We have developed a statistical mechanics algorithm, TANGO, to predict protein aggregation. TANGO is based on the physico-chemical principles of β-sheet formation, extended by the assumption that the ...core regions of an aggregate are fully buried. Our algorithm accurately predicts the aggregation of a data set of 179 peptides compiled from the literature as well as of a new set of 71 peptides derived from human disease-related proteins, including prion protein, lysozyme and β2-microglobulin. TANGO also correctly predicts pathogenic as well as protective mutations of the Alzheimer β-peptide, human lysozyme and transthyretin, and discriminates between β-sheet propensity and aggregation. Our results confirm the model of intermolecular β-sheet formation as a widespread underlying mechanism of protein aggregation. Furthermore, the algorithm opens the door to a fully automated, sequence-based design strategy to improve the aggregation properties of proteins of scientific or industrial interest.
We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed ...with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10
) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h
=0.35; BD II SNP-h
=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.
Abstract Bipolar disorder and alcohol use disorder (AUD) have a high rate of comorbidity, more than 50% of individuals with bipolar disorder also receive a diagnosis of AUD in their lifetimes. ...Although both disorders are heritable, it is unclear if the same genetic factors mediate risk for bipolar disorder and AUD. We examined 733 Costa Rican individuals from 61 bipolar pedigrees. Based on a best estimate process, 32% of the sample met criteria for bipolar disorder, 17% had a lifetime AUD diagnosis, 32% met criteria for lifetime nicotine dependence, and 21% had an anxiety disorder. AUD, nicotine dependence and anxiety disorders were relatively more common among individuals with bipolar disorder than in their non-bipolar relatives. All illnesses were shown to be heritable and bipolar disorder was genetically correlated with AUD, nicotine dependence and anxiety disorders. The genetic correlation between bipolar and AUD remained when controlling for anxiety, suggesting that unique genetic factors influence the risk for comorbid bipolar and AUD independent of anxiety. Our findings provide evidence for shared genetic effects on bipolar disorder and AUD risk. Demonstrating that common genetic factors influence these independent diagnostic constructs could help to refine our diagnostic nosology.
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•The surface of aramid fibers was functionalized by two acid treatments.•The treatment based on HNO3/H2SO4 reduced the mechanical properties of the fibers.•CNTs were deposited on the ...aramid fibers, reaching electrical conductivity.•Homogeneous CNT distribution was achieved by using pristine fibers or chlorosulfonic acid.
Multiwall carbon nanotubes (MWCNTs) oxidized by an acid treatment were deposited on the surface of as-received commercial aramid fibers containing a surface coating (“sizing”), and fibers modified by either a chlorosulfonic treatment or a mixture of nitric and sulfuric acids. The surface of the aramid fiber activated by the chemical treatments presents increasing density of CO, COOH and OH functional groups. However, these chemical treatments reduced the tensile mechanical properties of the fibers, especially when the nitric and sulfuric acid mixture was used. Characterization of the MWCNTs deposited on the fiber surface was conducted by scanning electron microscopy, Raman spectroscopy mapping and X-ray photoelectron spectroscopy. These characterizations showed higher areal concentration and more homogeneous distribution of MWCNTs over the aramid fibers for as-received fibers and for those modified with chlorosulfonic acid, suggesting the existence of interaction between the oxidized MWCNTs and the fiber coating. The electrical resistance of the MWCNT-modified aramid yarns comprising ∼1000 individual fibers was in the order of MΩ/cm, which renders multifunctional properties.
The stabilization of δ-phase of poly(vinylidene fluoride) PVDF in a 14 µm-thickness ferroelectric membrane is achieved by a simple route based on the use of a dimethylformamide (DMF)/acetone solvent, ...in which the application of external electric field is not required. X-ray diffraction and calorimetric experiments on heating reveal that, at 154 °C, the original mixture between ferroelectric δ-phase and paraelectric α-phase transits to a system with only this latter phase in the crystalline fraction. A gradual and slight increment of amorphous fraction up to the melting at 161 °C is also observed. The existence of δ-phase is corroborated by the occurrence of a broad maximum around 154 °C in dielectric permittivity measurements, as well as the hysteresis loops observed at room temperature. These results suggest a wide thermal window for a stable δ-phase, between room temperature and 154 °C, a subsequent transition into α-phase and the corresponding melting at 161 °C. The broad dielectric maximum observed around 154 °C in dielectric and calorimetric measurements, can be associated with a diffuse ferroelectric-paraelectric transition.
A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or ...related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
Antibody-mediated rejection (AMR) is related to a poor prognosis in graft survival, with 27% to 40% of patients experiencing graft loss within the first year. The mechanism of damage in AMR is ...mediated by donor-specific antibodies (DSA). No standard treatment for AMR exists, and conventional management includes high doses of steroids, plasmapheresis, intravenous immunoglobulin, and either rituximab or bortezomib. Because of the high cost of these medications and the lack of prospective studies to evaluate their efficacy and safety, their routine use is limited. In the following study, we describe the use of bortezomib for the treatment of AMR in 5 renal transplant recipients with a 24-month follow-up and compare this case with the reviewed literature.
Five cases of AMR diagnosed by biopsy are reported, and these patients received bortezomib at a rate of 1.3 mg/m2 on days 1, 4, 8, and 11; plasmapheresis; and 1 patient received 30 g of intravenous immunoglobulin.
All patients received his or her first transplant; 4 were from a cadaveric donor, and 1 patient received thymoglobulin at a standard dose. All patients had maintenance therapy based on cyclosporine, mycophenolate mofetil, and prednisone, with an average baseline creatinine level of 1.3 mg/dL. The average days until rejection event were 952 days.
AMR treatment with bortezomib was effective, showing stable renal function at 24 months. Patients had adequate tolerance for administration. So far, these results contrast with the literature reviewed, so additional studies and follow-up are required for a new evaluation.
•Antibody-mediated rejection (AMR) is related to a poor prognosis in graft survival.•There is no standard treatment for AMR.•Because of the high cost of medications and the lack of prospective studies to evaluate their efficacy and safety, their routine use is limited.•Bortezomib is an effective and safe medication in the management of AMR.
Mesoporous nanocrystalline TiO
2
and TiO
2
–V
2
O
5
microspheres were prepared by non-hydrolytic sol–gel from TiCl
4
, VOCl
3
, and
i
Pr
2
O at 110 °C without any solvent or additives. The samples ...were characterized by elemental analysis, X-ray diffraction, Raman spectroscopy, scanning electron microscopy, nitrogen physisorption, and impedance measurements. At low vanadium loadings, only TiO
2
anatase was detected, and V
2
O
5
scherbinaite was also detected at high vanadium loadings. The texture of the samples depended on the V loading, but all the samples appeared built of primary nanoparticles (≈10–20 nm in size) that aggregate to form mesoporous micron-sized spheres. The lithium insertion properties of these materials were evaluated by galvanostatic measurements taken using coin-type cells, in view of their application as electrode for rechargeable Li-ion batteries. The mesoporous TiO
2
microspheres showed good performances, with a specific reversible capacity of 145 and 128 mAh g
−1
at
C
/2 and
C
, respectively (
C
= 335.6 mA g
−1
), good coulombic efficiency, and a moderate capacity fade (6 %) from the 2nd to the 20th cycle at
C
/20. Although the addition of V effectively increased the electronic conductivity of the powders, the specific reversible capacity and cycling performances of the TiO
2
–V
2
O
5
samples were only minimally improved for a 5 at% V loading and were lower at higher V loading.
Graphical Abstract
Renal transplantation is the optimal renal replacement therapy. In Mexico, most of the kidney transplants are from living donors. It is essential to identify conditions that increase the risk of ...developing chronic kidney disease (CKD) in donors, such as metabolic syndrome (MS).
In retrospect from January 2008 to December 2018, the donation protocols for renal transplantation of the Hospital Central Sur Alta Especialidad “Picacho” were reviewed, classifying all the cases of donors by nephrectomy or no nephrectomy and describing the demographic characteristics, prevalence of metabolic diseases, and cause of rejection of the protocol.
A total of 178 donors were studied: 82 women (46%), 96 men (54%), mean age of 42 years, average body mass index (BMI) 27.9 kg/m2, glomerular filtration rate (GFR) by Chronic Kidney Disease Epidemiology Collaboration 99 mL/min, 59 patients with grade I and II obesity (BMI ≥ 30 kg/m2), and 1 patient with morbid obesity (BMI ≥ 40 kg/m2). A total of 39 patients (22%) underwent nephrectomy and 139 (78%) did not. The following characteristics and alterations were found: Of the 139 patients who did not undergo nephrectomy, 91 had metabolic disorders, 20 had low GFR, 21 had albuminuria, and 4 recipients received cadaveric transplants, 3 due to critical conditions of the recipient. The metabolic alterations in the rejected donors were as follows: MS 54 (59%), prediabetes 55 (39%), newly diagnosed hypertension 70 (76%), diabetes mellitus 20 (14%), obesity 47 (51.6%), dyslipidemia 76 (83%), hyperuricemia 17 (12%).
The prevalence of MS in apparently healthy donors is similar to that of other studies in Mexico. Both MS and its components are independently associated with an increased risk of cardiovascular disease and CKD. It has been shown that these donors have a greater degree of glomerular and interstitial fibrosis; therefore, diagnosis, prevention, and timely treatment in this group are important.
•Today, living kidney donors have more metabolic risk factors.•The metabolic syndrome is not an absolute contraindication for kidney donation.•We must know the outcomes and possible effects on renal function in long-term kidney donors.
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