How Complicated Can It Be? The Link Between APOL1 Risk Variants and Lipoprotein Heterogeneity in Kidney and Cardiovascular Diseases.

The beginning of human apolipoprotein L1 study (gene: APOL1; protein: ApoL1) originated from the identification of circulating ApoL1 as an interacting protein of ApoA1 and a minor component of high-density lipoprotein subfraction 3 (HDL3) in 1997 [1]. In the past 18 years, ApoL1 has been investigated in the context of complex human diseases such as African sleeping sickness, schizophrenia, host innate immunity, cancer, hyperlipidemia, cardiovascular diseases, stroke and type 2 diabetes [2–10]. A major breakthrough, however, was the documentation of two haplotypes of APOL1, harboring three coding-sequence mutations as risk variants associated with non-diabetic chronic kidney diseases (CKD) in African Americans [5, 6]. The first one, termed G1, is a two non-synonymous SNP haplotype [rs73885319 (A \u3e G; p.S342G) and rs60910145 (G \u3e T; p.I384M)]. The second one, termed G2, is a two codon deletion haplotype rs71785313 (6-bp in frame deletion; p.ΔN388Y389) [4, 5]. These two coding-sequence variants have been discovered mainly in kidney disease patients of African ancestry and linked to the pathogenesis of primary focal and segmental glomerulosclerosis, hypertension-attributed kidney disease and HIV-associated nephropathy (HIVAN), under a recessive inheritance pattern [3, 7, 10]. Moreover, these APOL1 variants and African American recipient ethnicity have been shown to associate with kidney transplant rejection and allograft failure [11–13]. Importantly, the expression of ApoL1 has been detected in renal proximal tubular epithelial cells, podocytes, medium-sized arteries, arteriolar endothelial cells and pre-glomerular vascular structures [3, 14, 15]. Thus, there is no doubt or controversy regarding the notion that the expression of APOL1 risk alleles in kidney cells is associated with the development and progression of non-diabetic CKD in African Americans. In fact, we and others have shown that interferon-α, -β and -γ and TNF-α can induce the expression of ApoL1 in endothelial cells and overexpression of ApoL1 can lead to autophagy- and/or necrosis-associated cell death in a variety of cell types, including endothelial cells and podocytes [15–19]. However, the role of ApoL1 in the outcome of cardiovascular diseases is a much more controversial topic [20]. Some studies suggest that the APOL1 risk alleles have an adverse effect [8], while others failed to detect an association between the risk alleles and these cardiovascular events [9], or showed improved survival in patients with two risk alleles [10]. Moreover, the potential role that extracellular/circulating ApoL1 might have on systemic endothelial and/or kidney cells is currently unknown. It is worth noting that besides being a component of HDL, ApoL1 is also a component of very low density lipoproteins (VLDL) and LDL [21]. This fact, however, has been frequently overlooked and the role of ApoL1 in VLDL and LDL has not been explored. In this issue, Gutierrez et al. [22] utilized a case–control sample of African Americas who were part of the Sea Islands Genetics Network (SIGNET) and assessed the relationship between the APOL1 risk variants, G1 and G2, and the circulating levels of different lipoproteins and sizes of HDL subclasses measured by nuclear magnetic resonance (NMR) spectroscopy. Using this well-established NMR technique, which is based on the assessment of distinct methyl groups of lipid species in plasma samples [23, 24], they found a modest increase of small-size HDL particles (small HDL) in the circulation of patients carrying the APOL1 G1/G2 risk alleles, independently of age, sex, diabetes and percentage of African ancestry. There were no significant differences in large or medium HDL, VLDL or LDL concentrations observed by APOL1 genotype in this study. Although the classification of large, medium and small of HDL is different from that of HDL 1, 2 and 3 subfractions defined by the density/density centrifugation [25–28], the small HDL should be lipid-poor and high density similar to, if not the same as, HDL3, of which ApoL1 is a component [1]. However, in this study the levels of ApoL1 in plasma samples were not measured and therefore cannot be correlated to the levels of small HDL or other lipoprotein particles. The results of Gutierrez et al. may be clinically relevant, since they suggest that the APOL1 genotype could play a direct role in determining the circulating concentration of small HDL, which have been associated with renal and cardiovascular diseases [7–10, 27]. However, as discussed in their article, these findings should be interpreted with caution. The authors propose that the APOL1 risk variants could contribute to the increase prevalence of renal disease by facilitating the formation of circulating HDL subpopulations with pro-atherogenic properties. Nonetheless, the difference in the circulating levels of small HDL between subjects with zero and two APOL1 risk alleles was modest (0.9 µmol/L), and although a previous study found that changes of this magnitude could be associated with albuminuria [27], no differences were found in the prevalence of CKD, albuminuria or other markers of cardiometabolic status across all the APOL1 categories in the subjects of this study [22]. In addition, the difference in small HDL concentration between individuals with one risk allele versus two risk alleles was minor (0.2 μmol/L) and very unlikely to be clinically relevant. Moreover, if two APOL1 risk alleles and higher circulating concentrations of small HDL interact to precipitate CKD, one should ask why two APOL1 risk alleles do not increase risk of diabetic nephropathy in African Americans with elevated HDL3. If the role of APOL1 rick alleles is to increase the concentration of small HDL (or HDL3), then adding elevated HDL3 is redundant; if the small HDL (or HDL3) are elevated already due to other factors, then APOL1 rick alleles cannot play an additional role by increasing small HDL (or HDL3). On the other hand, it is well known that once diabetic nephropathy is established, the progression of the renal disease is accelerated in patients carrying two APOL1 risk alleles [7]. In summary, given the negligible difference reported between the circulating levels of small HDL in patients carrying one versus two risk alleles (0.2 μmol/L), these changes are very unlikely to explain the increase risk of CKD conferred only by two risk alleles. As an alternative explanation, Gutierrez et al. argue that the elevated levels of small HDL could be due to changes in renal metabolic pathways. In this regard, a previous study showed that cubilin (gene: CUBN; protein: cubilin), an endocytic receptor highly expressed in renal proximal tubules, mediates the uptake of albumin and filtered forms of ApoA1-HDL [29]. Moreover, CUBN heterozygous deficient mice and transgenic mice overexpressing human cubilin showed either decreased or elevated levels of ApoA1, HDL cholesterol and HDL3 particles, respectively [29]. Nonetheless, the subjects carrying two risk alleles of APOL1 in the Gutierrez study showed only a minor increase in the circulating concentration of small HDL, suggesting that this isolated change is unlikely to be the result of renal metabolism. Taken together, the findings of Gutierrez et al. [22] add more fuel to the ongoing controversy regarding the association of APOL1 G1/G2 risk status with cardiovascular outcome among African Americans. However, if one speculates that the APOL1 risk alleles may directly modify the circulating levels of small HDL and/or other factors and induce a pro-atherogenic state that precipitates CKD and cardiovascular complications, then one should begin to answer the following several questions. (i) Why are the APOL1 risk variants not associated with an increased prevalence of diabetic nephropathy in African Americans? (ii) Would the APOL1 risk alleles alter the synthesis and function of other proteins in HDL3, VLDL and VDL? (iii) How do the circulating ApoL1 mutant proteins interact with the plasma membrane and initiate a signal transduction pathway from outside to inside of the targeted cell? (iv) What mechanisms modulate the transport of circulating ApoL1 mutant proteins inside the cells and its interaction with intracellular ApoL1 and/or other intracellular proteins, for example, apolipoprotein L6 (ApoL6), an ApoL1-related protein, which when overexpressed, induces atherosclerotic apoptosis [30]? Finally, as the expression of ApoL1 can be induced by inflammatory cytokines and intracellular accumulation of ApoL1 can initiate autophagy and cell death in endothelia cells, the crosstalk between inflammation, autophagy and cell death mediated by the overexpression of ApoL1 should be much more intensively investigated before one can properly interpret the meaning of these findings reported by Gutierrez et al. [22]

Hemorrhagic stroke in an adolescent female with HIV-associated thrombotic thrombocytopenic purpura

HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIVTTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (\u3c5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression

Infection of human primary renal epithelial cells with HIV-1 from children with HIV-associated nephropathy

Infection of human primary renal epithelial cells with HIV-1 from children with HIV-associated nephropathy. Children affected with human immunodefficiency virus (HIV)-associated nephropathy (HIVAN) usually develop significant renal glomerular and tubular epithelial cell injury. The pathogenesis of these changes is not clearly understood. Human renal tubular epithelial cells (RTEc) do not express CD4 surface receptors, and it is not clear whether these cells can be infected by HIV-1. Certain strains of HIV-1, however, have been shown capable of infecting CD4-negative epithelial cell lines. We hypothesized that the inability of laboratory strains of HIV-1 to infect renal epithelial cells may be due to a limited tropism, as opposed to wild-type viruses derived from children with HIVAN, and that viruses derived from these children are capable of infecting RTEc from the same patient. Here, we have demonstrated that HIV-1 isolates from children with HIVAN can productively infect RTEc through a CD4 independent pathway, and that infected mononuclear cells can transfer the virus to human RTEc. Human RTEc sustained low levels of viral replication and HIV-1 inhibited the growth and survival of cultured human RTEc. Thus, HIV-1 may directly induce degenerative changes in RTEc of children with HIVAN. Infected macrophages may play a relevant role in this process by transferring viruses to RTEc

Expression of a secreted fibroblast growth factor binding protein-1 (FGFBP1) in angioproliferative Kaposi sarcoma

Objective: Kaposi’s sarcoma (KS) is an angioproliferative disease frequently seen in patients with the acquired immunodeficiency syndrome (AIDS). Previous studies suggest that the HIV-1 protein Tat and Fibroblast Growth Factor 2 (FGF-2) have synergistic angiogenic effects in AIDS-KS tumors. However, the mechanisms by which FGF-2 is released and activated in KS tumors are not clearly defined. We carried out this study to determine whether an FGFbinding protein (FGFBP1 or BP1) that enhances the angiogenic activity of FGF-2 is expressed in AIDS-KS tumors, and to define whether BP1, FGF-2, and HIV-Tat protein-protein interactions could play a potential clinically role in the pathogenesis of AIDS-KS. Methods: BP1 was localized in AIDS-KS lesions by immunohistochemistry and in situ hybridization studies. The binding of radiolabeled FGF-2 to His-tagged BP1 or the FGF-receptor 1 was assessed in the presence and absence of HIV-Tat and other viral proteins. Mice carrying tetracycline-regulated BP1 transgene mice were used to determine whether activation of BP1 during wound healing induces KS-like lesions. Results: BP1 expression was detected in AIDS-KS tumor keratinocytes, spindle cells, and infiltrating mononuclear cells. In addition, HIV-Tat competed for the binding of FGF-2 to immobilized BP1, but does not affect the interactions of FGF-2 with its high affinity receptor (FGFR-1). In contrast, two other HIV-proteins, Nef and gp120, did not affect the binding of FGF-2 to BP1 or to FGFR-1. Finally, up-regulation of BP1 expression in tetracycline-regulated –conditional BP1 transgenic mice subjected to skin wounds, induced KS-like skin lesions. Conclusion: Taking into consideration the results of previous studies showing that both HIV-Tat and BP1 enhance the mitogenic and angiogenic activity of locally-stored FGF-2, both in vitro and in vivo, our findings suggest a novel mechanism by which the release and activity of FGFs can be modulated in AIDS-KS tumors by HIV-Tat as well as BP1

bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice

bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice. HIV-associated nephropathy is characterized by extensive tubulointerstitial disease with epithelial cell injury, microcystic proliferation, and tubular regeneration with glomerulosclerosis. To explore the role of bFGF as a mediator of HIV-induced interstitial disease, we utilized an HIV transgenic mouse model that manifests clinical and histological features observed in patients. In transgenic mice, simultaneous renal epithelial cell proliferation and injury were detected in vivo. In areas of microcystic proliferation, immunoreactive bFGF colocalized with extracellular matrix. Kidneys from transgenic mice had increased bFGF low affinity binding sites, particularly in the renal interstitium. In vitro, transgenic renal tubular epithelial cells proliferated more rapidly and generated tubular structures spontaneously, in marked contrast to nontransgenic renal cells where these pathologic features could be mimicked by exogenous bFGF. These studies suggest that renal bFGF and its receptors play an important role in the pathogenesis of HIV-associated nephropathy

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) conference

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address

Bottom trawl fishing footprints on the world’s continental shelves

Publication history: Accepted - 23 August 2018; Published online - 8 October 2018.Bottom trawlers land around 19 million tons of fish and invertebrates annually, almost one-quarter of wild marine landings. The extent of bottom trawling footprint (seabed area trawled at least once in a specified region and time period) is often contested but poorly described. We quantify footprints using high-resolution satellite vessel monitoring system (VMS) and logbook data on 24 continental shelves and slopes to 1,000-m depth over at least 2 years. Trawling footprint varied markedly among regions: from <10% of seabed area in Australian and New Zealand waters, the Aleutian Islands, East Bering Sea, South Chile, and Gulf of Alaska to >50% in some European seas. Overall, 14% of the 7.8 million-km2 study area was trawled, and 86% was not trawled. Trawling activity was aggregated; the most intensively trawled areas accounting for 90% of activity comprised 77% of footprint on average. Regional swept area ratio (SAR; ratio of total swept area trawled annually to total area of region, a metric of trawling intensity) and footprint area were related, providing an approach to estimate regional trawling footprints when highresolution spatial data are unavailable. If SAR was ≤0.1, as in 8 of 24 regions, therewas >95% probability that >90%of seabed was not trawled. If SAR was 7.9, equal to the highest SAR recorded, there was >95% probability that >70% of seabed was trawled. Footprints were smaller and SAR was ≤0.25 in regions where fishing rates consistently met international sustainability benchmarks for fish stocks, implying collateral environmental benefits from sustainable fishing.Funding for meetings of the study group and salary support for R.O.A. were provided by the following: David and Lucile Packard Foundation; the Walton Family Foundation; the Alaska Seafood Cooperative; American Seafoods Group US; Blumar Seafoods Denmark; Clearwater Seafoods Inc.; Espersen Group; Glacier Fish Company LLC US; Gortons Seafood; Independent Fisheries Limited N.Z.; Nippon Suisan (USA), Inc.; Pesca Chile S.A.; Pacific Andes International Holdings, Ltd.; San Arawa, S.A.; Sanford Ltd. N.Z.; Sealord Group Ltd. N.Z.; South African Trawling Association; Trident Seafoods; and the Food and Agriculture Organisation of the United Nations. Additional funding to individual authors was provided by European Union Project BENTHIS EU-FP7 312088 (to A.D.R., O.R.E., F.B., N.T.H., L.B.-M., R.C., H.O.F., H.G., J.G.H., P.J., S.K., M.L., G.G.-M., N.P., P.E.P., T.R., A.S., B.V., and M.J.K.); the Instituto Português do Mar e da Atmosfera, Portugal (C.S.); the International Council for the Exploration of the Sea Science Fund (R.O.A. and K.M.H.); the Commonwealth Scientific and Industrial Research Organisation (C.R.P. and T.M.); the National Oceanic and Atmospheric Administration (R.A.M.); New Zealand Ministry for Primary Industries Projects BEN2012/01 and DAE2010/ 04D (to S.J.B. and R.F.); the Institute for Marine and Antarctic Studies, University of Tasmania and the Department of Primary Industries, Parks, Water and Environment, Tasmania, Australia (J.M.S.); and UK Department of Environment, Food and Rural Affairs Project MF1225 (to S.J.)