Miracle-dz/UniFAR-FTUs huggingface dataset:
Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation

Significance Understanding how to optimize lipid-loading onto CD1d molecules is important to better harness invariant natural killer T (iNKT) cells’ central role at the interface between innate and adaptive immunity. We report that the lipid transfer proteins saposins play an essential role in modulating human iNKT cell autoreactivity to antigen-presenting cells activated by inflammatory stimuli. Lipid-loading occurs in an endo-lysosomal compartment, where saposins work as “lipid editors,” capable of fine-tuning loading and unloading of CD1d molecules and increasing the off-rate of CD1d-bound lipids. Lipid transfer proteins, such as molecules of the saposin family, facilitate extraction of lipids from biological membranes for their loading onto CD1d molecules. Although it has been shown that prosaposin-deficient mice fail to positively select invariant natural killer T (iNKT) cells, it remains unclear whether saposins can facilitate loading of endogenous iNKT cell agonists in the periphery during inflammatory responses. In addition, it is unclear whether saposins, in addition to loading, also promote dissociation of lipids bound to CD1d molecules. To address these questions, we used a combination of cellular assays and demonstrated that saposins influence CD1d-restricted presentation to human iNKT cells not only of exogenous lipids but also of endogenous ligands, such as the self-glycosphingolipid β-glucopyranosylceramide, up-regulated by antigen-presenting cells following bacterial infection. Furthermore, we demonstrated that in human myeloid cells CD1d-loading of endogenous lipids after bacterial infection, but not at steady state, requires trafficking of CD1d molecules through an endo-lysosomal compartment. Finally, using BIAcore assays we demonstrated that lipid-loaded saposin B increases the off-rate of lipids bound to CD1d molecules, providing important insights into the mechanisms by which it acts as a “lipid editor,” capable of fine-tuning loading and unloading of CD1d molecules. These results have important implications in understanding how to optimize lipid-loading onto antigen-presenting cells, to better harness iNKT cells central role at the interface between innate and adaptive immunity.
Analysis of a large multi‐generational family provides insight into the genetics of chronic lymphocytic leukemia

We report the genetic analysis of a large multi‐generational family composed of 144 individuals in which 11 members have been diagnosed with chronic lymphocytic leukaemia (CLL). The observation of a significant over‐representation of monoclonal B‐cell lymphocytosis (MBL) in unaffected family members strongly supports MBL being a surrogate marker of carrier status. A genome‐wide linkage scan of the family using high‐density 10K single nucleotide polymorphisms provided no significant evidence for a single gene model of disease susceptibility, inviting speculation that susceptibility to CLL has a more complex basis. The absence of a correlation in IGHV usage between affected family members does however argue strongly against exposure to a single super‐antigen in disease development.
Syntaxin‐11 is expressed in primary human monocytes/macrophages and acts as a negative regulator of macrophage engulfment of apoptotic cells and IgG‐opsonized target cells

Syntaxin‐11 is a member of a family of membrane‐trafficking proteins referred to as soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin‐11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin‐11 in other immune cells has remained elusive. This study found that stimulation with interferon‐γ upregulated syntaxin‐11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin‐11 (STX11), or monocytes from healthy individuals in which syntaxin‐11 was downregulated using specific short‐interfering RNA, demonstrated that syntaxin‐11 was not required for antibody‐dependent cellular cytotoxicity. On the other hand, silencing of syntaxin‐11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor‐α. Moreover, Fcγ‐receptor‐mediated uptake of target cells was also enhanced following silencing of syntaxin‐11 expression in macrophages. In addition, syntaxin‐11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin‐11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG‐opsonized red blood cells.
Emerging stem cell concepts for imatinib‐resistant chronic myeloid leukaemia: implications for the biology, management, and therapy of the disease

Chronic myeloid leukaemia (CML) is a myeloid neoplasm defined by the BCR/ABL oncoprotein that is considered essential for leukaemogenesis and accumulation of neoplastic cells. The BCR/ABL kinase inhibitor imatinib is an effective agent in most patients and can now be regarded as front‐line therapy. Hence, intrinsic and acquired resistance to imatinib has been described and is an emerging challenge in clinical practice. While CML stem cells display primary resistance, stem cell subclones may, in addition, acquire imatinib‐resistant mutants of BCR/ABL. Other factors that are considered to contribute to stem cell resistance include the genetic background, clonal evolution, additional biological features of subclones, gene amplifications, silencing of tumour suppressor genes and specific pharmacological aspects. In this article, mechanisms of resistance of CML (stem) cells against imatinib and other BCR/ABL inhibitors are discussed, together with strategies to overcome and/or to prevent resistance with available drugs or novel anti‐leukaemic approaches.
Delineation of distinct tumour profiles in mantle cell lymphoma by detailed cytogenetic, interphase genetic and morphological analysis

Mantle cell lymphoma (MCL) is an aggressive lymphoid tumour characterized by the translocation t(11;14)(q13;q32) and a poor clinical outcome (median survival: 3–4 years). Recent studies revealed that increased proliferation of the tumour cells and certain chromosomal aberrations, such as deletions of 17p13 and 9p21 represent major adverse biological markers in this disease, although the molecular targets of chromosomal imbalances in MCL have not been identified for the large majority of loci affected. To correlate histomorphological and proliferation features of MCL with genetic findings, we investigated 223 MCL by fluorescence in situ hybridization (FISH) (n = 157) and/or classical cytogenetic banding analysis (n = 129). FISH analysis turned out to be distinctly more sensitive in the delineation of aberrations. Complex karyotypic alterations were associated with higher proliferation indices and inferior prognosis. A comprehensive analysis of biological features including genetic alterations in MCL by hierarchical clustering resulted in the delineation of four tumour subgroups differing with respect to their genetic constitution and suggesting different transformation or progression pathways. Moreover, in one of the groups identified, a more indolent clinical behaviour was associated with few secondary aberrations and fewer known high‐risk chromosomal aberrations, which points to the importance of the quality of karyotypic evolution in MCL tumours.
Education, information, and smoking decisions : evidence from smoking histories, 1940-2000

The author tests the hypothesis that education improves health and increases people's life expectancy. Smoking histories-reconstructed from retrospective data in the National Health Interview Surveys in the United States-show that after 1950, when information about the dangers associated with tobacco consumption started to diffuse, the prevalence of smoking declined earlier and most dramatically for college graduates. More educated individuals are also more likely to quit smoking: incidence analysis of smoking cessation shows a strong education effect. The instrumental variable approach, which relies on the fact that during the Vietnam War college attendance provided a strategy to avoid the draft, indicates that education does affect decisions about whether to smoke or stop smoking.
The risk of peritonitis after an exit site infection: a time-matched, case-control study.

BACKGROUND Exit site infections (ESIs) have been previously associated with the development of peritonitis; however, the evidence to support this association is limited. We conducted a time-matched, case-control study to determine the association between ESIs and subsequent peritonitis. METHODS The cohort comprised 962 incident adult peritoneal dialysis (PD) patients from January 2000 to December 2009. Patients with an ESI were matched to those with no ESI based on the duration of PD. The subsequent risk of peritonitis was determined using Cox models and conditional logistic regression. RESULTS During the study period, there were a total of 1002 ESI and 1228 peritonitis episodes among 962 individuals. The time to subsequent peritonitis was shorter in individuals who had at least one ESI [hazard ratio (HR) 1.59; 95% confidence interval (CI) 1.22-2.07, P<0.001]. The risk of peritonitis post-ESI was increased for all Gram-positive infections [adjusted hazard ratio (aHR) 1.75; 95% CI 1.25-2.43], and for the subtypes of coagulase-negative Staphylococcus (CNS) and S. aureus, but not for Gram-negative or culture-negative infections. These findings were similar when examining the odds of subsequent peritonitis within prespecified time intervals of the ESI through conditional logistic regression. CONCLUSIONS The risk of peritonitis after ESI is increased, particularly with S. aureus and CNS, despite appropriate antibiotic treatment of the ESI.
The Exosome ‐ A Naturally Secreted Nanoparticle and its Application to Wound Healing

Wound healing is a complex process and often delayed in patients with underlying chronic conditions. The cost of wound care is a significant burden to the society, warranting new techniques to prompt wound healing. Several studies have reported on the beneficial effects of mesenchymal stem cells (MSCs) function in recruiting host cells, releasing secretory factors and matrix proteins thereby increasing wound heal. These secrete bioactive trophic factors from MSCs also includes extracellular vesicles (EVs) or exosomes. Recent studies have shown that EVs are one of the key secretory products of MSCs mediating cell‐to‐cell communication to enhance wound healing. Current knowledge related to the potential use of EVs in wound healing is reviewed and the promising future for EVs ‐ a naturally secreted nanoparticle ‐ as an alternative to cell‐based therapy is discussed.
Clinical features and outcome of pulmonary embolism in children

Pulmonary embolism (PE) is rare in childhood but evidence suggests it is under‐recognised. Children diagnosed with PE at a large tertiary centre over an 8‐year period were retrospectively reviewed. Fifty‐six children with radiologically proven PE were identified, 31 males and 25 females, median age 12 years. Eighty‐four per cent had symptoms of PE. Risk factors for thromboembolism were present in 54 patients (96·4%); most commonly immobility (58·9%), central venous line (35·7%) and recent surgery (28·6%). Investigation revealed a thrombophilic abnormality in 14/40 patients (35%). Concurrent deep vein thrombosis was confirmed in 31 patients (55·4%), predominantly lower limb. D dimer was elevated at presentation in 26/30 patients (86·7%). Eight patients underwent systemic thrombolysis. An inferior vena cava filter was placed in five patients. Therapy was complicated by major haemorrhage in 12 patients (21·4%). The majority (82·1%) had complete or partial resolution of PE following a median of 3 months anticoagulation. Seven patients had a recurrent thromboembolic event and 12 patients died (mortality 21·4%); five due to thromboembolism (8·9%) and two due to haemorrhage. Risk factors for PE in children are distinct from adults and morbidity and mortality is significant. Multicentre prospective studies are required to determine optimal treatment and long‐term outcome of childhood PE.
Evidence for soft bounds in Ubuntu package sizes and mammalian body masses

Significance Not unlike a big city, a large software project grows in a complex way, involving many developers and even more users, but a predictive framework to understand these temporal patterns is lacking. We focus on software size and analyze the changes of the Ubuntu open source operating system, finding two quantitative laws. First, growth is driven by changes in scale rather than by addition–subtraction; second, evolution toward larger sizes between two consecutive releases is limited by bounds that depend on the starting size of a package. Strikingly, a stochastic model that implements these two laws is predictive. Finally, we provide evidence that similar principles could be in place for the evolution of body mass in mammals. The development of a complex system depends on the self-coordinated action of a large number of agents, often determining unexpected global behavior. The case of software evolution has great practical importance: knowledge of what is to be considered atypical can guide developers in recognizing and reacting to abnormal behavior. Although the initial framework of a theory of software exists, the current theoretical achievements do not fully capture existing quantitative data or predict future trends. Here we show that two elementary laws describe the evolution of package sizes in a Linux-based operating system: first, relative changes in size follow a random walk with non-Gaussian jumps; second, each size change is bounded by a limit that is dependent on the starting size, an intriguing behavior that we call “soft bound. ” Our approach is based on data analysis and on a simple theoretical model, which is able to reproduce empirical details without relying on any adjustable parameter and generates definite predictions. The same analysis allows us to formulate and support the hypothesis that a similar mechanism is shaping the distribution of mammalian body sizes, via size-dependent constraints during cladogenesis. Whereas generally accepted approaches struggle to reproduce the large-mass shoulder displayed by the distribution of extant mammalian species, this is a natural consequence of the softly bounded nature of the process. Additionally, the hypothesis that this model is valid has the relevant implication that, contrary to a common assumption, mammalian masses are still evolving, albeit very slowly.
Altering plasma sodium concentration rapidly changes blood pressure during haemodialysis.

BACKGROUND Plasma sodium is increased following each meal containing salt. There is an increasing interest in the effects of plasma sodium concentration, and it has been suggested that it may have direct effects on blood pressure (BP) and possibly influences endothelial function. Experimental increases of plasma sodium concentration rapidly raise BP even when extracellular volume falls. METHODS Ten patients with end-stage renal failure established on haemodialysis were studied during the first 2 h of dialysis without fluid removal during this period. They were randomized to receive haemodialysis with (i) dialysate sodium concentration prescribed to 135 mmol/L and (ii) 145 mmol/L in random order in a prospective, single-blinded crossover study. BP measurements and blood samples were taken every 30 min. RESULTS Pre-dialysis sitting BP was 137/76 ± 7/3 mmHg. Lower dialysate sodium concentration (135 mmol/L) reduced plasma sodium concentration [139.49 ± 0.67 to 135.94 ± 0.52 mmol/L (P < 0.001)], whereas plasma sodium concentration was not altered by higher dialysate sodium (145 mmol/L) (140.17 ± 0.66 mmol/L at baseline to 140.72 ± 0.43 mmol/L at 120 min). Systolic BP was lower with dialysate sodium concentration 135 mmol/L [area under the curve (AUC) 15823.50 ± 777.15 (mmHg)min] compared with 145 mmol/L [AUC 17018.20 ± 1102.17 (mmHg)min], mean difference 1194.70 ± 488.41 (mmHg)min, P < 0.05. There was a significant positive relationship between change in plasma sodium concentration and change in systolic BP. This direct relationship suggests that a fall of 1 mmol/L in plasma sodium concentration would be associated with a 1.7 mmHg reduction in systolic BP (P < 0.05). CONCLUSIONS The potential mechanism for the increase in BP seen with salt intake may be through small but significant changes in plasma sodium concentration.
Comparative studies of Munc18c and Munc18-1 reveal conserved and divergent mechanisms of Sec1/Munc18 proteins

Significance Sec1/Munc18 (SM) proteins are essential for every vesicle fusion pathway, but their molecular mechanisms remain poorly understood. Our comparative studies of two functionally distinct SM proteins, Munc18c and Munc18-1, suggest that one conserved function of SM proteins is to recognize their cognate trans-SNARE complexes and accelerate fusion kinetics. The “closed” syntaxin binding mode of Munc18-1, however, is not conserved in Munc18c. Unexpectedly, we discovered that the architecture of the SNARE/SM complex differs across fusion pathways. Together, these findings reveal conserved as well as divergent functions of SM proteins in vesicle fusion. Sec1/Munc18 (SM) family proteins are essential for every vesicle fusion pathway. The best-characterized SM protein is the synaptic factor Munc18-1, but it remains unclear whether its functions represent conserved mechanisms of SM proteins or specialized activities in neurotransmitter release. To address this question, we dissected Munc18c, a functionally distinct SM protein involved in nonsynaptic exocytic pathways. We discovered that Munc18c binds to the trans-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex and strongly accelerates the fusion rate. Further analysis suggests that Munc18c recognizes both vesicle-rooted SNARE and target membrane-associated SNAREs, and promotes trans-SNARE zippering at the postdocking stage of the fusion reaction. The stimulation of fusion by Munc18c is specific to its cognate SNARE isoforms. Because Munc18-1 regulates fusion in a similar manner, we conclude that one conserved function of SM proteins is to bind their cognate trans-SNARE complexes and accelerate fusion kinetics. Munc18c also binds syntaxin-4 monomer but does not block target membrane-associated SNARE assembly, in agreement with our observation that six- to eightfold increases in Munc18c expression do not inhibit insulin-stimulated glucose uptake in adipocytes. Thus, the inhibitory “closed” syntaxin binding mode demonstrated for Munc18-1 is not conserved in Munc18c. Unexpectedly, we found that Munc18c recognizes the N-terminal region of the vesicle-rooted SNARE, whereas Munc18-1 requires the C-terminal sequences, suggesting that the architecture of the SNARE/SM complex likely differs across fusion pathways. Together, these comparative studies of two distinct SM proteins reveal conserved as well as divergent mechanisms of SM family proteins in intracellular vesicle fusion.
Dysregulated NOD2 predisposes SAMP1/YitFc mice to chronic intestinal inflammation

Significance We discovered that SAMP1/YitFc (SAMP) mice, which develop spontaneous Crohn’s disease (CD)-like ileitis in the absence of nucleotide-binding oligomerization domain-containing 2 (NOD2) genetic mutations, fail to respond to muramyl dipeptide and display impaired bacterial clearance. These results support the concept that a dysregulated NOD2 in SAMP mice predisposes them to chronic intestinal inflammation. We believe that our study provides a paradigm shift by demonstrating that CD-like ileitis is caused by an innate immune defect, rather than an overly aggressive adaptive immune response. Therefore, preventive and curative treatments for CD should be directed to boost, rather than suppress, mucosal innate immune responses. Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular receptor that plays an essential role in innate immunity as a sensor of a component of the bacterial cell wall, muramyl dipeptide (MDP). Crohn’s disease (CD)-associated NOD2 variants lead to defective innate immune responses, including decreased NF-κB activation and cytokine production. We report herein that SAMP1/YitFc (SAMP) mice, which develop spontaneous CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and dysregulated NOD2 signaling compared with parental AKR control mice. We show that, unlike in other mouse strains, in vivo administration of MDP does not prevent dextran sodium sulfate-induced colitis in SAMP mice and that the abnormal NOD2 response is specific to the hematopoietic cellular component. Moreover, we demonstrate that MDP fails to enhance intracellular bacterial killing in SAMP mice. These findings shed important light on the initiating molecular events underlying CD-like ileitis.
Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Significance Bacterial pathogens use multiple mechanisms to survive and proliferate within an infected host, including blunting the host’s ability to defend itself from pathogenic assaults. We identified a new immune suppression mechanism by Burkholderia pseudomallei, the causative agent of melioidosis, which a life-threatening disease in humans. Analyses of whole-genome transcriptional responses of Caenorhabditis elegans to B. pseudomallei infection revealed that B. pseudomallei, through its type III secretion system, recruits the host ubiquitin–proteasome system to specifically degrade a GATA transcription factor. This GATA factor is critical for host immune defense; thus, its degradation leads to suppression of the host’s ability to mount an effective antimicrobial defense. Burkholderia pseudomallei is a Gram-negative soil bacterium that infects both humans and animals. Although cell culture studies have revealed significant insights into factors contributing to virulence and host defense, the interactions between this pathogen and its intact host remain to be elucidated. To gain insights into the host defense responses to B. pseudomallei infection within an intact host, we analyzed the genome-wide transcriptome of infected Caenorhabditis elegans and identified ∼6% of the nematode genes that were significantly altered over a 12-h course of infection. An unexpected feature of the transcriptional response to B. pseudomallei was a progressive increase in the proportion of down-regulated genes, of which ELT-2 transcriptional targets were significantly enriched. ELT-2 is an intestinal GATA transcription factor with a conserved role in immune responses. We demonstrate that B. pseudomallei down-regulation of ELT-2 targets is associated with degradation of ELT-2 protein by the host ubiquitin–proteasome system. Degradation of ELT-2 requires the B. pseudomallei type III secretion system. Together, our studies using an intact host provide evidence for pathogen-mediated host immune suppression through the destruction of a host transcription factor.