Soluble ligands for the NKG2D receptor are released during HIV‐1 infection and impair NKG2D expression and cytotoxicity of NK cells

In humans, the interaction of the natural killer group 2 member D (NKG2D)‐activating receptor on natural killer (NK) and CD8 + T cells with its major histocompatibility complex class I‐related chain (MIC) and UL16 binding protein (ULBP) ligands (NKG2DLs) promotes recognition and elimination of stressed cells, such as tumor or infected cells. Here, we investigated the capacity of HIV‐1 to modulate NKG2DL expression and escape NGK2D‐mediated immunosurveillance. In CD4 + T lymphocytes, both cell surface expression and release of MICA, MICB, and ULBP2 were up‐regulated > 2‐fold by HIV‐1 infection. In HIV‐infected CD4 + T lymphocytes or Jurkat T‐cell lines, increased shedding of soluble NKG2DLs (sNKG2DLs) was impaired by a matrix metalloproteinase inhibitor (MMPI). Moreover, naive HIV + patients displayed increased plasma sMICA and sULBP2 levels and reduced NKG2D expression on NK and CD8 + T cells compared to patients receiving highly active antiretroviral therapy (HAART) or healthy donors. In individual patients, HAART uptake resulted in the drop of sNKG2DL and recovery of NKG2D expression. Finally, sNKG2DLs in patients' plasma down‐regulated NKG2D on NK and CD8 + T cells and impaired NKG2D‐mediated cytotoxicity of NK cells. Thus, NKG2D detuning by sNKG2DLs may promote HIV‐1 immune evasion and compromise host resistance to opportunistic infections, but HAART and MMPI have the potential to avoid such immune dysfunction.—Matusali, G., Tchidjou, H. K., Pontrelli, G., Bernardi, S., D'Ettorre, G., Vullo, V., Buonomini, A. R., Andreoni, M., Santoni, A., Cerboni, C., Doria, M. Soluble ligands for the NKG2D receptor are released during HIV‐1 infection and impair NKG2D expression and cytotoxicity of NK cells. FASEB J. 27, 2440–2450 (2013). www.fasebj.org

Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy

Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.

The effects of maternal thyroid hormone function on early pregnancy

It is unclear whether pregnancy outcomes are impacted by nonovert thyroid disease, and whether detection and treatment of abnormalities improve outcomes. Consequently, there is an ongoing debate regarding universal thyroid screening in pregnancy. A lack of solid evidence has prompted researchers to evaluate the role of screening and to examine pregnancy outcomes in women with thyroid dysfunction. In addition, as IVF has developed into a commonly used procedure, its impact on thyroid function has also been investigated. The most current literature on these topics will be summarized in this review.

Renoprotective Effects of Direct Renin Inhibition in Glomerulonephritis

The development of glomerulonephritis causes glomerular injury and renal dysfunction and is thought to increase renin release, thus activating the renin-angiotensin system (RAS). The aims of this study were to demonstrate activation of the intrarenal RAS and determine the effects of direct renin inhibition (DRI) on the progression of glomerulonephritis. Rats were treated with anti-Thy1.1 antibody with or without DRI, aliskiren (30 mg/kg/d). In the glomerulonephritic rats, protein, microalbumin excretion levels, urinary angiotensinogen excretion, glomerular expansion score and intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 mRNA levels were augmented compared with control rats; however, hypertension was not observed in the glomerulonephritic rats, and aliskiren treatment did not modify their blood pressure. The increases in urinary protein (94.7 ± 13.0 mg/d) and microalbumin (7.52 ± 2.6 mg/d) excretion were reduced by aliskiren (43.6 ± 4.5 mg/d of protein and 2.57 ± 0.7 mg/d of microalbumin). Furthermore, the progression of glomerular expansion and elevation of intrarenal transforming growth factor-β and plasminogen activator inhibitor-1 levels were prevented by aliskiren. Importantly, aliskiren suppressed the augmentation of urinary angiotensinogen levels, the increased angiotensinogen expression in the kidneys and the increases in Ang II levels in renal medulla induced by the anti-Thy1.1 antibody. These results suggest that DRI with aliskiren prevents intrarenal RAS activation leading to mitigation of the development of glomerulonephritis. In addition, the renoprotective effects of DRI on glomerulonephritis occur in a blood pressure-independent manner. Accordingly, treatment with aliskiren may be an effective approach to treat glomerulonephritis and other intrarenal RAS-associated kidney diseases.

Raising Awareness of Non-Hodgkin Lymphoma in HIV-infected Adolescents

Human immunodeficiency virus (HIV) chronically infected patients are at increased risk of developing non-Hodgkin lymphoma compared with the general population. Highly active antiretroviral therapy has had a dramatic effect on the natural history of HIV infection, reducing the incidence of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma and improving overall survival. However, problems related to adherence to treatment, frequently experienced during adolescence, may increase the risk of acquired immunodeficiency syndrome-related cancers. Optimizing highly active antiretroviral therapy and monitoring noncompliant patients with persisting HIV replication should be considered by physicians who take care of these patients. We herein report 2 cases of relapsed/progressive Burkitt lymphoma in HIV vertically infected adolescents.

The Retinal Nerve Fiber Layer of Patients With Neuromyelitis Optica and Chronic Relapsing Optic Neuritis is More Severely Damaged than Patients With Multiple Sclerosis

To compare the retinal nerve fiber layer (RNFL) in eyes of patients with relapsing remitting multiple sclerosis (RRMS), neuromyelitis optica (NMO) and chronic relapsing inflammatory optic neuritis (CRION).

A social and ecological assessment of tropical land uses at multiple scales: the Sustainable Amazon Network

Science has a critical role to play in guiding more sustainable development trajectories. Here, we present the Sustainable Amazon Network (Rede Amazônia Sustentável , RAS): a multidisciplinary research initiative involving more than 30 partner organizations working to assess both social and ecological dimensions of land-use sustainability in eastern Brazilian Amazonia. The research approach adopted by RAS offers three advantages for addressing land-use sustainability problems: (i) the collection of synchronized and co-located ecological and socioeconomic data across broad gradients of past and present human use; (ii) a nested sampling design to aid comparison of ecological and socioeconomic conditions associated with different land uses across local, landscape and regional scales; and (iii) a strong engagement with a wide variety of actors and non-research institutions. Here, we elaborate on these key features, and identify the ways in which RAS can help in highlighting those problems in most urgent need of attention, and in guiding improvements in land-use sustainability in Amazonia and elsewhere in the tropics. We also discuss some of the practical lessons, limitations and realities faced during the development of the RAS initiative so far.

A social and ecological assessment of tropical land uses at multiple scales: the Sustainable Amazon Network

Mitochondrial Dysfunction and Defective Autophagy in the Pathogenesis of Collagen VI Muscular Dystrophies

Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy (BM) and Congenital Myosclerosis are diseases due to mutations in the genes encoding the extracellular matrix protein collagen VI. A dystrophic mouse model where collagen VI synthesis was prevented by targeted inactivation of the Col6a1 gene allowed the investigation of pathogenesis, which revealed the existence of a Ca2+-mediated dysfunction of mitochondria and sarcoplasmic reticulum, and of defective autophagy. Key events are dysregulation of the mitochondrial permeability transition pore, an inner membrane high-conductance channel that for prolonged open times causes mitochondrial dysfunction; and inadequate removal of defective mitochondria, which amplifies the damage. Consistently, the Col6a1-/- myopathic mice could be cured with through inhibition of cyclophilin D, a matrix protein that sensitizes the pore to opening, and through stimulation of autophagy. Similar defects contribute to disease pathogenesis in patients irrespective of the genetic lesion causing the collagen VI defect. These studies indicate that PTP opening and defective autophagy represent key elements for skeletal muscle fiber death, and provide a rationale for the use of cyclosporin A and its non immunosuppressive derivatives in patients affected by collagen VI myopathies, a strategy that holds great promise for treatment

Large resistivity change and phase transition in the antiferromagnetic semiconductors LiMnAs and LaOMnAs

Antiferromagnetic semiconductors are new alternative materials for spintronic applications and spin valves. In this work, we report a detailed investigation of two antiferromagnetic semiconductors AMnAs (A = Li, LaO), which are isostructural to the well-known LiFeAs and LaOFeAs superconductors. Here we present a comparison between the structural, magnetic, and electronic properties of LiMnAs, LaOMnAs, and related materials. Interestingly, both LiMnAs and LaOMnAs show a variation in resistivity with more than five orders of magnitude, making them particularly suitable for use in future electronic devices. Neutron and x-ray diffraction measurements on LiMnAs show a magnetic phase transition corresponding to the Neel temperature of 373.8 K, and a structural transition from the tetragonal to the cubic phase at 768 K. These experimental results are supported by density functional theory calculations