Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

CTIP2 Expression in Human Head and Neck Squamous Cell Carcinoma Is Linked to Poorly Differentiated Tumor Status

We have demonstrated earlier that CTIP2 is highly expressed in mouse skin during embryogenesis and in adulthood. CTIP2 mutant mice die at birth with epidermal differentiation defects and a compromised epidermal permeability barrier suggesting its role in skin development and/or homeostasis. CTIP2 has also been suggested to function as tumor suppressor in cells, and several reports have described a link between chromosomal rearrangements of CTIP2 and human T cell acute lymphoblast leukemia (T-ALL). The aim of the present study was to look into the pattern of CTIP2 expression in Head and Neck Squamous Cell Carcinoma (HNSCC).In the present study, we analyzed CTIP2 expression in human HNSCC cell lines by western blotting, in paraffin embedded archival specimens by immunohistochemistry (IHC), and in cDNA samples of human HNSCC by qRT-PCR. Elevated levels of CTIP2 protein was detected in several HNSCC cell lines. CTIP2 staining was mainly detected in the basal layer of the head and neck normal epithelium. CTIP2 expression was found to be significantly elevated in HNSCC (p<0.01), and increase in CTIP2 expression was associated with poorly differentiated tumor status. Nuclear co-localization of CTIP2 protein and cancer stem cell (CSC) marker BMI1 was observed in most, if not all of the cells expressing BMI1 in moderately and poorly differentiated tumors.We report for the first time expression of transcriptional regulator CTIP2 in normal human head and neck epithelia. A statistically significant increase in the expression of CTIP2 was detected in the poorly differentiated samples of the human head and neck tumors. Actual CTIP2, rather than the long form of CTIP2 (CTIP2(L)) was found to be more relevant to the differentiation state of the tumors. Results demonstrated existence of distinct subsets of cancer cells, which express CTIP2 and underscores the use of CTIP2 and BMI1 co-labeling to distinguish tumor initiating cells or cancer stem cells (CSCs) from surrounding cancer cells

Computing Brane and Flux Superpotentials in F-theory Compactifications

In four-dimensional F-theory compactifications with N=1 supersymmetry the fields describing the dynamics of space-time filling 7-branes are part of the complex structure moduli space of the internal Calabi-Yau fourfold. We explicitly compute the flux superpotential in F-theory depending on all complex structure moduli, including the 7-brane deformations and the field corresponding to the dilaton-axion. Since fluxes on the 7-branes induce 5-brane charge, a local limit allows to effectively match the F-theory results to a D5-brane in a non-compact Calabi-Yau threefold with threeform fluxes. We analyze the classical and instanton contributions to the F-theory superpotential using mirror symmetry for Calabi-Yau fourfolds. The F-theory compactifications under consideration also admit heterotic dual descriptions and we discuss the identification of the moduli in this non-perturbative duality.Comment: 75 pages, 1 figure; typos corrected, references adde

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis

Data Availability Statement: The raw data supporting the conclusions of this article and code used for analysis will be made available by the authors on reasonable request pending appropriate study approvals and data transfer agreements between participating institutions.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/brainsci14070669/s1, Table S1: Inclusion/exclusion criteria for each data source; Table S2: Deficit in words recalled for each clinical condition relative to matched controls. Refs. [61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100] are cited in the Supplementary Materials.Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.This research was funded by the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military Relevant Brain Injury Consortium (LIMBIC), Grant/Award Numbers: W81XWH18PH, TBIRPLIMBIC under Awards Numbers: W81XWH1920067 and W81XWH1320095; US Department of Defense, Grant/Award Number: AZ150145; US Department of Veterans Affairs, Grant/Award Numbers: I01 CX002097, I01 CX002096, I01 HX003155, I01 RX003444, I01 RX003443, I01 RX003442, I01 CX001135, I01 CX001246, I01 RX001774, I01 RX001135, I01 RX002076, I01 RX001880, I01 RX002172, I01 RX002173, I01 RX002171, I01 RX002174, I01 RX002170, 1I01 RX003444; National Institutes of Health (NIH), Grant/Award Number(s): RF1NS115268, RF1NS128961, U01NS086625, U01MH124639, P50MH115846, R01MH113827, R25MH080663, K08MH068540, R01NS100973, R01EB006841, P20GM103472, RO1MH083553, T32MH019535, R01 HD061504, RO1MH083553, R01AG050595, R01AG076838, R01AG060470, R01AG064955, P01AG055367, K23MH095661, R01MH094524, R01MH121246, T32MH019535, R01NS124585, R01NS122827, R61NS120249, R01NS122184, U54EB020403, R01MH116147, R56AG058854, P41EB015922, R01MH111671, P41RR14075, M01RR01066, R01EB006841, R01EB005846, R01 EB000840, RC1MH089257, U24 RR021992, and NCRR 5 month-RR001066 (MGH General Clinical Research Center); National Institute of Mental Health (NIMH), Grant/Award Number: 1P20RR021938; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Grant/Award Numbers: PI15-00852, PI18-00945, JR19-00024, PI17-00481, PI20-00721; Sara Borrell contract, Grant/Award Number: CD19-00149; German Research Foundation DFG grant FOR2107, Grant/Award Numbers: JA 1890/7-1, JA 1890/7-2, NE2254/1-2, NE2254/2-1, NE2254/3-1, NE2254/4-1, KI588/14-1, KI588/14-2, DA1151/5-1, DA1151/5-2, SFB-TRR58, Projects C09 and Z02; European Union, NextGenerationEU, Grant/Award Numbers: PMP21/00051, PI19/01024; Structural Funds; Seventh Framework Program; H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2, Grant/Award Number: 101034377; Project AIMS-2-TRIALS, Grant/Award Number: 777394; Horizon Europe; NSF, Grant/Award Number: 2112455; Madrid Regional Government, Grant/Award Number: B2017/BMD-3740 AGES-CM-2; Dalhousie Medical Research Foundation; Research Nova Scotia, Grant/Award Number: RNS-NHIG-2021-1931; NJ Commission on TBI Research Grants, Grant/Award Numbers: CBIR11PJT020, CBIR13IRG026; Department of Psychology, University of Oslo; Sunnaas Rehabilitation Hospital, Grant/Award Number: HF F32NS119285; Canadian Institutes of Health Research, Grant/Award Number: 166098; Neurological Foundation of New Zealand, Grant/Award Number: 2232 PRG; Canterbury Medical Research Foundation, University of Otago; Biogen US Investigator-initiated grant; Italian Ministry of Health, Grant/Award Number: RF-2019-12370182 and Ricerca Corrente RC 23; National Institute on Aging; National Health and Medical Research Council, Investigator Grant/Award Number: APP1176426; PA Health Research, Grant/Award Number: 4100077082; La Caixa Foundation, Grant/Award Number: 100010434, fellowship code: LCF/BQ/PR22/11920017; Research Council of Norway, Grant/Award Number: 248238; Health Research Council of New Zealand Sir Charles Hercus Early Career Development, Grant/Award Numbers: 17/039 and 14-440; Health Research Council of New Zealand, Grant/Award Numbers: 20/538 and 14/440; Research and Education Trust Pacific Radiology, Grant/Award Number: MRIJDA; South-Eastern Norway Regional Health Authority, Grant/Award Number: 2018076; Norwegian ExtraFoundation for Health and Rehabilitation, Grant/Award Numbers: 2015/FO5146; South-Eastern Norway Regional Health Authority, Grant/Award Number: 2015044; Stiftelsen K.G. Jebsen, Grant/Award Number: SKGJ MED-02; The Liaison Committee between Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU), Grant/Award Number: 2020/39645; National Health and Medical Research Council, Grant/Award Number: APP1020526; Brain Foundation; Wicking Trust; Collie Trust; Sidney and Fiona Myer Family Foundation; U.S. Army Medical Research and Materiel Command (USAMRMC), Grant/Award Number: 13129004; Department of Energy, Grant/Award Number: DE-FG02-99ER62764; Mind Research Network; National Association for Research in Schizophrenia and Affective Disorders, Young Investigator Award; Blowitz Ridgeway and Essel Foundations; Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster; NOW ZonMw TOP, Grant/Award Number: 91211021; UCLA Easton Clinic for Brain Health; UCLA Brain Injury Research Center; Stan and Patty Silver; Clinical and Translational Research Center, Grant/Award Numbers: UL1RR033176, UL1TR000124; Mount Sinai Institute for NeuroAIDS Disparities; VA Rehab SPIRE; CDMRP PRAP; VA RR&D, Grant/Award Number: IK2RX002922; Veski Fellowship; Femino Foundation grant; Fundación Familia Alonso; Fundación Alicia Koplowitz; CIBERSAM, Madrid Regional Government, Grant/Award Numbers: B2017/BMD-3740 AGES-CM-2, 2019R1C1C1002457, 21-BR-03-01, 2020M3E5D9079910, 21-BR-03-01; Deutsche Forschungsgemeinschaft (DFG), Grant/Award Numbers: NE2254/1-2, NE2254/2-1, NE2254/3-1, NE2254/4-1