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ABSTRACT: Weed species is one of the factors contributing to grain yield losses due to crop-weed competition. Two of the most common weeds of soybean fields in Brazil are from the Rubiaceae family: Borreria latifolia and Richardia brasiliensis. This study aimed to evaluate the effects of B. latifolia and R. brasiliensis on plant development, yield components, and soybean productivity. Two assays were conducted in a randomized block design with four replications, using a two-level factorial design, in which the first factor consisted of the species B. latifolia and R. brasiliensis and the second factor consisted of the densities 0, 2, 4, 6, 8, 10, and 12 plants m-2. Plant height, leaf area and total chlorophyll in the V6 and R5 stages, number of pods per plant, number of grains per pod, 1000-grain weight, and grain yield loss were evaluated in both cultivars. Grain yield of both soybean cultivars was negatively affected by the interference with B. latifolia and R. brasiliensis. The species B. latifolia was more competitive with soybean when compared to R. brasiliensis, causing higher reductions for all variables. Each B. latifolia plant per square meter is able to reduce the yield of soybean by 3 a 4.4%, while each R.brasiliensis plant reduces yield by 2 a 2.6%. For both species, the reduction in soybean yield due to competition was caused by a decrease in the number of pods per plant, number of grains per pod, and 1000-grain weight.

ABSTRACT: Infesting species of Rubiaceae family have great importance in soybean crops in Southwest of Paraná and North of Santa Catarina, especially due to the selection of tolerant populations caused by the pressure of selection exerted by intensive use of glyphosate. The study aimed to evaluate the levels of tolerance to glyphosate in biotypes of broadleaf buttonweed (Borreria latifolia) (BL) and white-eye (Richardia brasiliensis) (RB) by means of dose-response curves. Two experiments were conducted in a greenhouse, in completely randomized design (CRD), with four replications. Fourteen BL biotypes and eleven RB biotypes were evaluated, collected in soybean fields of Paraná and Santa Catarina. The doses of glyphosate were 0, 74, 163, 360, 792 and 1,742 g ha-1, applied when the plants had 6 to 8 leaves. Visual control was evaluated at 14 and 28 days after application (DAA), as well as mass of green shoots and mass of dry shoots at 28 DAA. It was verified that there is response variability among the biotypes studied. BL biotypes 277, 283 and 300, and RB biotypes 283, 285 and Papanduva were not controlled with glyphosate at doses superior to those normally used in crops (720 g ha-1), indicating selection by the recurrent use of glyphosate. The tolerance factors ranged from 1.1 to 4.1 and 2.8 to 8.1 for RB and BL, respectively. The greatest difficulties of control were reported in areas where RR technology had been adopted for more than six years.

ABSTRACT The objectives of this study were to determine the effect of herbicide ethoxysulfuron on the development of commom bean (Phaseolus vulgaris), to evaluate the impact of the herbicide on the crop grain yield and to determine the mechanism of tolerance of common bean to ethoxysulfuron. Field experiments were carried out with several doses of ethoxysulfuron to determine its effect on the grain yield of two varieties of common bean ("IPR Andorinha", "IPR Tangará"). The mechanism of plant tolerance was evaluated through several methods, including the analysis of the ALS enzyme sensitivity to herbicide and the use of P450 inhibitors (the insecticides malathion + chlorpyrifos) and the use of antidote (mefenpyr-diethyl). When the rate of ethoxysulfuron was 83.2 g ha-1, the grain yield loss reached 25% (IPR Tangará) and 35% (IPR Andorinha). The ALS enzyme activity was severely reduced even at low concentrations ethoxysulfuron (1 μM), indicating that the mechanism of tolerance is not the insensitivity of the herbicide target enzyme. The inhibitors of herbicide detoxification increased the sensitivity of the bean plants to ethoxysulfuron, and the antidote (stimulator of herbicide degradation) mitigated the herbicidal effect. These results strongly support the hypothesis that the mechanism of tolerance of common bean plants to ethoxysulfuron is enhanced herbicide detoxification.

ABSTRACT: In literature, there are few studies evaluating the response of different bean cultivars to herbicides, particularly the ALS enzyme inhibitors. The objective of this study was to evaluate the selectivity of common bean cultivars to the herbicide ethoxysulfuron and to select cultivars that are more tolerant to it. An experiment was conducted in a greenhouse, in a completely randomized experimental design with four replications. Factors consisted in 20 bean cultivars (IPR Eldorado, IPR Siriri, IPR Gralha, IPR 81, IPR Uirapuru, IPR Colibri, IPR Tuiuiú, BRS Esplendor, IPR Tangará, IPR Juriti, IPR Corujinha, IPR Andorinha, IPR Curió, BRS Campeiro, BRS Pérola, BRS Notável, BRS Estilo, UTF 3, UTF 5 e UTF 6), and four doses of ethoxysulfuron (0, 50, 100 and 200 g ha-1) were used. At the dose of 200 g ha-1, the reduction of the shoot dry matter of plants ranged from 30 to 80%, indicating that there was high variability in the response of bean cultivars to the herbicide. The bean cultivars classified as more tolerant to ethoxysulfuron are: IPR 81, IPR Uirapuru, BRS Estilo, IPR Gralha and BRS Pérola, while the less tolerant cultivars are: IPR Eldorado, IPR Tuiuiú, IPR Tangará, IPR Curió, UTF 3, UTF 5 and BRS Esplendor.

Understanding spatial distribution of weeds in the crop enables to perform localized herbicide applications, increasing the technical and economic efficiency of operations and reducing environmental impacts. This work aimed to characterize the spatial and phytosociological variability of weeds occurring in soybean commercial field. It was conducted in an agricultural area located at the municipality of Boa Vista das Missões - RS, during the 2010/2011 harvest season. The area, that had been managed under no-tillage with soybean monoculture (summer) for five years, was divided in regular squares of 50 x 50 m (0.25 ha), totalizing 356 points. For species identification, 0.5 x 0.5 m sample squares were used. During the survey, 1,739 individuals were identified, distributed in 19 species of 13 families. The weed species Cardiospermum halicacabum, Digitaria horizontalis, Urochloa plantaginea and Raphanus raphanistrum showed the highest population variation in the area; however, only C. halicacabum, U. plantaginea and R. raphanistrum stood out based on the Importance Index Value (IVI). Localized management strategies considering the spatial variability of weed species placed in the Magnoliopsidas and Liliopsidas group show a high potential for use in soybean crop. The results show that the sampling method through regular grid was capable of characterizing the occurrence, population density and spatial variability of weed species in soybean crop.

A antecipação da colheita da soja é possível com uso da prática de dessecação pré-colheita, a qual reduz o tempo de permanência das sementes no campo, após a maturação fisiológica. O objetivo deste trabalho foi avaliar o efeito da época de aplicação do herbicida paraquat, como dessecante na pré-colheita da soja, sobre a produtividade e qualidade fisiológica de sementes. O trabalho constou de duas etapas: um experimento em campo, conduzido no município de Jaboticaba-RS, safra 2010/2011, e uma análise da qualidade fisiológica das sementes. Os tratamentos consistiram de três épocas de aplicação do paraquat (240 g i.a. ha‑1), R6, R7.1 e R7.3, bem como de um tratamento testemunha (sem dessecação). Foram avaliados a produtividade de grãos e os componentes da produtividade. A análise da qualidade das sementes foi conduzida no Laboratório de Produção e Tecnologia de Sementes da UFSM, Campus de Frederico Westphalen, RS, onde se realizaram os seguintes testes: germinação; primeira contagem de germinação, comprimento de parte aérea e radicular, matéria seca de plântulas, envelhecimento acelerado, condutividade elétrica, emergência em campo e índice de velocidade de emergência. A aplicação de paraquat como dessecante na pré‑colheita da soja, nos estádios R6 e R7.1, provoca queda acentuada na produtividade da cultura. A dessecação sem perda de potencial produtivo da soja só é viável a partir do estádio R7.3. Sementes oriundas de plantas com dessecação nos estádios R6 e R7.1 apresentam percentual superior e maior velocidade de germinação. Entretanto, sementes de plantas com dessecação no estádio R6 possuem menor vigor de plântulas.

A habilidade competitiva constitui-se em importante ferramenta para o manejo integrado de plantas daninhas. Objetivou-se com este trabalho avaliar o potencial de cultivares de trigo em competir com as plantas daninhas azevém e nabo, em diferentes períodos de convivência. O delineamento experimental foi o de blocos ao acaso, arranjado em esquema fatorial 4 x 2 x 3, com três repetições. No fator A alocaram-se os cultivares de trigo (BRS Guamirim - ciclo precoce e estatura baixa; Fundacep Cristalino - ciclo precoce e estatura média; Fundacep Raízes - ciclo médio e estatura média; e BRS 296 - ciclo precoce e estatura alta); no B, a ausência ou presença de controle das espécies daninhas; e no C, a época de manejo das plantas daninhas (todo o ciclo da cultura ou até a colheita, até 15 dias após a semeadura e até 30 dias após a semeadura - DAS). O cultivar Fundacep Cristalino, precoce e de estatura média, demonstrou maior habilidade competitiva do que o azevém e o nabo, quando comparado aos demais cultivares, em todos os períodos avaliados. O controle das plantas daninhas em trigo deve ser realizado precocemente, em especial para cultivares com menor habilidade competitiva.

Conyza bonariensis tornou-se a principal planta daninha da cultura da soja no Sul do Brasil, em decorrência da evolução para resistência ao herbicida glyphosate. O objetivo deste trabalho foi avaliar o efeito de diferentes coberturas de inverno e da associação de manejo de dessecação pré-semeadura da soja, visando ao controle de C. bonariensis resistente ao glyphosate. Um experimento foi conduzido em campo, na safra 2010/2011. Os tratamentos foram conduzidos em esquema de parcelas subdivididas, em que as coberturas de inverno foram alocadas nas parcelas principais: aveia-preta, nabo, ervilhaca, azevém, trigo e pousio. Nas subparcelas, foram alocados os tratamentos de manejo de dessecação pré-semeadura da soja: glyphosate (720 g e.a ha-1), glyphosate (720 g e.a ha-1) + 2,4-D (1.050 g e.a ha-1), glyphosate (720 g e.a ha-1) + 2,4-D (1.050 g e.a ha-1)/paraquat (200 g i.a ha-1) + diuron (100 g i.a ha-1), glyphosate (720 g e.a ha-1) + chlorimuron-ethyl (80 g i.a ha-1), glyphosate (720 g e.a ha-1) + chlorimuron-ethyl (80 g i.a ha-1)/paraquat (200 g i.a ha-1) + diuron (100 g i.a ha‑1) e roçada. O nabo foi a espécie de cobertura que produziu o maior volume de massa seca durante o inverno, enquanto a ervilhaca foi a que apresentou maior efeito supressor sobre a germinação e o desenvolvimento inicial de C. bonariensis. Associações de glyphosate com 2,4-D ou chlorimuron-ethyl, seguidas da aplicação sequencial de paraquat + diuron, causaram maior redução na infestação de C. bonariensis.Conyza bonariensis became the main weed in soybean crop in Southern Brazil, as a consequence of the evolution of resistance to the herbicide glyphosate. The objective of this work was to evaluate the effect of different winter cover crops and the association of burn-down herbicides on the control of glyphosate-resistant C. bonariensis. A field experiment was conducted in the 2010/2011 season. The treatments were arranged in a split-plot scheme, with the winter cover crops lopsided oat, radish, common vetch, Italian ryegrass, wheat, and fallow in the main plots, and in the subplots, the following burn-down treatments: glyphosate (720 g e.a ha-1), glyphosate (720 g e.a ha-1) + 2,4-D (1.050 g e.a ha-1), glyphosate (720 g e.a ha-1) + 2,4-D (1.050 g e.a ha‑1)/paraquat (200 g i.a ha-1) + diuron (100 g i.a ha-1), glyphosate (720 g e.a ha-1) + chlorimuron-ethyl (80 g i.a ha-1), glyphosate (720 g e.a ha-1) + chlorimuron-ethyl (80 g i.a ha-1)/paraquat (200 g i.a ha-1) + diuron (100 g i.a ha-1) and mowing. Radish was the cover crop species that produced the highest amount of shoot dry mass during the winter season, while common vetch had the highest suppressive effect on germination and initial development of C. bonariensis. Associations of glyphosate with 2,4-D or chlorimuron-ethyl, followed by the sequential application of paraquat + diuron, caused the highest reductions in C. bonariensis infestation.

ABSTRACT: Increased use of glyphosate in transgenic soybean areas has selected resistant and tolerant weed species. The aim of this study was to evaluate chemical management strategies for controlling Borreria latifolia and Richardia brasiliensis at pre-emergence (Pre), early post-emergence (Poste) and late post-emergence (Postl). Six experiments were carried out in a completely randomized design with four replicates per treatment in the Pre experiments and three in the Poste and Postl experiments, for each of the species. In the Pre experiments, tests were performed with herbicides imazethapyr, sulfentrazone, chlorimuron, diclosulam, S-metolachlor and saflufenacil. In the Poste experiments, seedlings were sprayed with herbicides bentazon, fomesafen, lactofen, flumioxazin and glyphosate. In Postl experiments, adult plants received glyphosate application associated with herbicides 2,4-D, carfentrazone, imazethapyr, flumiclorac, flumioxazin, sulfentrazone, chlorimuron, saflufenacil and glufosinate, plus three sequential applications with glyphosate only and paraquat/diuron. In the experiments, there was a control treatment without application of herbicides. In the Pre experiments, the plants established at 14 and 28 days after application (DAA) were evaluated. In the Poste and Postl experiments, shoot dry matter evaluation and visual control were performed at 14 and 28 DAA. The herbicides sulfentrazone, S-metolachlor and saflufenacil suppressed the emergence of both B. latifolia as R. brasiliensis; chlorimuron-ethyl and diclosulam were effective only on R. brasiliensis. In Poste, fomesafen, lactofen and flumioxazin reached levels of control over 90% of plants of both species. In Postl, glyphosate associated with carfentrazone, flumiclorac, flumioxazin, chlorimuron-ethyl, saflufenacil, glufosinate, and sequential applications of glyphosate/glyphosate, glyphosate/paraquat+diuron, glyphosate+2,4-D/paraquat+diuron reached levels control higher than 95%.

O feijoeiro é uma cultura de ciclo vegetativo curto, bastante sensível à interferência de plantas daninhas. O objetivo deste trabalho foi avaliar a eficácia de herbicidas aplicados em pré-emergência no controle de Digitaria sanguinalis na cultura do feijão-carioca, bem como determinar a seletividade deles para a cultura. Os tratamentos avaliados foram: S-metolachlor (960, 1.440 e 1.920 g ha-1), alachlor (1.440, 1.920 e 2.400 g ha-1) e duas testemunhas sem aplicação de herbicidas (com e sem capinas). Avaliações visuais de controle para D. sanguinalis e fitotoxicidade para o feijão foram realizadas aos 20 e 40 dias após a emergência (DAE). Os herbicidas, em todas as doses avaliadas, foram eficientes no controle de D. sanguinalis. Aos 40 DAE, observou-se injúria no feijoeiro nas parcelas aspergidas com S-metolachlor nas maiores doses, porém sem efeito deletério na produtividade de grãos da cultura. O herbicida alachlor, embora eficiente no manejo de D. sanguinalis, causou fitotoxicidade ao feijão-carioca, reduzindo a produtividade da cultura em até 47%.The common bean is a culture with a short vegetative cycle, highly susceptible to weed interference. The objective of this work was to evaluate the efficacy of herbicides applied in pre emergence for Digitaria sanguinalis control in "Carioca" bean crop, as well as to determine their selectivity to the crop. The treatments evaluated were: S-metolachlor (960; 1,440 and 1,920 g ha-1), alachlor (1,440; 1,920 and 2,400 g ha-1), and two untreated checks without herbicide application (with and without hoeing control). Visual evaluations of control for D. sanguinalis and injury to the common bean plants were conducted at 20 and 40 days after emergence (DAE). At all the evaluated rates, the herbicides were efficient in D. sanguinalis control. At 40 DAE, injury to the common bean was observed in the plots sprayed with S-metolachlor at the highest rates, but without deleterious effect on the crop grain yield. Despite being efficient in D. sanguinalis management, alachlor caused phytotoxicity to the "Carioca" common bean, reducing crop yield up to 47%.

Wild Asparagus shoots are consumed worldwide, although most species remain understudied. In this work, a total of four wild Asparagus species were collected from different locations and analyzed compared with farmed A. officinalis . Shoots were screened for (i) phenolic compounds by HPLC-DAD and LC-MS; (ii) total phenolic acids and total flavonoid content by the Folin-Ciocalteu and aluminum chloride methods; (iii) vitamin C by HPLC-DAD; (iv) antioxidant activity by the DPPH and ABTS •+ methods; and (v) the in vitro antiproliferative activities against HT-29 colorectal cancer cells by the MTT assay. Phenolics ranged from 107.5 ( A. aphyllus ) to 605.4 mg/100 g dry weight (dw) ( A. horridus ). Vitamin C ranged from 15.8 ( A. acutifolius ) to 22.7 mg/100 g fresh weight (fw) ( A. officinalis ). The antioxidant activity was similar in all species, standing out in A. officinalis with 5.94 (DPPH) and 4.64 (ABTS) mmol TE/100 g dw. Among phenolics, rutin reached the highest values (574 mg/100 g dw in A. officinalis ), followed by quercetin, nicotiflorin, asterin, and narcissin. The MTT assay revealed the inhibitory effects of ethanol extracts against HT-29 cancer cells, highlighting the cell growth inhibition exercised by A. albus (300 µg/mL after 72 h exposure to cells). This work improves knowledge on the phytochemicals and bioactivities of the shoots of wild Asparagus species and confirms their suitability for use as functional foods.

Berry consumption is increasing worldwide due to their high content of bioactive compounds. However, such fruits have a very short shelf life. To avoid this drawback and to offer an effective alternative for its consumption at any time of the year, an agglomerated berry powder mix (APB) was developed. The aim of this work was to evaluate the stability of APB during a 6-months-period storage at 3 temperatures. The stability of APB was determined by moisture, a w , antioxidant activity, total phenolics, total anthocyanins, vitamin C, color, phenolic profiles, and MTT assay. APB showed differences in antioxidant activity between 0 and 6 months. It experimented non-enzymatic browning, which was more remarkable at 35 °C. APB at time 0 exhibited growth inhibitory effects against HT-29 human cancer cells. Most properties were significantly modified by storage temperature and time, which induces a significant decreasing of bioactive compounds., Competing Interests: The authors declare no conflict of interest., (©2023PublishedbyElsevierLtd.)

Sertraline hydrochloride is a first-line antidepressant with potential antineoplastic properties because of its structural similarity with other drugs capable to inhibit the translation-controlled tumor protein (TCTP), a biomolecule involved in cell proliferation. Recent studies suggest it could be repositioned for cancer treatment. In this review, we systematically map the findings that repurpose sertraline as an antitumoral agent, including the mechanisms of action that support this hypotesis. From experimental in vivo and in vitro tumor models of thirteen different types of neoplasms, three mechanisms of action are proposed: apoptosis, autophagy, and drug synergism. The antidepressant is able to inhibit TCTP, modulate chemotherapeutical resistance and exhibit proper cytotoxicity, resulting in reduced cell counting (in vitro) and shrunken tumor masses (in vivo). A mathematical equation determined possible doses to be used in human beings, supporting that sertraline could be explored in clinical trials as a TCTP-inhibitor., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic human disease, with around 12.5 million people affected worldwide. ADPKD results from mutations in either PKD1 or PKD2 , which encode the atypical G-protein coupled receptor polycystin-1 (PC1) and the transient receptor potential channel polycystin-2 (PC2), respectively. Although altered intracellular trafficking of PC1 and PC2 is an underlying feature of ADPKD, the mechanisms which govern vesicular transport of the polycystins through the biosynthetic and endosomal membrane networks remain to be fully elucidated. Here, we describe an interaction between PC2 and retromer, a master controller for the sorting of integral membrane proteins through the endo-lysosomal network. We show that association of PC2 with retromer occurs via a region in the PC2 cytoplasmic amino-terminal domain, independently of the retromer-binding Wiskott-Aldrich syndrome and scar homologue (WASH) complex. Based on observations that retromer preferentially interacts with a trafficking population of PC2, and that ciliary levels of PC1 are reduced upon mutation of key residues required for retromer association in PC2, our data are consistent with the identification of PC2 as a retromer cargo protein.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α 5 β 1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

The retromer complex acts as a scaffold for endosomal protein complexes that sort integral membrane proteins to various cellular destinations. The retromer complex is a heterotrimer of VPS29, VPS35, and VPS26. Two of these paralogues, VPS26A and VPS26B, are expressed in humans. Retromer dysfunction is associated with neurodegenerative disease, and recently, three VPS26A mutations (p.K93E, p.M112V, and p.K297X) were discovered to be associated with atypical parkinsonism. Here, we apply quantitative proteomics to provide a detailed description of the retromer interactome. By establishing a comparative proteomic methodology, we identify how this interactome is perturbed in atypical parkinsonism-associated VPS26A mutants. In particular, we describe a selective defect in the association of VPS26A (p.K297X) with the SNX27 cargo adaptor. By showing how a retromer mutant leads to altered endosomal sorting of specific PDZ ligand-containing cargo proteins, we reveal a new mechanism for perturbed endosomal cargo sorting in atypical parkinsonism., (© 2016 McMillan et al.)

The composition of the neuronal cell surface dictates synaptic plasticity and thereby cognitive development. This remodeling of the synapses is governed by the endocytic network which internalize transmembrane proteins, then sort them back to the cell surface or carry them to the lysosome for degradation. The multi-protein retromer complex is central to this selection, capturing specific transmembrane proteins and remodeling the cell membrane to form isolated cargo-enriched transport carriers. We investigated a consanguineous family with four patients who presented in infancy with intractable myoclonic epilepsy and lack of psychomotor development. Using exome analysis, we identified a homozygous deleterious mutation in SNX27, which encodes sorting nexin 27, a retromer cargo adaptor. In western analysis of patient fibroblasts, the encoded mutant protein was expressed at an undetectable level when compared with a control sample. The patients' presentation and clinical course recapitulate that reported for the SNX27 knock-out mouse. Since the cargo proteins for SNX27-mediated sorting include subunits of ionotropic glutamate receptors and endosome-to-cell surface synaptic insertion of AMPA receptors is severely perturbed in SNX27(-/-) neurons, it is proposed that at least part of the neurological aberrations observed in the patients is attributed to defective sorting of ionotropic glutamate receptors. SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction.

The evolutionarily conserved endosomal retromer complex rescues transmembrane proteins from the lysosomal degradative pathway and facilitates their recycling to other cellular compartments. Retromer functions in conjunction with numerous associated proteins, including select members of the sorting nexin (SNX) family. In the present article, we review the molecular architecture and cellular roles of retromer and its various functional partners. The endosomal network is a crucial hub in the trafficking of proteins through the cellular endomembrane system. Transmembrane proteins, here termed cargos, enter endosomes by endocytosis from the plasma membrane or by trafficking from the trans-Golgi network (TGN). Endosomal cargo proteins face one of the two fates: retention in the endosome, leading ultimately to lysosomal degradation or export from the endosome for reuse ('recycling'). The balance of protein degradation and recycling is crucial to cellular homoeostasis; inappropriate sorting of proteins to either fate leads to cellular dysfunction. Retromer is an endosome-membrane-associated protein complex central to the recycling of many cargo proteins from endosomes, both to the TGN and the plasma membrane (and other specialized compartments, e.g. lysosome-related organelles). Retromer function is reliant on a number of proteins from the SNX family. In the present article, we discuss this inter-relationship and how defects in retromer function are increasingly being linked with human disease.

Retromer is a protein assembly that orchestrates the sorting of transmembrane cargo proteins into endosome-to-Golgi and endosome-to-plasma-membrane transport pathways. Here, we have employed quantitative proteomics to define the interactome of human VPS35, the core retromer component. This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3) and VPS9-ankyrin-repeat protein (VARP, also known as ANKRD27). Depletion of these proteins resulted in trafficking defects of retromer-dependent cargo, but differential and cargo-specific effects suggested a surprising degree of functional heterogeneity in retromer-mediated endosome-to-plasma-membrane sorting. Extending this, suppression of the retromer-associated WASH complex did not uniformly affect retromer cargo, thereby confirming cargo-specific functions for retromer-interacting proteins. Further analysis of the retromer-VARP interaction identified a role for retromer in endosome-to-melanosome transport. Suppression of VPS35 led to mistrafficking of the melanogenic enzymes, tyrosinase and tryrosine-related protein 1 (Tyrp1), establishing that retromer acts in concert with VARP in this trafficking pathway. Overall, these data reveal hidden complexities in retromer-mediated sorting and open up new directions in our molecular understanding of this essential sorting complex., (© 2014. Published by The Company of Biologists Ltd.)

The sorting nexin 27 (SNX27)-retromer complex is a major regulator of endosome-to-plasma membrane recycling of transmembrane cargos that contain a PSD95, Dlg1, zo-1 (PDZ)-binding motif. Here we describe the core interaction in SNX27-retromer assembly and its functional relevance for cargo sorting. Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. With disruption of SNX27 and retromer function linked to synaptic dysfunction and neurodegenerative disease, our work provides the first step, to our knowledge, in the molecular description of this important sorting complex, and more broadly describes a unique interaction between a PDZ domain and an arrestin-like fold.

The PDZ-domain-containing sorting nexin 27 (SNX27) promotes recycling of internalized transmembrane proteins from endosomes to the plasma membrane by linking PDZ-dependent cargo recognition to retromer-mediated transport. Here, we employed quantitative proteomics of the SNX27 interactome and quantification of the surface proteome of SNX27- and retromer-suppressed cells to dissect the assembly of the SNX27 complex and provide an unbiased global view of SNX27-mediated sorting. Over 100 cell surface proteins, many of which interact with SNX27, including the glucose transporter GLUT1, the Menkes disease copper transporter ATP7A, various zinc and amino acid transporters, and numerous signalling receptors, require SNX27-retromer to prevent lysosomal degradation and maintain surface levels. Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. Our data identify the SNX27-retromer as a major endosomal recycling hub required to maintain cellular nutrient homeostasis.

Dementia is a common illness that is increasing in frequency and set to challenge the resources and expertise of health and social care services over the coming years. Increasingly, there has been interest in the management of behavioural and psychological symptoms of dementia (BPSD), as they are both common and associated with a range of negative outcomes. BPSD are associated with the admission of people with dementia to care homes. Limited resources and lack of knowledge in permanent care settings often lead to BPSD being managed with antipsychotic medications, which are associated with significant morbidity and mortality. There is evidence for the benefits of exercise within care home settings, although only a few studies include those with cognitive impairment. Tai Chi is a mind-body exercise combining relaxed physical movement and meditation, and has been suggested to have many health benefits. This article discusses the rationale and available options for treating BPSD and the current practice and reviews the literature regarding the benefits of exercise and, in particular, Tai Chi in the management of BPSD.

Purpose: Previous studies of cutaneous eyelid lesions have been retrospective using multiple contributing surgeons. The purpose of this study was to determine prospectively the accuracy of the clinical diagnosis of benign, premalignant, and malignant cutaneous eyelid lesions and to determine if all clinical diagnoses require histopathologic confirmation, or if an experienced clinician can reliably distinguish benign from malignant lesions on the basis of history and clinical examination alone., Methods: This prospective study was conducted between January 1988 and January 1995. All patients presenting during this time with periocular cutaneous eyelid lesions were evaluated and a specific clinical diagnosis made in each case before biopsy and histopathologic evaluation. The lesions were categorized prospectively as benign, premalignant, or malignant, and histopathologic evaluation then correlated to determine the accuracy of the clinical diagnosis. Only patients who presented without previous biopsy were eligible for inclusion in the study., Results: A biopsy was done on a total of 864 eyelid lesions during the 85 month study period. One hundred fifty-three lesions clinically were thought to represent malignancies. Of these, 140 (91.5%) were found to have malignant histopathologies. Nineteen lesions clinically were thought to represent premalignant processes. Histopathologic evaluation of these 19 lesions showed 16 to be actually premalignant, 1 to be a malignancy, and 2 to be benign. Six hundred ninety-two lesions clinically were thought to be benign. Of these, 13 (1.9%) proved on histopathologic evaluation to be malignant. These included 10 basal cell carcinomas, 1 squamous cell carcinoma, 1 non-Hodgkin lymphoma, and 1 adenoid cystic carcinoma. Three (0.4%) of the 692 clinically benign lesions were found to be premalignant. The 13 missed malignancies were distributed among a number of different clinical diagnoses, including papilloma, epidermal inclusion cyst, melanocytic nevus, hydrocystoma, and trichoepithelioma. Of the 153 clinically malignant lesions, 6 lesions that clinically were highly suspicious for malignancy had initial benign histopathologic diagnoses. Rebiopsy results in all of these six subsequently confirmed the suspected malignant diagnosis., Conclusions: Malignant eyelid lesions may masquerade as a number of different clinically benign conditions. The authors conclude that all excised eyelid lesions should be submitted for histopathologic confirmation because it is not possible to obtain 100% accuracy in diagnosing eyelid lesions on clinical grounds alone. However, strong clinical suspicion of a malignancy is highly significant, and if initial histopathologic evaluation does not agree with the malignant clinical diagnosis, repeat biopsy should be performed.