8α+ DCs completely abrogated the anti-leukemia response in Mertk-/- mice, while immunity remained partially intact in mice with selective depletion of CD8+ T cells. Similarly, protection from leukemia was abrogated in Mertk-/- scid mice, which lack functional B and T cells and have defects in DC function. These data demonstrate a critical immunosuppressive role for MERTK in DCs of the leukemia microenvironment. Similar to Mertk-/- mice, B-ALL growth was almost completely prevented in Tyro3-/- mice, while Axl-/- did not impact leukemogenesis, implicating TYRO3, but not AXL, as an additional immunotherapeutic target. However, in contrast to Mertk-/- mice, CD8α+ DCs with enhanced antigen-presentation capacity were not significantly increased in Tyro3-/- mice compared to WT, indicating differences in the underlying mechanisms by which MERTK and TYRO3 contribute to the immunosurveillance of leukemia cells. Indeed, in vivo depletion experiments confirmed differential roles for MERTK and TYRO3 in the leukemia microenvironment. In contrast to Mertk-/- mice, selective depletion of CD8+ T cells completely abrogated protection from leukemia in Tyro3-/- mice, indicating a mechanism less dependent on DCs. Together, these findings reveal novel and distinct mechanistic insights into the immunosuppressive roles for MERTK and TYRO3 in the leukemia microenvironment, demonstrate a critical role for MERTK in DC activity, and validate a similar mechanism mediated by MRX-2843. Thus, these studies provide strong rationale for development of MERTK and/or TYRO3-targeted immunotherapies for treatment of acute leukemia. Citation Format: Justus M Huelse, Swati S Bhasin, Kristen M Jacobsen, Beena E Thomas, Madison L Chimenti, Travon A Baxter, Xiaodong Wang, Stephen V Frye, Curtis J Henry, H. Shelton Earp, Manoj Bhasin, Deborah DeRyckere, Douglas K Graham. MERTK inhibition induces an anti-leukemia dendritic cell – T cell axis while TYRO3 inhibition protects by a separate mechanism [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A35.

In most sensory modalities, neuronal connectivity reflects behaviorally relevant stimulus features, such as spatial location, orientation, and sound frequency. By contrast, the prevailing view in the olfactory cortex, based on the reconstruction of dozens of neurons, is that connectivity is random. Here, we used high-throughput sequencing-based neuroanatomical techniques to analyze the projections of 5,309 mouse olfactory bulb and 30,433 piriform cortex output neurons at single-cell resolution. Surprisingly, statistical analysis of this much larger dataset revealed that the olfactory cortex connectivity is spatially structured. Single olfactory bulb neurons targeting a particular location along the anterior-posterior axis of piriform cortex also project to matched, functionally distinct, extra-piriform targets. Moreover, single neurons from the targeted piriform locus also project to the same matched extra-piriform targets, forming triadic circuit motifs. Thus, as in other sensory modalities, olfactory information is routed at early stages of processing to functionally diverse targets in a coordinated manner.

Measures of research productivity have become widely used for obtaining tenure, third-party funding, and additional resources from universities. However, previous studies indicate that men might have a higher research output than women, with mixed conclusions about the factors that drive these differences. This study explores to what extent the research productivity of psychology professors in Germany is related to gender and, furthermore, how any gender gaps can be explained by controlling for individual and organizational factors. In addition, three publication dimensions (publications in top 10% journals, journal articles, and book and collection chapters) are distinguished to determine the effect of gender on research productivity as precisely as possible. A unique data set based on all full professors in psychology in Germany and their publication record in 2013 and 2014 is used ( $$N_\mathrm{authors}$$ = 294; $$N_\mathrm{articles}$$ = 2252, $$N_\mathrm{chapters}$$ = 439). Thus, this study provides a current overview of the state of research productivity in an entire discipline after researchers receive tenure and external restrictions are lessened. Our research helps to further locate the point at which gender differences in publication numbers occur. As we are the first to systematically to analyze different publication types, we are able to show that there is no difference in publication numbers for less-prestigious book chapters. However, we find significant gender differences for research productivity in academic journals that are more important for career advancement and peer recognition, even after we control for the most important individual and organizational factors that might explain gender differences. Our results point to the direction that women do research and write manuscripts, but may have different publication patterns: instead of submitting to competitive journals, they may be satisfied with less-prestigious book chapters. As publications in peer-reviewed journals are especially important for career advancement as well as peer recognition, this publication pattern may be disadvantageous for women. Overall, we conclude that additional research to understand these developments is needed that focuses on the motives and beliefs of researchers, both to improve gender equality in academia and to give women better chances to gain recognition and prestige.

OBJECTIVE To investigate emergency clinicians' comfort level in assessing neurological emergencies and to identify opportunities to foster enhanced training of clinical neurology in the emergency room. DESIGN Internet-based survey. SETTING University teaching hospitals and private referral centers. SUBJECTS One hundred and ninety-two emergency and critical care specialists and resident trainees (ECC) and 104 neurology specialists and resident trainees (NEUR) in clinical practice. INTERVENTIONS An internet-based survey was distributed via veterinary professional organizations' listserves and message boards and responses were collected between March and April 2020. ECC completed a survey evaluating stress levels associated with neurological emergencies, confidence with neurological examinations, and neuroanatomical localization. NEUR completed a similar survey to report their perception of their ECC colleagues' confidence in the assessment of neurological cases. Chi-square and Mann-Whitney U-tests were used to compare categorical responses and confidence scores between groups. P 75% of cases. CONCLUSIONS Noticeable discrepancies between ECC and NEUR perceptions of ECC clinical confidence were seen, while no firm evidence of neurophobia could be inferred. Improvements in interdepartmental communication and teaching of clinical neurology may be warranted.

Osteoporosis is a systemic bone disease that affects more than 200 million people worldwide and is caused by the disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation. Sphingosine-1-phosphate (S1P) is a natural, bioactive sphingolipid that has been shown to play a major role in cardiovascular and immunological pathologies by regulating biological and cellular processes, including migration, differentiation, proliferation and survival. Recent studies also suggest a central role for S1P in bone diseases, including osteoporosis; however, the effects of S1P, particularly in bone metabolism, remain to be further elucidated. In this review, we summarize the available literature on the role of S1P in bone metabolism with a focus on osteoporosis. On the cellular level, S1P acts as an osteoclast-osteoblast coupling factor to promote osteoblast proliferation and bone formation. Moreover, the recruitment of osteoclast precursors to resorption sites is regulated by the interplay of S1P gradients and S1P receptor expression. From a clinical perspective, increasing evidence suggests that systemically elevated S1P blood levels may serve as an independent risk factor for osteoporosis-related fractures. Taken together, S1P signaling is a potential therapeutic target and may serve as a novel biomarker in patients with systemic bone disease.

Objective The aim of this study was to validate an imaging technique for evaluation of spinal surgery accuracy and to establish accuracy and safety of freehand technique in the thoracolumbar spine of large breed dogs. Study Design After thoracolumbar spine computed tomography (CT), 26 drilling corridors were planned then drilled to receive 3.2 mm positive profile pins using a freehand technique. After pin removal, CT was repeated. All entry points, exit points and angles of the preoperative planned trajectories were compared with postoperative ones using an image registration and fusion technique by three observers. Corridor coordinates for entry and exit points were evaluated in three dimensions and angles were measured in one plane. Intraclass correlation coefficient (ICC) was used to establish the imaging technique reliability and descriptive statistics were used to report on the freehand technique accuracy. Safety was evaluated using a vertebral cortical breach grading scheme. Results Intraclass correlation coefficient for the entry points, exit points and angle were 0.79, 0.96 and 0.92 respectively. Mean deviations for the entry points, exit points and angle were 3.1 mm, 6.3 mm and 7.6 degrees respectively. Maximum deviations were 6.3 mm, 11.0 mm and 16.4 degrees. Most deviations were lateral and caudal. All corridors were judged as safe. Conclusion The imaging technique reliability was good to excellent to study spinal surgery accuracy. Implant deviations should be anticipated when planning stabilization surgery in large breed dogs using the freehand-guided technique.

Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of anti-tumor agents selectively targeting the TYRO3, AXL and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of FRAgments in Structural Environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and non-small cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by x-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.

The Menyanthaceae is a family of aquatic flowering plants with diverse leaf and floral traits, leading to uncertainty about taxonomic, phylogenetic and evolutionary relationships within this family. In order to study the molecular evolution and phylogeny within Menyanthaceae, we sequenced the complete chloroplast (cp) genomes of six representative species from Nymphoides and the monotypic genus Menyanthes. In our study, the chloroplast genomes sizes ranged from 151,985 bp for Nymphoides coronata to 154,313 bp for Menyanthes trifoliata in length. Large Single-Copy (LSC), Small Single-Copy (SSC) and Inverted Repeat regions (IRs) portrayed normal length similar to most reported angiosperms. Menyanthaceae family chloroplast genomes possess a typical quadripartite structure, conserved in genomic structure and gene order. The size of the cp genome for the seven Menyanthaceae species consistently encoded 112–113 unique genes, including 79–80 protein-coding genes, 29 transfer RNA (tRNAs), and four ribosomal RNAs (rRNAs), 17 genes were duplicated in the inverted repeat region (IR) in both Nymphoides to 18 genes in Menyanthes respectively. Comparative analysis of the chloroplast genomes showed that Nymphoides species have lost the rpl2 intron which could be a derived feature in Nymphoides species. Phylogenetic analyses were conducted using 70 protein-coding genes in other families in order Asterales. Menyanthaceae divided into two clades with robust support. The genus Nymphoides was closely related to Menyanthes. In all studied chloroplast genomes, 30 codons had relative synonymous codon usage RSCU > 1 (higher preference), 29 codons had RSCU

Laboratory experiments were conducted to determine the repellent activities of the ornamental plant Dioscorea sansibarensis leaf essential oil against the Bruchus chinensis bean weevil in the protection of stored legumes. The leaves exhibited potential repellency in a Y-tube olfactometer. The tabulated data show that 10µL of leaf oil exhibited a repellency of 41.33%, with a grouped median of 53.33%, which was better than 10 µL of Actellic 50 EC, which had a repellency of 36.00% and a grouped median of 40%. Statistically, there was no significant difference in the percentage repellency obtained from the leaf oil and Actellic 50 EC at different concentrations (10, 20, 30 and 40 µL/mL, X2(7, N=200) = 114.93, P< 0.05). The GC-MS analysis identified 16 compounds in the leaf oil. The main compounds and their percentage composition were phytol (19.46%), 1-epi-α-gurjunene (11.71%), palmitic acid (10.48%), ethyl palmitate (8.87%), methyl palmitate (7.72%), isophytol (5.99%), 2-heptadecanone (4.59%) and α-selinene (4.5%). The repellency caused by the by leaf oil may have been due to the presence of α-selinene, also known as naphthalene, 1,2,3,5,6,7,8,8a-octahydro-1,8a-dimethyl-7-(1-methylethenyl)-, [1S- (1.α.,7.α.,8a.α.)]-. Dioscorea sansibarensis may be a good choice for repellent formulations.

Background The response rate on patient-reported outcome measurements (PROMs) necessary to adequately evaluate a treatment and improve patient care is unknown. Hospitals generally aim for the highest possible response rate without insight into the increase in costs involved. This study aimed to investigate which PROMs response rate is achievable in relation to the costs in an orthopaedic practice. Methods In an observational study, patients planned for orthopaedic surgery were asked to participate per surgical procedure (5769 surgical procedures at 5300 patients). Patient-reported outcomes (PROs) collection with a digital online automated PROMs collection system (minimal effort) was compared to a combined automated system and manual collection (maximal effort). Response rate was calculated preoperative and at two postoperative time points separately, and on all three time points together. Costs were calculated for the study period, per year and per surgical procedure. Calculations were executed for all surgical procedures and for three subgroups: knee arthroplasty, hip arthroplasty and anterior cruciate ligament reconstruction (ACLR). Results Using maximal effort the response rate increased for all surgical procedures compared to minimal effort; the preoperative response rate from 86% to 100% and the postoperative response rates from 55% to 83% (3 or 6 months) and 53% to 83% (12 months). Concerning the response at all three time points for all surgical procedures, minimal effort resulted in 44% response rate and increased to 76% with maximal effort. Lowest postoperative response rates were found in the ACLR group for both maximal and minimal effort. A costs difference of €5.55–€5.98 per surgical procedure between maximal and minimal effort was found. Conclusions A two times higher PROMs response rate for patients responding at all three time points (44% versus 76%) is achievable with maximal effort compared to the use of an automated PROMs collection system only. Manual collection adds a cost of €5.5–€6 per surgical procedure to automated PROMs collection alone. It is debatable if these additional costs are justifiable from a value-based health care perspective as the response rate for adequate evaluation of a treatment is still unknown.

Dioscorea sansibarensis bulbils are well known for their toxicity and medicinal applications. In this study, the attraction and mortality of the Phaseolus vulgaris weevil (Bruchus chinensis) caused by Dioscorea sansibarensis bulbil oil was examined in a Completely Randomized Design experiment using a Y-tube olfactometer on a laboratory bench. Statistical analysis at P < 0.05 showed 10 µL had an attraction of 42.67%. In the case of mortality, the results showed that Phaseolus vulgaris seeds treated with 40 µL of the bulbil oil had a harmonic mean of 55.8% mortality of the weevil population, which was higher than with 10 µL of Actellic 50 EC. GC-MS analysis identified 17 compounds in the bulbil oil, the main constituents of which were 2- pentanone, 4-hydroxy-4-methyl- (17.8%), phenol, 4-ethyl- (11.41%), hexadecanoic acid, methyl ester (11.05%), phenol (7.35%), 9-octadecenoic acid, (E)- (7.2%) and phenol, 4-ethyl-2-methoxy- (7.14%). Attraction by bulbil oil may have been due to the presence of phenolic compounds, and mortality may have been due to hexadecanoic acid, methyl ester and 9-octadecenoic acid, (E)-. Attractants are used for the surveillance and detection of an infestation in stored products. The added advantage of the bulbil oil to cause mortality makes Dioscorea sansibarensis bulbil oil useful in the formulation of a botanical pesticide in stored pest management.

The structure of neuronal connectivity often provides insights into the relevant stimulus features, such as spatial location, orientation, sound frequency, etc1-6. The olfactory system, however, appears to lack structured connectivity as suggested by reports of broad and distributed connections both from the olfactory bulb to the piriform cortex7-22 and within the cortex23-25. These studies have inspired computational models of circuit function that rely on random connectivity26-33. It remains, nonetheless, unclear whether the olfactory connectivity contains spatial structure. Here, we use high throughput anatomical methods (MAPseq and BARseq)34-38 to analyze the projections of 5,309 bulb and 30,433 piriform cortex output neurons in the mouse at single-cell resolution. We identify previously unrecognized spatial organization in connectivity along the anterior-posterior axis (A-P) of the piriform cortex. We find that both the bulb projections to the cortex and the cortical outputs are not random, but rather form gradients along the A-P axis. Strikingly, these gradients are matched: bulb neurons targeting a given location within the piriform cortex co-innervate extra-piriform regions that receive strong inputs from neurons within that piriform locus. We also identify signatures of local connectivity in the piriform cortex. Our findings suggest an organizing principle of matched direct and indirect olfactory pathways that innervate extra-piriform targets in a coordinated manner, thus supporting models of information processing that rely on structured connectivity within the olfactory system.

Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.