Miracle-dz/UniFAR-FTUs huggingface dataset:
Pretreatment Cancer-Related Cognitive Impairment—Mechanisms and Outlook

Cognitive changes are common in patients with active cancer and during its remission. This has largely been blamed on therapy-related toxicities and diagnosis-related stress, with little attention paid to the biological impact of cancer itself. A plethora of clinical studies demonstrates that cancer patients experience cognitive impairment during and after treatment. However, recent studies show that a significant portion of patients with non-central nervous system (CNS) tumors experience cognitive decline prior to treatment, suggesting a role for tumor-derived factors in modulating cognition and behavior. Cancer-related cognitive impairment (CRCI) negatively impacts a patient’s quality of life, reduces occupational and social functioning, and increases morbidity and mortality. Furthermore, patients with cancer cachexia frequently experience a stark neurocognitive decline, suggesting peripheral tumors exert an enduring toll on the brain during this chronic paraneoplastic syndrome. However, the scarcity of research on cognitive impairment in non-CNS cancers makes it difficult to isolate psychosocial, genetic, behavioral, and pathophysiological factors in CRCI. Furthermore, clinical models of CRCI are frequently confounded by complicated drug regimens that inherently affect neurocognitive processes. The severity of CRCI varies considerably amongst patients and highlights its multifactorial nature. Untangling the biological aspects of CRCI from genetic, psychosocial, and behavioral factors is non-trivial, yet vital in understanding the pathogenesis of CRCI and discovering means for therapeutic intervention. Recent evidence demonstrating the ability of peripheral tumors to alter CNS pathways in murine models is compelling, and it allows researchers to isolate the underlying biological mechanisms from the confounding psychosocial stressors found in the clinic. This review summarizes the state of the science of CRCI independent of treatment and focuses on biological mechanisms in which peripheral cancers modulate the CNS.
Proposal for Standardization of Optimized Mycobacterial Interspersed Repetitive Unit-Variable-Number Tandem Repeat Typing of Mycobacterium tuberculosis

ABSTRACT Molecular typing based on 12 loci containing variable numbers of tandem repeats of mycobacterial interspersed repetitive units (MIRU-VNTRs) has been adopted in combination with spoligotyping as the basis for large-scale, high-throughput genotyping of Mycobacterium tuberculosis. However, even the combination of these two methods is still less discriminatory than IS6110 fingerprinting. Here, we define an optimized set of MIRU-VNTR loci with a significantly higher discriminatory power. The resolution and the stability/robustness of 29 loci were analyzed, using a total of 824 tubercle bacillus isolates, including representatives of the main lineages identified worldwide so far. Five loci were excluded for lack of robustness and/or stability in serial isolates or isolates from epidemiologically linked patients. The use of the 24 remaining loci increased the number of types by 40%—and by 23% in combination with spoligotyping—among isolates from cosmopolitan origins, compared to those obtained with the original set of 12 loci. Consequently, the clustering rate was decreased by fourfold—by threefold in combination with spoligotyping—under the same conditions. A discriminatory subset of 15 loci with the highest evolutionary rates was then defined that concentrated 96% of the total resolution obtained with the full 24-locus set. Its predictive value for evaluating M. tuberculosis transmission was found to be equal to that of IS6110 restriction fragment length polymorphism typing, as shown in a companion population-based study. This 15-locus system is therefore proposed as the new standard for routine epidemiological discrimination of M. tuberculosis isolates and the 24-locus system as a high-resolution tool for phylogenetic studies.
Healthy Donors Exhibit a CD4 T Cell Repertoire Specific to the Immunogenic Human Hormone H2-Relaxin before Injection

Key Points H2-relaxin–specific T cells are detected in the blood of healthy donors. T cell response to H2-relaxin relies on several CD4 T cell epitopes. An H2-relaxin–specific T cell repertoire might account for its clinical immunogenicity. H2-relaxin (RLN2) is a two-chain peptide hormone structurally related to insulin with a therapeutic potential in multiple indications. However, multiple injections of human RLN2 induced anti-RLN2 Abs in patients, hampering its clinical development. As T cell activation is required to produce Abs, we wondered whether T cells specific for RLN2 might be already present in the human blood before any injection. We therefore quantified the RLN2-specific T cell repertoire using PBMCs collected from healthy donors. CD4 T cells were stimulated in multiple replicates by weekly rounds of stimulation by dendritic cells loaded with RLN2, and their specificity was assessed by IFN-γ ELISPOT. The number of specific T cell lines was used to estimate the frequency of circulating T cells. In vitro T cell response was demonstrated in 18 of the 23 healthy donors, leading to the generation of 70 independent RLN2-specific T cell lines. The mean frequency of RLN2-specific CD4 T cells was similar to that of T cells specific for known immunogenic therapeutic proteins. Using overlapping peptides, we identified multiple T cell epitopes hosted in the N-terminal parts of the α- and β-chains and common to multiple donors, in agreement with their capacity to bind to multiple HLA-DR molecules. Our results provide important clues to the immunogenicity of RLN2 and highlight the weak central immune tolerance induced against this self-hormone.
Splice variants of tissue factor promote monocyte‐endothelial interactions by triggering the expression of cell adhesion molecules via integrin‐mediated signaling

Summary. Background: TF is highly expressed in cancerous and atherosclerotic lesions. Monocyte recruitment is a hallmark of disease progression in these pathological states. Objective: To examine the role of integrin signaling in TF‐dependent recruitment of monocytes by endothelial cells. Methods: The expression of flTF and asTF in cervical cancer and atherosclerotic lesions was examined. Biologic effects of the exposure of primary microvascular endothelial cells (MVEC) to truncated flTF ectodomain (LZ‐TF) and recombinant asTF were assessed. Results: flTF and asTF exhibited nearly identical expression patterns in cancer lesions and lipid‐rich plaques. Tumor lesions, as well as stromal CD68+ monocytes/macrophages, expressed both TF forms. Primary MVEC rapidly adhered to asTF and LZ‐TF, and this was completely blocked by anti‐β1 integrin antibody. asTF‐ and LZ‐TF‐treatment of MVEC promoted adhesion of peripheral blood mononuclear cells (PBMCs) under orbital shear conditions and under laminar flow; asTF‐elicited adhesion was more pronounced than that elicited by LZ‐TF. Expression profiling and western blotting revealed a broad activation of cell adhesion molecules (CAMs) in MVEC following asTF treatment including E‐selectin, ICAM‐1 and VCAM‐1. In transwell assays, asTF potentiated PMBC migration through MVEC monolayers by ∼3‐fold under MCP‐1 gradient. Conclusions: TF splice variants ligate β1 integrins on MVEC, which induces the expression of CAMs in MVEC and leads to monocyte adhesion and transendothelial migration. asTF appears more potent than flTF in eliciting these effects. Our findings underscore the pathophysiologic significance of non‐proteolytic, integrin‐mediated signaling by the two naturally occurring TF variants in cancer and atherosclerosis.
CO2 emissions from an undrained tropical peatland: Interacting influences of temperature, shading and water table depth

Emission of CO2 from tropical peatlands is an important component of the global carbon budget. Over days to months, these fluxes are largely controlled by water table depth. However, the diurnal cycle is less well understood, in part, because most measurements have been collected daily at midday. We used an automated chamber system to make hourly measurements of peat surface CO2 emissions from chambers root‐cut to 30 cm. We then used these data to disentangle the relationship between temperature, water table and heterotrophic respiration (Rhet). We made two central observations. First, we found strong diurnal cycles in CO2 flux and near‐surface peat temperature (<10 cm depth), both peaking at midday. The magnitude of diurnal oscillations was strongly influenced by shading and water table depth, highlighting the limitations of relying on daytime measurements and/or a single correction factor to remove daytime bias in flux measurements. Second, we found mean daily Rhet had a strong linear relationship to the depth of the water table, and under flooded conditions, Rhet was small and constant. We used this relationship between Rhet and water table depth to estimate carbon export from both Rhet and dissolved organic carbon over the course of a year based on water table records. Rhet dominates annual carbon export, demonstrating the potential for peatland drainage to increase regional CO2 emissions. Finally, we discuss an apparent incompatibility between hourly and daily average observations of CO2 flux, water table and temperature: water table and daily average flux data suggest that CO2 is produced across the entire unsaturated peat profile, whereas temperature and hourly flux data appear to suggest that CO2 fluxes are controlled by very near surface peat. We explore how temperature‐, moisture‐ and gas transport‐related mechanisms could cause mean CO2 emissions to increase linearly with water table depth and also have a large diurnal cycle.
Distribution of dystrophin and neurofilament protein in muscle spindles of normal and mdx‐dystrophic mice: An immunocytochemical study

Dystrophin is a high molecular weight protein localized under the sarcolemma of normal extrafusal muscle fibers but absent in skeletal muscle of Duchenne muscular dystrophy patients and mdx mice. Muscle spindles in the soleus of 32‐week‐old normal and age‐matched mdx mice were examined by immunocytochemical methods to determine the localization of dystrophin in polar and equatorial regions of the intrafusal fibers. Spindles were serially sectioned in transverse and longitudinal planes, and were double‐labelled with an antibody to dystrophin and with an antibody to a 200 kD neurofilament protein, which revealed their sensory innervation. By fluorescence microscopy, intrafusal fibers in the soleus of mdx mice were deficient in dystrophin throughout their lengths, whereas their sensory nerve terminals stained intensely with the nerve‐specific antibody and appeared unaltered in dystrophy. In the normal soleus, intrafusal fibers displayed a regional variability in the distribution of dystrophin. Polar regions of bag and chain fibers exhibited a peripheral rim of sarcolemmal staining equivalent to that seen in the neighboring extrafusal fibers. Dystrophin labelling in equatorial regions of normal intrafusal fibers, however, showed dystrophin‐deficient segments alternating in a spiral fashion with positive‐staining domains along the sarcolemma. Double‐labelling for dystrophin and neurofilament protein showed that these dystrophin‐deficient sites were subjacent to the annulospiral sensory nerve wrappings terminating on the intrafusal fibers. These findings suggest that dystrophin is not an integral part of the subsynaptic sensory membrane in equatorial regions of normal intrafusal fibers and thus is not directly related to sensory signal transduction. The complete absence of this protein in mdx intrafusal fibers indicates that these fibers exhibit the same primary defect in muscular dystrophy as seen in the extrafusal fibers. However, because of their small diameters, capsular investment, and relatively low tension outputs, dystrophic intrafusal fibers may be less prone to the sarcolemmal membrane disruption that is characteristic of extrafusal fibers in this disorder. © 1993 Wiley‐Liss, Inc.
Conserving involution in residuated structures

This paper establishes several algebraic embedding theorems, each of which asserts that a certain kind of residuated structure can be embedded into a richer one. In almost all cases, the original structure has a compatible involution, which must be preserved by the embedding. The results, in conjunction with previous findings, yield separative axiomatizations of the deducibility relations of various substructural formal systems having double negation and contraposition axioms. The separation theorems go somewhat further than earlier ones in the literature, which either treated fewer subsignatures or focussed on the conservation of theorems only. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
ABSORPTION OF SUPPLEMENTAL IRON DURING PREGNANCY‐A LONGITUDINAL STUDY WITH REPEATED BONE‐MARROW STUDIES AND ABSORPTION MEASUREMENTS

Abstract. Iron absorption, bone‐marrow smears and haematological parameters were repeatedly studied during pregnancy in 50 women. The same studies were repeated two months after delivery. The material was randomly divided into two groups. Twenty‐four women were treated with 200 mg of ferrous iron daily while 26 were given placebo. The iron absorption was measured from radioiron‐labelled test doses of 100 mg ferrous iron in a whole‐body counter with high sensitivity.
Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2.

Immunotherapy with the lymphokine interleukin-2 (IL-2), with or without lymphokine activated killer (LAK) cells, offers a new approach to the treatment of solid tumors. Unfortunately, most patients receiving IL-2 and LAK cells develop a "third space syndrome" from a presumed generalized increase of vascular permeability. We have investigated the role of IL-2 on lung fluid balance, by measuring changes in lung water and albumin intake. Rats were injected with IL-2 500,000 U i.p. three times a day for 1 to 4 days. At the completion of the injections, lungs were isolated and perfused, and total lung water (TLW) and 125I-albumin uptake were measured. After 1 day of injections, TLW increased from 4.90 +/- 0.14 to 5.57 +/- 0.34 ml/g dry lung and albumin uptake nearly doubled from 0.47 +/- 0.08 to 0.91 +/- 0.28 cm3/s/g dry lung X 10(-3). Longer injection periods increased both TLW and albumin uptake further. After 2 days, TLW and albumin uptake were also significantly increased by 160,000 U i.p. three times a day, but not by 40,000 or 10,000 U. To eliminate possible contributions to increased permeability by (a) LAK cells generated in vivo, or (b) circulating leukocytes, we isolated lungs from normal rats and perfused them for 5 min with a cell-free perfusate containing IL-2 (2, 10, or 5 X 10(-3) U/ml) excipient or 0.9% NaCl placebo. TLW was similar in all groups, but albumin uptake was significantly increased by 10,000 and 50,000 U/ml (0.94 +/- 0.15 and 0.82 +/- 0.16 cm3/s/g dry lung X 10(-3), respectively), but not by 2,000 U/ml. We conclude that lung microvascular albumin permeability is increased following administration of IL-2 in vivo and in vitro. We suggest that LAK cells are not required for the initiation of increased permeability and that IL-2 may have some direct effect on the pulmonary microvasculature.
Hepatitis C Infection, Time in Renal-Replacement Therapy, and Outcome after Kidney Transplantation

Background. Hepatitis C virus (HCV) infection is common in kidney transplantation and is known to affect long-term patient and graft survival, as is time in renal-replacement therapy (RRT). The aim of this study was to investigate HCV in relation to time in RRT and its impact on outcome after transplantation. Methods. A follow-up cohort study using Kaplan-Meier analysis and Cox proportional hazards model was performed in 545 kidney and 26 kidney-pancreas transplant recipients receiving transplants between 1989 and 1997, with last follow-up on December 31, 2002. HCV status at transplantation and time in RRT were analyzed. Results. Time in RRT was significantly longer (P<0.0001), and previous transplantations were more common (P=0.04) in the HCV-positive group. HCV significantly reduced patient (P=0.0012) and graft survival (P=0.0003) after transplantation. Adjustment for age, sex, diabetes, previous transplantations, type of transplant, and time in RRT resulted in a relative risk (RR) for death of 2.23, 1.92, and 1.07 for HCV, diabetes, and age, respectively. The RR for graft loss was 1.96 and 1.03 for HCV and age. Sex, previous transplants, and time in RRT did not affect HCV as an independent risk factor for patient or graft survival. The leading cause of death was cardiovascular disease in both groups. Conclusions. HCV was, in our series, more important than time in RRT for patient death and graft loss posttransplant. Successful pretransplant antiviral therapy could be more beneficial for HCV-infected patients rather than early transplantation for long-term outcome, but this needs to be studied prospectively.
Intravitreal Fluocinolone Acetonide May Decelerate Diabetic Retinal Neurodegeneration

Purpose There is no prevention or treatment for diabetic retinal neurodegeneration (DRN), which is a complication of diabetes that can occur independently of diabetic retinopathy (DR). We hypothesized that an intravitreal fluocinolone acetonide (FAc) implant may affect the rate of DRN when used in patients with diabetic macular edema (DME). Methods In this retrospective analysis, optical coherence tomography with neuroretinal analysis was obtained at 3-month intervals from 130 patients in the USER study both before (mean duration 903 days, range 35–4005 days) and after administration of FAc (mean 408 days, range 7 to 756 days). The rate of DRN was defined as the change over time on inner neuroretinal thickness using logistic regression. A DRN rate was calculated independently for two areas: region 1 located within 1.5 mm of the fovea, and region 2 from 1.5 mm to 3.0 mm from the fovea. Results In regions of the macula more than 1.5 mm from the central fovea, there was a statistically significant decrease in the rate of DRN in the post-FAc period. The pre-FAc neuroretinal loss in this area occurred at 4.0 μm/y, compared with a post-FAc loss rate of 1.1 μm/y (P = 0.001). Conclusions This retrospective study suggests that FAc may decelerate the rate of inner retinal thinning in patients with persistent DME. Further prospective studies are necessary to determine the effects of FAc on the rate of DRN in patients with DME.
Variability in the functional composition of coral reef fish communities on submerged and emergent reefs in the central Great Barrier Reef, Australia

On coral reefs, depth and gradients related to depth (e.g. light and wave exposure) influence the composition of fish communities. However, most studies focus only on emergent reefs that break the sea surface in shallow waters (<10 m). On the Great Barrier Reef (GBR), submerged reefs (reefs that do not break the sea surface) occupy an area equivalent to all emergent reefs. However, submerged reefs have received comparatively little research attention, and fish communities associated with submerged reefs remain poorly quantified. Here, we quantify fish assemblages at each of three depths (10, 20 and 30 m) on eight submerged reefs (four mid-shelf and four outer-shelf) and two nearby emergent reefs in the central GBR where reef habitat extends from 0-~25 m depth. We examine how total fish abundance, the abundance of 13 functional groups, and the functional composition of fish communities varies among depths, reef types (submerged versus emergent reefs), and shelf position (mid-shelf versus outer-shelf). Overall fish abundance decreased sevenfold with depth, but declined less steeply (twofold) on outer-shelf submerged reefs than on both mid-shelf submerged reefs and emergent reefs. The functional composition of the fish assemblage also varied significantly among depths and reef types. Turnover in the functional composition of the fish community was also steeper on the mid-shelf, suggesting that shallow-affiliated groups extend further in deeper water on the outer-shelf. Ten of the 13 functional groups were more strongly associated with the shallowest depths (the upper reef slope of emergent reefs or the ‘crests’ of submerged reefs), two groups (soft coral/sponge feeders and mesopredators) were more abundant at the deepest sites. Our results confirm that submerged reefs in the central GBR support a wide range of coral reef fishes, and are an important component of the GBR ecosystem.
Vitamin C and Vitamin E Mitigate the Risk of Pancreatic Ductal Adenocarcinoma from Meat-Derived Mutagen Exposure in Adults in a Case-Control Study.

BACKGROUND Previous studies have found that meat-derived mutagens increase, and vitamin C or E decrease, the risk of pancreatic cancer. OBJECTIVE The aim of this study was to determine whether intake of vitamin C or E modulates the association between meat-derived mutagen exposure and risk of pancreatic cancer. DESIGN We conducted a case-control study in 1321 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 1061 healthy controls (aged 28-88 y). Cases and controls were frequency-matched by age, sex, and race/ethnicity. Mutagen intake was assessed using a meat preparation questionnaire. Intakes of vitamin C, E, and other dietary components were assessed via a food-frequency questionnaire in a subset of 811 cases and 818 controls. ORs and 95% CIs were estimated in multivariable-adjusted logistic regression models. RESULTS The risk of PDAC was not associated with meat intake but was associated with consumption of well-done grilled or barbecued chicken (OR: 1.57; 95% CI: 1.18, 2.09; P = 0.001). Intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was associated with increased PDAC risk (Ptrend = 0.047). Participants in the highest, as compared with the lowest, quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (PhIP) intake experienced a 38% increased risk of PDAC (95% CI: 1.00, 1.90; P = 0.048). Intakes of total vitamin C or E from food and supplements or from supplements alone were each inversely associated with PDAC risk. Stratified analyses showed differential associations for PhIP intake and PDAC risk, such that risk increased among individuals with lower intake of vitamin C or E and decreased among those with higher vitamin intake. Significant interactions of dietary vitamin C, dietary vitamin E, and total vitamin E with PhIP intake were detected (Pinteraction = 0.023, <0.001, and 0.013, respectively). CONCLUSIONS Consistent with experimental evidence, this study of 811 cases and 818 controls has shown that high intake of dietary vitamin C or E mitigates the risk of PhIP-related PDAC.
Three-dimensional Reconstruction of a Membrane-bending Complex

A three-dimensional model of the dimeric reaction center-light harvesting I-PufX (RC-LH1-PufX) complex from Rhodobacter sphaeroides, calculated from electron microscope single particle analysis of negatively stained complexes, shows that the two halves of the dimer molecule incline toward each other on the periplasmic side, creating a remarkable V-shaped structure. The distribution of negative stain is consistent with loose packing of the LH1 ring near the 14th LH1 α/β pair, which could facilitate the migration of quinone and quinol molecules across the LH1 boundary. The three-dimensional model encloses a space near the reaction center QB site and the 14th LH1 α/β pair, which is ∼20Å in diameter, sufficient to sequester a quinone pool. Helical arrays of dimers were used to construct a three-dimensional membrane model, which matches the packing lattice deduced from electron microscope analysis of the tubular dimer-only membranes found in mutants of Rba. sphaeroides lacking the LH2 complex. The intrinsic curvature of the dimer explains the shape and ∼70-nm diameter of these membrane tubules, and at least partially accounts for the spherical membrane invaginations found in wild-type Rba. sphaeroides. A model of dimer aggregation and membrane curvature in these spherical membrane invaginations is presented.