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The endoplasmic reticulum (ER)-Golgi system has been studied using biochemical, genetic, electron and light microscopic techniques. We now understand many aspects of trafficking from the ER to the Golgi apparatus, including some of the signals and mechanisms for selective retention and retrieval of ER resident proteins and export of cargo proteins. Proteins that leave the ER emerge in ‘export complexes’ or ER ‘exit sites’ and accumulate in pleiomorphic transport carriers referred to sometimes as VTCs or intermediate compartments. These structures then transit from the ER to the Golgi apparatus along microtubules using the dynein/dynactin motor and fuse with the cis cisterna of the Golgi apparatus. Many proteins (including vSNAREs, ERGIC53/p58 and the KDEL receptor) must cycle back to the ER from pre-Golgi intermediates or the Golgi. We will discuss both the currently favored model that this cycling occurs via 50-nm COPI-coated vesicles and in vivo evidence that suggests retrograde trafficking may occur via tubular structures. [ABSTRACT FROM AUTHOR]

This paper employs insights from earth science on the financial risk of project developments to present an economic theory of critical minerals. Our theory posits that back-ended critical mineral projects that have unaddressed technical and non-technical barriers, such as those involving lithium and cobalt, exhibit an additional risk for investors which we term the "back-ended risk premium". We show that the back-ended risk premium increases the cost of capital and, therefore, has the potential to reduce investment in the sector. We posit that the back-ended risk premium may also reduce the gains in productivity expected from artificial intelligence (AI) technologies in the mining sector. Progress in AI may, however, lessen the back-ended risk premium itself by shortening the duration of mining projects and the required rate of investment by reducing the associated risk. We conclude that the best way to reduce the costs associated with energy transition is for governments to invest heavily in AI mining technologies and research. Vespignani and Smyth present an economic theory of risk in critical minerals they term the "back-ended risk premium." They apply AI approaches to reduce this risk premium and lower costs in energy transition. [ABSTRACT FROM AUTHOR]

Background: Psychological readiness is an important consideration for athletes and clinicians when making return to sport decisions following anterior cruciate ligament reconstruction (ACLR). To improve our understanding of the extent of deficits in psychological readiness, a systematic review is necessary. Objective: To investigate psychological readiness (measured via the Anterior Cruciate Ligament-Return to Sport after Injury scale (ACL-RSI)) over time after ACL tear and understand if time between injury and surgery, age, and sex are associated with ACL-RSI scores. Methods: Seven databases were searched from the earliest date available to March 22, 2022. Articles reporting ACL-RSI scores after ACL tear were included. Risk of bias was assessed using the ROBINS-I, RoB-2, and RoBANS tools based on the study design. Evidence certainty was assessed for each analysis. Random-effects meta-analyses pooled ACL-RSI scores, stratified by time post-injury and based on treatment approach (i.e., early ACLR, delayed ACLR, and unclear approach). Results: A total of 83 studies were included in this review (78% high risk of bias). Evidence certainty was 'weak' or 'limited' for all analyses. Overall, ACL-RSI scores were higher at 3 to 6 months post-ACLR (mean = 61.5 [95% confidence interval (CI) 58.6, 64.4], I2 = 94%) compared to pre-ACLR (mean = 44.4 [95% CI 38.2, 50.7], I2 = 98%), remained relatively stable, until they reached the highest point 2 to 5 years after ACLR (mean = 70.7 [95% CI 63.0, 78.5], I2 = 98%). Meta-regression suggests shorter time from injury to surgery, male sex, and older age were associated with higher ACL-RSI scores only 3 to 6 months post-ACLR (heterogeneity explained R2 = 47.6%), and this reduced 1–2 years after ACLR (heterogeneity explained R2 = 27.0%). Conclusion: Psychological readiness to return to sport appears to improve early after ACL injury, with little subsequent improvement until ≥ 2-years after ACLR. Longer time from injury to surgery, female sex and older age might be negatively related to ACL-RSI scores 12–24 months after ACLR. Due to the weak evidence quality rating and the considerable importance of psychological readiness for long-term outcomes after ACL injury, there is an urgent need for well-designed studies that maximize internal validity and identify additional prognostic factors for psychological readiness at times critical for return to sport decisions. Registration: Open Science Framework (OSF), https://osf.io/2tezs/. Key Points: Over 70% of studies measuring ACL-RSI scores were judged to have high risk of bias (i.e., low internal validity), leading to a certainty of evidence rating of weak for all analyses. ACL-RSI scores do not appear to increase during typical rehabilitation periods after anterior cruciate ligament reconstruction. Age, sex, and time from injury to surgery (i.e., treatment approach) appear prognostic for early ACL-RSI scores, but their prognostic ability diminishes for later ACL-RSI scores. [ABSTRACT FROM AUTHOR]

This paper examines the impact of gender diversity on financial reporting quality (accrual and real earnings management). We use a sample of 78 Egyptian listed companies over the period 2009–2021. The quality of financial reporting is measured using different models of earnings management (accrual and real earnings management). Accrual earnings management (AEM) is detected through four different models developed by modified Jones model, the Kasznik model, Kothari model, Raman and Shahrur model, while real earnings management (REM) is measured using six different model which are abnormal cash flows from operations (ABCFO), abnormal production costs (ABPROD), abnormal discretionary expenditures (ABDISEXP) and three aggregate proxies (RM1, RM2, RM3). Using the system generalized method of moments, companies with more gender diversity are more effective in reducing accrual earnings manipulation (AEM). The exception is the modified Jones model. Moreover, we find that gender diversity is positively and significantly correlated with financial reporting quality based on proxies of real earnings-based activity, except for RM2. The study found a non-significant and negative relationship between board diversity and RM2 as a proxy for REM. Overall, the empirical results based on accrual and real earnings management models (AEM and REM) support the notion that enterprises with more gender diversity on the board are more effective in controlling earnings manipulation practices. The predictions of corporate governance theories are confirmed. Policy makers should continue to promote and support gender diversity in leadership positions within organizations. This can be achieved through initiatives such as diversity quotas, mentoring programs, and leadership development opportunities for women. [ABSTRACT FROM AUTHOR]

The Golgi Apparatus (GA) is pivotal in vesicle sorting and protein modifications within cells. Traditionally, the GA has been described as a perinuclear organelle consisting of stacked cisternae forming a ribbon-like structure. Changes in the stacked structure or the canonical perinuclear localization of the GA have been referred to as "GA fragmentation", a term widely employed in the literature to describe changes in GA morphology and distribution. However, the precise meaning and function of GA fragmentation remain intricate. This review aims to demystify this enigmatic phenomenon, dissecting the diverse morphological changes observed and their potential contributions to cellular wound repair and regeneration. Through a comprehensive analysis of current research, we hope to pave the way for future advancements in GA research and their important role in physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.Protein-protein interactions underlie all aspects of a viral infection. Here the authors employ a pan-viral approach for systematic identification of motif-mediated interactions between viral and human proteins and show that the information can be used to find targets for antiviral drug development. [ABSTRACT FROM AUTHOR]

Nanomembrane is an independent structure with a thickness of 1–100 nm and with much large lateral dimensions. Due to the unique properties of nanomembranes, research on the category of structures is valuable. Furthermore, nanomembranes have received a lot of attention from scientists because those types of structures can be used in various bioengineering branches. However, biocompatibility and toxicity of nanomembranes are not fully understood yet. In terms of mechanical engineering, nanomembranes must have mechanical strength, surface treatment to ensure the required structure. Mechanical properties can be affected through the material, fabrication method, porosity. For the application of nanomembranes in bioengineering, it is important to develop research to improve the biocompatibility and mechanical strength of nanomembranes. In this paper, according to the recent achievements, classification of materials, fabrication methods, and porosity are reviewed and summarized. Applications of nanomaterials in tissue engineering (bone and skin) as well as in drug delivery systems are also presented. The aim of the paper is to highlight the role of synthetic nanomembranes in the context of nanotechnologies and provide applications of functionalized nanomembranes in bioengineering. Before continuing noble and costly research, it is necessary to know the key principles and references for understanding progress of nanomembranes over the past decade. [ABSTRACT FROM AUTHOR]

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)1–3. It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding α-toxin4—a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues2,5,6. Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against α-toxin through the release of ADAM10 on exosomes—extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins. In response to infection with Staphylococcus aureus in vitro and in vivo, host cells increase their secretion of exosomes containing ADAM10—vesicular structures that can provide protection by sequestering bacterial toxins. [ABSTRACT FROM AUTHOR]

Several African Solanum species, including scarlet eggplant (Solanum aethiopicum L.) and the gboma eggplant (S. macrocarpon L.), are recently domesticated green leafy vegetables. The aim of the study was to determine if domestication process affected the amounts of selected nutrient and anti-nutrient compounds in plant lines bearing edible and inedible leaves in comparison to their wild relatives. Leaves from fourteen accessions of five Solanum species were evaluated for phenolics (385-1002 mg gallic acid equivalent/100 g dry weight), fatty acid (0.9-3.2 g/100 g DW), sterol (32-99 mg/100 g DW), saponin and glycoalkaloid content (0-1000 mg and 0-55 mg/100 g DW, respectively, expressed as aglycone content). There were no significant differences between plants with edible and inedible leaves. Similarly, wild and domesticated plants produced comparable amounts of nutrient and anti-nutrient compounds, with exception of wild S. anguivi Lam., which displayed fatty acid content higher than other species. The gboma eggplant complex (S. macrocarpon-S. dasyphyllum Schum. et Thonn.) had lower anti-nutrient and phenolics content than scarlet eggplant (S. aethiopicum-S. anguivi). Semi-domesticated S. scabrum Mill. revealed high anti-nutrient and low nutrient production. Selection based on plant morphology is then suggested as the dominating mechanism at the early stage of domestication of African solanaceous plants. [ABSTRACT FROM AUTHOR]

Cleome gynandra is one of the most promising African leafy vegetables consumed in most parts of Africa. The crop is a rich source of vitamins A and C and minerals such as calcium, iron, magnesium and protein. The leaves and seeds of spider plant are used in indigenous medicine in several countries. Despite the numerous nutritive benefits and ethnopharmacological uses of the plant, C. gynandra is still underutilized due to lack of awareness and promotion of production technologies and utilization. Available information is limited and short on several relevant and rudimentary components. Hence, this review focuses on the current knowledge on C. gynandra, with regards to its botany, ecology, cultivation systems, utilization, nutraceutical properties as well as the breeding avenues that will contribute to promoting the species, aimed at ensuring food and nutritional security and efficient management of its genetic resources. Breeding programmes aimed at minimizing the bitterness of the leaves so to arouse the interest of consumers, and the mechanisms involved in the responses and adaptation of C. gynandra as a C4 plant to salinity stress, were also explored. [ABSTRACT FROM AUTHOR]

The metacommunity approach emerged with the interest in investigating how local and regional processes interact to determine community structure. However, species distribution may differ according to biological features (e.g., dispersal mode) or system connectivity. We investigated the distribution patterns and the importance of environmental and spatial variables for benthic invertebrate metacommunity structures in a Neotropical floodplain according to hydrological periods (flood and drought) and dispersal modes (active or passive). We sampled 18 lakes during flood and drought periods in 2011. In both hydrological periods, we found a Clementsian pattern for active dispersers, with environment as the main structuring factor. The high environmental heterogeneity of this floodplain is an important factor providing high availability of favorable habitats for the establishment of active dispersers. Passive dispersers were randomly distributed in both hydrological periods. The importance of only spatial factors during the drought may indicate a restricted dispersal by inability of tracking environmental gradients. We emphasize that understanding biological community determinants could rely on trait-based analysis (i.e., dispersal mode) and complementary approaches (i.e., variance partitioning, and metacommunity structure), considering their variations over time. [ABSTRACT FROM AUTHOR]

We provide direct evidence that Bin/Amphiphysin/Rvs (BAR) family members bend the steady state membrane architecture of organelles in intact cells. In response to inducible BAR molecular actuators, organelles exhibit distinct changes to the orientation and degree of their membrane curvature. This rapidly inducible system may offer a mechanism by which to better understand the structure-function relationship of intracellular organelles. [ABSTRACT FROM AUTHOR]

Background:Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg−1 among patients participating in an expanded access programme in Italy.Methods:Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg−1 every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events.Results:Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported.Conclusions:For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials. [ABSTRACT FROM AUTHOR]

Imp13, a member of importin-β superfamily, is found to be one of two bidirectional transport receptors in many nuclear transport activities in mammals. Several cargoes of imp13 have been identified; most of these are essential factors involved in cell cycle and development. The expression and localization of imp13 may influence its cargoes in playing their roles in appropriate time and space. To gain insight into the role of imp13 in brain development, we generated an anti-imp13 polyclonal antibody and investigated the expressions of imp13 in mouse embryonic brains during development, including E13.5, E15.5, E17.5, P0, and adult, at both transcriptional and translational levels. In addition, we performed immunohistochemical analysis and revealed that imp13 tends to be localized in the cytoplasm at the early stages and relocates into the nucleus at the late stages in neuronal cells of mouse brains. These findings suggested that the expression and localization of imp13 in brain tissues are regulated developmentally, which extends our knowledge of the dynamic presence of imp13. These observations also imply that imp13 contributes to the neural cell-specific cargo trafficking and potentially to other functions during brain development. [ABSTRACT FROM AUTHOR]

Reports of Staphylococcus aureus including methicillin-resistant S. aureus (MRSA) detected in marine environments have occurred since the early 1990s. This investigation sought to isolate and characterize S. aureus from marine waters and sand at a subtropical recreational beach, with and without bathers present, in order to investigate possible sources and to identify the risks to bathers of exposure to these organisms. During 40 days over 17 months, 1,001 water and 36 intertidal sand samples were collected by either bathers or investigators at a subtropical recreational beach. Methicillin-sensitive S. aureus (MSSA) and MRSA were isolated and identified using selective growth media and an organism-specific molecular marker. Antimicrobial susceptibility, staphylococcal cassette chromosome mec (SCC mec) type, pulsed-field gel electrophoresis (PFGE) pattern, multi-locus sequence type (MLST), and staphylococcal protein A ( spa) type were characterized for all MRSA. S. aureus was isolated from 248 (37 %) bather nearby water samples at a concentration range of <2-780 colony forming units per ml, 102 (31 %) ambient water samples at a concentration range of <2-260 colony forming units per ml, and 9 (25 %) sand samples. Within the sand environment, S. aureus was isolated more often from above the intertidal zone than from intermittently wet or inundated sand. A total of 1334 MSSA were isolated from 37 sampling days and 22 MRSA were isolated from ten sampling days. Seventeen of the 22 MRSA were identified by PFGE as the community-associated MRSA USA300. MRSA isolates were all SCC mec type IVa, encompassed five spa types (t008, t064, t622, t688, and t723), two MLST types (ST8 and ST5), and 21 of 22 isolates carried the genes for Panton-Valentine leukocidin. There was a correlation ( r = 0.45; p = 0.05) between the daily average number of bathers and S. aureus in the water; however, no association between exposure to S. aureus in these waters and reported illness was found. This report supports the concept that humans are a potential direct source for S. aureus in marine waters. [ABSTRACT FROM AUTHOR]

Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I-IV patients and healthy controls by ELISPOT. A broad array of CD4 and CD8 cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific CD4 and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target. [ABSTRACT FROM AUTHOR]

Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids. [ABSTRACT FROM AUTHOR]

This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses. [ABSTRACT FROM AUTHOR]

Over the last few years, several newly developed immune-based cancer therapies have been shown to induce clinical responses in significant numbers of patients. As a result, there is a need to identify immune biomarkers capable of predicting clinical response. If there were laboratory parameters that could define patients with improved disease outcomes after immunomodulation, product development would accelerate, optimization of existing immune-based treatments would be facilitated and patient selection for specific interventions might be optimized. Although there are no validated cancer immunologic biomarkers that are predictive of clinical response currently in widespread use, there is much published literature that has informed investigators as to which markers may be the most promising. Population-based studies of endogenous tumor immune infiltrates and gene expression analyses have identified specific cell populations and phenotypes of immune cells that are most likely to mediate anti-tumor immunity. Further, clinical trials of cancer vaccines and other cancer directed immunotherapy have identified candidate immunologic biomarkers that are statistically associated with beneficial clinical outcomes after immune-based cancer therapies. Biomarkers that measure the magnitude of the Type I immune response generated with immune therapy, epitope spreading, and autoimmunity are readily detected in the peripheral blood and, in clinical trials of cancer immunotherapy, have been associated with response to treatment. [ABSTRACT FROM AUTHOR]

Vav proteins are guanine nucleotide exchange factors for Rho GTPases that regulate cell adhesion, motility, spreading and proliferation in response to growth factor signalling. In this work, we show that Vav2 expression delayed epidermal growth factor receptor (EGFR) internalization and degradation, and enhanced EGFR, ERK and Akt phosphorylations. This effect of Vav2 on EGFR degradation is dependent on its guanine nucleotide exchange function. Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation. epidermal growth factor stimulation led to co-localization of Vav2 with EGFR and Rab5 in endosomes. We further show that the effect of Vav2 on EGFR stability is modulated by its interaction with two endosome-associated proteins and require RhoA function. Thus, in this work, we report for the first time that Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins. [ABSTRACT FROM AUTHOR]

Verticillium wilt is a destructive disease with international consequences for cotton production. Breeding broad-spectrum resistant cultivars is considered to be one of the most effective means for reducing crop losses. A resistant cotton cultivar, 60182, was crossed with a susceptible cultivar, Junmian 1, to identify markers for Verticillium resistance genes and validate the mode of its inheritance. Genetic segregation analysis for Verticillium wilt resistance was evaluated based upon infected leaf percentage in the seedling stage using major gene-polygene mixed inheritance models and joint analysis of P1, P2, F1, B1, B2 and F2 populations obtained from the cultivar cross. We found that resistance of upland cotton cultivar 60182 to isolates BP2, VD8 and T9, and their isoconcentration mixture was controlled by two major genes with additive-dominance-epistatic effects, and the inheritance of the major gene was dominant. Furthermore, a genetic linkage map was constructed using F2 segregating population and resistance phenotypic data were obtained using F2:3 families inoculated with different isolates and detected in different developmental stages. The genetic linkage map with 139 loci was comprised of 31 linkage groups covering 1165 cM, with an average distance of 8.38 cM between two markers, or 25.89% of the cotton genome length. From 60182, we found 4 QTL on chromosome D7 and 4 QTL on D9 for BP2, 5 QTL on D7 and 9 QTL on D9 for VD8, 4 QTL on D7 and 5 QTL on D9 for T9 and 3 QTL on D7 and 7 QTL on D7 for mixed pathogens. The QTL mapping results revealed that QTL clusters with high contribution rates were screened simultaneously on chromosomes D9 and D7 by multiple interval mapping (CIM), whether from resistance phenotypic data from different developmental stages or for different isolates. The result is consistent with the genetic model of two major genes in 60182 and suggests broad-spectrum resistance to both defoliating isolates of V. dahliae and nondefoliating isolates. The markers associated with resistance QTL may facilitate the use of Verticillium wilt resistance genes in improving breeding programs for cotton. [ABSTRACT FROM AUTHOR]

The events that lead to choroidal neovascularization in eyes with age-related macular degeneration are poorly understood. One possibility that has been explored in a number of studies is that macrophages can promote neovascular changes. In this paper, we summarize the evidence for inflammation in general and macrophages in particular in pathologic neovascularization, and discuss how the diverse functions of these cells may promote or inhibit macular disease. We also discuss some of the conflicting findings regarding the role of macrophages in experimental choroidal neovascularization in mouse models, and suggest areas for future research.Eye (2009) 23, 747–755; doi:10.1038/eye.2008.206; published online 4 July 2008 [ABSTRACT FROM AUTHOR]

Reticulons (RTNs) are membrane-spanning proteins sharing a typical domain named reticulon homology domain (RHD). RTN genes have been identified in all eukaryotic organisms examined so far, and the corresponding proteins have been found predominantly associated to the endoplasmic reticulum membranes. In animal and yeast, in which knowledge of the protein family is more advanced, RTNs are involved in numerous cellular processes such as apoptosis, cell division and intracellular trafficking. Up to now, a little attention has been paid to their plant counterparts, i.e., RTNLBs. In this review, we summarize the data available for RTNLB proteins and, using the data obtained with animal and yeast models, several functions for RTNLBs in plant cells are proposed and discussed. [ABSTRACT FROM AUTHOR]

This study examines how state merit-based scholarships individually and simultaneously with prepaid tuition plans influence the interstate migration of college-bound freshmen. State freshman migration percentages were examined over a 10-year period. Results of an interrupted time-series model suggested that students generally respond to merit-based tuition aid in accordance with our initial prediction based on factors influencing student choice in attending postsecondary institutions. More specifically, many students choose to attend an in-state college in order to be eligible for state merit-based scholarships. Moreover, for home states that adopted both merit-based scholarships and prepaid tuition contracts, student out-migration was further reduced over time. [ABSTRACT FROM AUTHOR]

Despite the significant efforts to enhance immune reactivity against malignancies the clinical effect of anti-tumor vaccines and cancer immunotherapy is still below expectations. Understanding of the possible causes of such poor clinical outcome has become very important for improvement of the existing cancer treatment modalities. In particular, the critical role of HLA class I antigens in the success of T cell based immunotherapy has led to a growing interest in investigating the expression and function of these molecules in metastatic cancer progression and, especially in response to immunotherapy. In this report, we illustrate that two types of metastatic lesions are commonly generated in response to immunotherapy according to the pattern of HLA class I expression. We found that metastatic lesions, that progress after immunotherapy have low level of HLA class I antigens, while the regressing lesions demonstrate significant upregulation of these molecules. Presumably, immunotherapy changes tumor microenvironment and creates an additional immune selection pressure on tumor cells. As a result, two subtypes of metastatic lesions arise from pre-existing malignant cells: (a) regressors, with upregulated HLA class I expression after therapy, and (b) progressors with resistance to immunotherapy and with low level of HLA class I. Tumor cells with reversible defects (soft lesions) respond to therapy by upregulation of HLA class I expression and regress, while tumor cells with structural irreversible defects (hard lesions) demonstrate resistance to immunostimulation, fail to upregulate HLA class I antigens and eventually progress. These two types of metastases appear independently of type of the immunotherapy used, either non-specific immunomodulators (cytokines or BCG) or autologous tumor vaccination. Similarly, we also detected two types of metastatic colonies in a mouse fibrosarcoma model after in vitro treatment with IFN-γ. One type of metastases characterized by upregulation of all MHC class I antigens and another type with partial IFN-γ resistance, namely with lack of expression of Ld-MHC class I molecule. Our observations may shed new light on the understanding of the mechanisms of tumor escape and might have implications for improvement of the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cholesterol, certain lipids, membrane-bound and soluble proteins, as well as viruses that are synthesized in the endoplasmic reticulum (ER), reach the plasma membrane (PM) via non-classical pathway(s) that remain poorly understood. Typical for this transport is (i) its insensitivity to brefeldin A (BFA), which dissociates selected coat complexes from membranes, resulting in the disassembly of the Golgi apparatus; (ii) its rapid kinetics as compared to the classical secretory pathway; and (iii) its role in the trafficking of lipid raft components. Based on results showing that the intermediate compartment (IC) at the ER-Golgi boundary constitutes a stable tubular network that maintains its dynamics in the presence of BFA, we propose that two bidirectional Golgi-bypass pathways to the PM exist, a direct route from early IC elements, and another, reminescent of the yeast secretory pathway, from late IC elements via the endosomal system. These pathways have implications for the organization of the secretory processes in different cell types. (Part of a Multi-author Review) [ABSTRACT FROM AUTHOR]

The physiological state of eukaryotic cells controls nuclear trafficking of numerous cargos. For example, stress results in the inhibition of classical protein import, which is characterized by the redistribution of several transport factors. As such, importin-α and cellular apoptosis susceptibility protein (CAS) accumulate in nuclei of heat-shocked cells; however, the mechanisms underlying this relocation are not fully understood. We now show that heat upregulates the initial docking of importin-α at the nuclear envelope and stimulates the translocation of CAS into the nuclear interior. Moreover, heat exposure compromises the exit of importin-α from nuclei and drastically increases its retention in the nucleoplasm, whereas CAS nuclear exit and retention are less affected. Taken together, our results support the idea that heat shock regulates importin-α and CAS nuclear accumulation at several levels. The combination of different stress-induced changes leads to the nuclear concentration of both transport factors in heat-stressed cells. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) consists of at least two major prognostic subgroups, characterized by different cellular and molecular markers. This observation sparked studies on the function and clinical importance of these markers. In order to address their function adequately, an efficient and reliable method for gene transfer is needed. In this study, we compared efficiency and utility of different gene transfer techniques in CLL. Lenti-, retro- and adenoviral transduction did not yield appreciable numbers of marker gene enhanced green fluorescent protein (EGFP) positive CLL cells, despite various prestimulation protocols. Efficient transgene expression was observed after nucleofection of CLL cells with plasmid DNA, at the expense of low survival rates. After optimization, electroporation of in vitro transcribed mRNA yielded up to 90% EGFP+CLL cells without affecting survival. Transgene expression remained detectable for at least 2 weeks after electroporation. Furthermore, we could demonstrate overexpression of ZAP70 and of a ZAP70-EGFP fusion protein after electroporation with ZAP70 or ZAP70-EGFP mRNA. We conclude that mRNA electroporation is a novel and straightforward method for highly efficient gene transfer in CLL. The application of this technique should facilitate functional studies on CLL cells, as well as clinical research.Leukemia (2008) 22, 323–329; doi:10.1038/sj.leu.2405007; published online 1 November 2007 [ABSTRACT FROM AUTHOR]

The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.Leukemia (2007) 21, 1859–1874; doi:10.1038/sj.leu.2404787; published online 5 July 2007 [ABSTRACT FROM AUTHOR]

The revived cancer immune surveillance theory has emphasized the active role the immune system plays in eliminating tumor cells and in facilitating the emergence of their immunoresistant variants. MHC class I molecule abnormalities represent, at least in part, the molecular phenotype of these escape variants, given the crucial role of MHC class I molecules in eliciting tumor antigen-specific T cell responses, the high frequency of HLA class I antigen abnormalities in malignant lesions and their association with a poor clinical course of the disease. Here, we present evidence for this possibility and review the potential mechanisms by which T cell selective pressure participates in the generation of tumor cells with MHC class I molecule defects. Furthermore, we discuss the strategies to counteract tumor cell immune evasion. [ABSTRACT FROM AUTHOR]

Therapeutic cancer vaccines need to stimulate a refractory immune system to make an effective anti-tumour response. We have explored the use of lentiviral vectors to deliver tumour antigen genes to dendritic cells (DC) as a possible mechanism of immune stimulation. Direct injection of a lentiviral vector encoding the melanoma antigen NY-ESO-1 in HLA-A2 transgenic mice primed NY-ESO-1-specific CD8+ cells that could be expanded by boosting with an NY-ESO-1 vaccinia virus. The expanded cells could kill NY-ESO-1157–165 peptide-pulsed targets in vivo. In order to examine the priming step directly, we constructed another lentiviral vector expressing the melanoma antigen Melan-A (MART-1). Here we show that Melan-A protein is also efficiently expressed after transduction of human DC cultured from peripheral blood mononuclear cells. When these transduced DC are co-cultured with autologous naïve T cells, they cause the expansion of cells that recognise the HLA-A2 restricted Melan-A27–35 epitope. The expanded cells are functional in that they release IFN-γ upon antigen stimulation. Melan-A lentiviral vector transduced DC caused a similar level of naïve T-cell expansion to Melan-A27–35 peptide-pulsed DC in four experiments using different HLA-A2 positive donors. These data suggest that a vaccine based either on DC transduced with a lentiviral vector ex vivo, or on direct lentiviral vector injection, should be assessed in a phase I clinical trial. [ABSTRACT FROM AUTHOR]

Membrane curvature is no longer seen as a passive consequence of cellular activity but an active means to create membrane domains and to organize centres for membrane trafficking. Curvature can be dynamically modulated by changes in lipid composition, the oligomerization of curvature scaffolding proteins and the reversible insertion of protein regions that act like wedges in membranes. There is an interplay between curvature-generating and curvature-sensing proteins during vesicle budding. This is seen during vesicle budding and in the formation of microenvironments. On a larger scale, membrane curvature is a prime player in growth, division and movement. [ABSTRACT FROM AUTHOR]

Although it is well known that high Na concentrations induce Ca deficiency in acidic conditions, the effect of high pH on this competitive mechanism is not so well understood. The effect of Ca activity ratio (CAR) and pH on the Ca uptake of mungbeans (Vigna radiata(L.) Wilczek cv. Emerald) and Rhodes grass (Chloris gayanacv. Pioneer) in Na dominated solution cultures and in soil was investigated. Changes in pH in the alkaline range were shown not to affect the critical CAR of 0.024 (corresponding to 90% relative root length) for mungbeans grown in solution culture. Results from soil grown mungbeans confirmed those from solution culture, with a critical CAR of 0.025. A critical CAR of 0.034 was also established for soil grown Rhodes grass. The similarity of critical values established for mungbeans and Rhodes grass in solution culture and soil justifies the use of both solution culture and soil solution measurement as techniques for studying plant growth and limitations across plant species. [ABSTRACT FROM AUTHOR]

Since its discovery, the Golgi complex has attracted the attention of cell biologists because of its ‘fashionable’ morphology and central position within the secretory system of the cell. Here, we discuss how the three-dimensional architecture of the Golgi complex relates to its multiple functions in protein sorting and processing, and how an analysis of the morphology of the Golgi complex can help to provide an understanding of the mechanisms involved in transport through this unique organelle. [ABSTRACT FROM AUTHOR]

In less than a decade the green fluorescent protein (GFP) has become one of the most popular tools for cell biologists for the study of dynamic processes in vivo. GFP has revolutionised the scientific approach for the study of vital organelles, such as the Golgi apparatus. As Golgi proteins can be tagged with GFP, in most cases without altering their targeting and function, it is a great substitute to conventional dyes used in the past to highlight this compartment. In this review, we cover the application of GFP and its spectral derivatives in the study of Golgi dynamics in mammalian and plant cells. In particular, we focus on the technique of selective photobleaching known as fluorescence recovery after photobleaching, which has successfully shed light on essential differences in the biology of the Golgi apparatus in mammalian and plant cells. [ABSTRACT FROM AUTHOR]

Protein coats deform flat lipid membranes into buds and capture membrane proteins to form transport vesicles. The assembly/disassembly cycle of the COPI coat on Golgi membranes is coupled to the GTP/GDP cycle of the small G protein Arf1. At the heart of this coupling is the specific interaction of membrane-bound Arf1-GTP with coatomer, a complex of seven proteins that forms the building unit of the COPI coat. Although COPI coat disassembly requires the catalysis of GTP hydrolysis in Arf1 by a specific GTPase-activating protein (ArfGAP1), the precise timing of this reaction during COPI vesicle formation is not known. Using time-resolved assays for COPI dynamics on liposomes of controlled size, we show that the rate of ArfGAP1-catalysed GTP hydrolysis in Arf1 and the rate of COPI disassembly increase over two orders of magnitude as the curvature of the lipid bilayer increases and approaches that of a typical transport vesicle. This leads to a model for COPI dynamics in which GTP hydrolysis in Arf1 is organized temporally and spatially according to the changes in lipid packing induced by the coat. [ABSTRACT FROM AUTHOR]

This study assessed the effects of Friendship Circles on the social interactions between students with mild disabilities and their nondisabled peers. A multiple probe design was used to analyze the social interactions during lunch. Data also were collected in the form of sociograms and anecdotal records. In addition, generalization was assessed during recess observations. Results indicated that the Friendship Circle intervention produced increases in appropriate interactions at lunch for all three students and for two there were increases in friendly play at recess. Anecdotal data suggested improved social interactions for two of the students throughout the day and improved social behaviors in the general education classroom such as cooperation during group activities. Implications for future research are discussed. [ABSTRACT FROM AUTHOR]

While whole sediment toxicity tests with macrofaunal polychaetes are well developed and standardized, they are oftentimes not very sensitive to environmental contaminants. Meiofaunal polychaetes, however, are sensitive to contaminants, easy to culture, and representative of the interstitial habitat. These are desirable attributes for ecotoxicological assessments of marine and estuarine sediments. The meiofaunal polychaete, Dinophilus gyrociliatus Schmidt, 1857, is a cosmopolitan species that has become a useful tool for ecotoxicological assessments, particularly for its use in toxicity testing with sediment pore waters. Due to its short life cycle it is suitable for sublethal toxicity tests, with egg production by the females as a sensitive endpoint, which can be assessed in a 7-day exposure period. Toxicity assessments of pore waters from an industrialized bay in Texas, U.S.A., and of pore waters from sediments spiked with nitroaromatic explosives, demonstrated that the D. gyrociliatus reproduction endpoint was consistently among the most sensitive, when compared to early-life stage tests with several other marine species, including macro-algae, sea urchins and fish. There was also excellent agreement among the results of porewater tests with D. gyrociliatus, nauplii of the meiofaunal copepod, Longipedia americana, and embryos of the sea urchin, Arbacia punctulata in a survey with pore waters extracted from sediments collected in the vicinity of an oil platform in the Gulf of Mexico, where metals were the primary contaminants of concern. [ABSTRACT FROM AUTHOR]

Membrane fission is essential in various intracellular dissociative transport steps. The molecular mechanisms by which endocytic vesicles detach from the plasma membrane are being rapidly elucidated. Much less is known about the fission mechanisms operating at Golgi tubular networks; these include the Golgi transport and sorting stations, the trans-Golgi and cis-Golgi networks, where the geometry and physical properties of the membranes differ from those at the cell surface. Here we discuss the lipid and protein machineries that have so far been related to the fission process, with emphasis on those acting in the Golgi complex. [ABSTRACT FROM AUTHOR]

Presents a study which presented two models to explain the growth of new golgi during the cell cycle in Toxoplasma gondii. Process of showing the golgi growth; Results of golgi duplication; Information on the results of the models; Problem in studying golgi duplication.

Examines the structural basis for recognizing acidic-cluster dileucine sequence. Details on the transport of soluble protein from trans-Golgi network; Evaluation on the carboxy-terminal peptide of cation-dependent mannose 6-phosphate receptor; Description on the super helix with alpha helices.

We summarize the properties of integral membrane proteins that reside in the inner nuclear membrane, including lamin B receptor (LBR), lamina-associated polypeptide (LAP) 1, LAP2, emerin, MAN1 and nurim. Most of these proteins interact with lamins and chromatin. Some data also suggest more speculative functions such as gene regulation and possibly sterol metabolism. Mutations in emerin and nuclear lamins have been associated with muscular dystrophies and lipodystrophy, raising new questions about the functions of inner nuclear membrane proteins. Integral proteins of the inner nuclear membrane are synthesized on the rough endoplasmic reticulum (ER) and reach the inner nuclear membrane by lateral diffusion in the connected ER and nuclear envelope membranes. Associations with nuclear ligands retain them in the inner nuclear membrane. Further investigation of the functions and targeting of inner nuclear membrane proteins are needed to determine how they are involved in human disease. [ABSTRACT FROM AUTHOR]

The peripheral nuclear lamina is located near the nuclear inner membrane and consists of lamin filaments and integral membrane proteins, including the lamin B receptor and various isoforms of lamina-associated polypeptides (LAP) 1 and 2. Several nuclear membrane proteins also interact with chromatin proteins BAF and Hp1. Lamins in the nuclear interior associate with at least one soluble (non-membrane-bound) LAP2 isoform named LAP2α. The internal lamins, together with Tpr-based filaments that connect to nuclear pore complexes, are proposed to be major structural elements of the internal nuclear matrix. We describe the structural links between the peripheral lamina and the internal nuclear matrix that are thought to be mediated by LAP2 family members, filament protein Tpr and nucleoporin Nup153. These findings are discussed in relation to human diseases that arise from mutations in nuclear lamina proteins. [ABSTRACT FROM AUTHOR]

The nuclear envelope is a highly dynamic structure that reversibly disassembles and reforms at mitosis. The nuclear envelope also breaks down - irreversibly - during apoptosis, a process essential for development and tissue homeostasis. Analyses of fixed cells, time-lapse, imaging studies of live cells and the development of powerful cell-free extracts derived from gametes or mammalian somatic cells have provided insights on the fate of nuclear envelope proteins during mitosis and apoptosis, and on the mechanisms behind nuclear envelope modifications in these processes. In this review, we discuss evidence leading to our understanding of the dynamics of the nuclear envelope alterations at mitosis and during apoptosis. We also present novel imaging and genetic approaches to the study of nuclear envelope dynamics and function. [ABSTRACT FROM AUTHOR]

: The trans-Golgi network (TGN) is a major secretory pathway sorting station that directs newly synthesized proteins to different subcellular destinations. The TGN also receives extracellular materials and recycled molecules from endocytic compartments. In this review, we summarize recent progress on understanding TGN structure and the dynamics of trafficking to and from this compartment. Protein sorting into different transport vesicles requires specific interactions between sorting motifs on the cargo molecules and vesicle coat components that recognize these motifs. Current understanding of the various targeting signals and vesicle coat components that are involved in TGN sorting are discussed, as well as the molecules that participate in retrieval to this compartment in both yeast and mammalian cells. Besides proteins, lipids and lipid-modifying enzymes also participate actively in the formation of secretory vesicles. The possible mechanisms of action of these lipid hydrolases and lipid kinases are discussed. Finally, we summarize the fundamentally different apical and basolateral cell surface delivery mechanisms and the current facts and hypotheses on protein sorting from the TGN into the regulated secretory pathway in neuroendocrine cells. [ABSTRACT FROM AUTHOR]

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