Reciprocal amplification of caspase-3 activity by nuclear export of a putative human RNA-modifying protein, PUS10 during TRAIL-induced apoptosis.

Pus10 is a pseudouridine synthase present in Archaea and Eukarya, but not in Bacteria and yeast. It has been suggested that the human PUS10 (DOBI) gene is needed during TRAIL-induced apoptosis. We analyzed the role of PUS10 in TRAIL-induced apoptosis by immunofluorescence, immunoblotting and several indicators of apoptosis. We examined several TRAIL-sensitive cell lines and we also examined some resistant cell lines after treatment with cycloheximide. PUS10 is mainly present in the nucleus. Early during apoptosis, PUS10 translocates to mitochondria via CRM1-mediated export with the concurrent release of cytochrome c and SMAC. Caspase-3 is required for PUS10 translocation, which reciprocally amplifies the activity of caspase-3 through the intrinsic/mitochondrial pathway. This suggests that in addition to cytoplasmic factors, nuclear factors also have a direct role in the major apoptosis pathways. However, p53 is not involved in TRAIL-induced PUS10 movement. The caspase-3-mediated movement of PUS10 and the release of mitochondrial contents enhancing caspase-3 activity creates a feedback amplification loop for caspase-3 action. Therefore, any defect in the movement or interactions of PUS10 would reduce the TRAIL sensitivity of tumor cells

A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer.

Lessons learnedThe combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.BackgroundAndrogen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.MethodsThis phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.ResultsSix patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.ConclusionThe combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43

The role of skin trauma in the distribution of morphea lesions: A cross-sectional survey of the Morphea in Adults and Children cohort IV

Background: Skin trauma may play a role in the development of morphea lesions. The association between trauma and the distribution of cutaneous lesions has never been examined to our knowledge. Objective: We sought to determine whether patients enrolled in the Morphea in Adults and Children (MAC) cohort exhibit skin lesions distributed in areas of prior (isotopic) or ongoing (isomorphic) trauma. Methods: This was a cross-sectional analysis of the MAC cohort. Results: Of 329 patients in the MAC cohort, 52 (16%) had trauma-associated lesions at the onset of disease. Patients with lesions in an isotopic distribution had greater clinical severity as measured by a clinical outcome measure (mean modified Rodnan Skin Score of 13.8 vs 5.3, P = .004, 95% confidence interval 3.08-13.92) and impact on life quality (mean Dermatology Life Quality Index score 8.4 vs 4.1, P = .009, 95% confidence interval 1.18-7.50) than those with an isomorphic distribution. Most frequent associated traumas were chronic friction (isomorphic) and surgery/isotopic. Limitations: Recall bias for patient-reported events is a limitation. Conclusion: Of patients in the MAC cohort, 16% developed initial morphea lesions at sites of skin trauma. If these findings can be confirmed in additional series, they suggest that elective procedures and excessive skin trauma or friction might be avoided in these patients

The proposed Caroline ESA M3 mission to a Main Belt Comet

We describe Caroline, a mission proposal submitted to the European Space Agency in 2010 in response to the Cosmic Visions M3 call for medium-sized missions. Caroline would have travelled to a Main Belt Comet (MBC), characterizing the object during a flyby, and capturing dust from its tenuous coma for return to Earth. MBCs are suspected to be transition objects straddling the traditional boundary between volatile–poor rocky asteroids and volatile–rich comets. The weak cometary activity exhibited by these objects indicates the presence of water ice, and may represent the primary type of object that delivered water to the early Earth. The Caroline mission would have employed aerogel as a medium for the capture of dust grains, as successfully used by the NASA Stardust mission to Comet 81P/Wild 2. We describe the proposed mission design, primary elements of the spacecraft, and provide an overview of the science instruments and their measurement goals. Caroline was ultimately not selected by the European Space Agency during the M3 call; we briefly reflect on the pros and cons of the mission as proposed, and how current and future mission MBC mission proposals such as Castalia could best be approached

Random insights into the complexity of two-dimensional tensor network calculations

Projected entangled pair states (PEPS) offer memory-efficient representations of some quantum many-body states that obey an entanglement area law, and are the basis for classical simulations of ground states in two-dimensional (2d) condensed matter systems. However, rigorous results show that exactly computing observables from a 2d PEPS state is generically a computationally hard problem. Yet approximation schemes for computing properties of 2d PEPS are regularly used, and empirically seen to succeed, for a large subclass of (not too entangled) condensed matter ground states. Adopting the philosophy of random matrix theory, in this work we analyze the complexity of approximately contracting a 2d random PEPS by exploiting an analytic mapping to an effective replicated statistical mechanics model that permits a controlled analysis at large bond dimension. Through this statistical-mechanics lens, we argue that: i) although approximately sampling wave-function amplitudes of random PEPS faces a computational-complexity phase transition above a critical bond dimension, ii) one can generically efficiently estimate the norm and correlation functions for any finite bond dimension. These results are supported numerically for various bond-dimension regimes. It is an important open question whether the above results for random PEPS apply more generally also to PEPS representing physically relevant ground state

Reproductive isolation among Acropora Species (Scleractinia: Acroporidae) in a marginal coral assemblage

Hybridization was proposed as being an important source of evolutionary novelty in broadcast-spawning reef-building corals. In addition, hybridization was hypothesized to be more frequent at the periphery of species' ranges and in marginal habitats. We tested the potential for hybridization in 2 ways: observations of the time of spawning and non-choice interspecific fertilization experiments of 4 sympatric Acropora species in a non-reefal coral assemblage at Chinwan Inner Bay (CIB), Penghu Is., Taiwan. We found that colonies of more than 1 species rarely released gametes at the same time, thus limiting the opportunities for cross-fertilization in the wild. On the few occasions when different species released gametes in synchrony, interspecific fertilization in experimental crosses was uniformly low (the proportion of eggs fertilized ranged 0%-4.58% with a mode of 0%), and interspecific-crossed embryos ceased development and died within 12 h after initially being fertilized. Ecological and experimental analyses indicated that reproductive isolation exists in these 4 Acropora species even though they have the opportunities to spawn synchronously, suggesting that hybridization is not very frequent in this marginal coral habitat at CIB

Murine Anti-vaccinia Virus D8 Antibodies Target Different Epitopes and Differ in Their Ability to Block D8 Binding to CS-E

The IMV envelope protein D8 is an adhesion molecule and a major immunodominant antigen of vaccinia virus (VACV). Here we identified the optimal D8 ligand to be chondroitin sulfate E (CS-E). CS-E is characterized by a disaccharide moiety with two sulfated hydroxyl groups at positions 4′ and 6′ of GalNAc. To study the role of antibodies in preventing D8 adhesion to CS-E, we have used a panel of murine monoclonal antibodies, and tested their ability to compete with CS-E for D8 binding. Among four antibody specificity groups, MAbs of one group (group IV) fully abrogated CS-E binding, while MAbs of a second group (group III) displayed widely varying levels of CS-E blocking. Using EM, we identified the binding site for each antibody specificity group on D8. Recombinant D8 forms a hexameric arrangement, mediated by self-association of a small C-terminal domain of D8. We propose a model in which D8 oligomerization on the IMV would allow VACV to adhere to heterogeneous population of CS, including CS-C and potentially CS-A, while overall increasing binding efficiency to CS-E

Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer’s disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases

A urinary common rejection module (uCRM) score for non-invasive kidney transplant monitoring

A Common Rejection Module (CRM) consisting of 11 genes expressed in allograft biopsies was previously reported to serve as a biomarker for acute rejection (AR), correlate with the extent of graft injury, and predict future allograft damage. We investigated the use of this gene panel on the urine cell pellet of kidney transplant patients. Urinary cell sediments collected from patients with biopsy-confirmed acute rejection, borderline AR (bAR), BK virus nephropathy (BKVN), and stable kidney grafts with normal protocol biopsies (STA) were analyzed for expression of these 11 genes using quantitative polymerase chain reaction (qPCR). We assessed these 11 CRM genes for their abundance, autocorrelation, and individual expression levels. Expression of 10/11 genes were elevated in AR when compared to STA. Psmb9 and Cxcl10could classify AR versus STA as accurately as the 11-gene model (sensitivity = 93.6%, specificity = 97.6%). A uCRM score, based on the geometric mean of the expression levels, could distinguish AR from STA with high accuracy (AUC = 0.9886) and correlated specifically with histologic measures of tubulitis and interstitial inflammation rather than tubular atrophy, glomerulosclerosis, intimal proliferation, tubular vacuolization or acute glomerulitis. This urine gene expression-based score may enable the non-invasive and quantitative monitoring of AR

Experimental Treatments for Spinal Cord Injury: What you Should Know

Experiencing a spinal cord injury (SCI) is extremely distressing, both physically and psychologically, and throws people into a complex, unfamiliar world of medical procedures, terminology, and decision making. You may have already had surgery to stabilize the spinal column and reduce the possibility of further damage. You are understandably distressed about the functions you may have lost below the level of spinal injury. You wish to recover any lost abilities as soon as possible. You, your family, or friends may have searched the Internet for treatments and cures