Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow–derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress–triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

Organ shortage continues to limit the lives of patients who require liver transplantation. While extending criteria for liver organs provides a needed resource, tissue damage from prolonged ischemic injury can result in early allograft dysfunction and consequent rejection. In this issue of the JCI, Nakamura et al. used a mouse transplantation model with prolonged ex vivo cold storage to explore liver graft protection. The authors found that liver grafts with absent carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) exhibited increased ischemia-reperfusion injury inflammation and decreased function in wild-type recipients. The authors went on to correlate CEACAM1 levels with postreperfusion damage in human liver transplant recipients. Notably, this study identified a potential biomarker for liver transplant donor graft quality.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti–CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor–driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.

Microsoft plans to add trackpad and mouse support to its Word, Excel, and PowerPoint apps for iPad by the fall, according to TechCrunch and The Verge.

iPadOS 13.4 introduced trackpad and mouse support on all iPad models released in the past four to five years. Keyboards with trackpads include Apple's Magic Keyboard and Brydge's Pro+ for the iPad Pro and Logitech's Combo for the 10.2-inch iPad and the 10.5-inch iPad Air.

When using a trackpad, the cursor displays as a circle on the screen, popping up only when you have a finger on the trackpad. The circle then morphs into various other shapes when hovering over app icons, text fields, or other on-screen elements.

This article, "Microsoft to Add Trackpad Support to Word, Excel, and PowerPoint Apps on iPad" first appeared on MacRumors.com

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A nationwide class action lawsuit filed against Apple in Northern California court this week accuses the company of knowingly concealing a defect with a display-related flex cable on recent 13-inch and 15-inch MacBook Pro models.


As discovered by repair website iFixit last year, some MacBook Pro models released in 2016 and 2017 have experienced issues with uneven backlighting caused by a delicate flex cable that can wear out and break after repeated opening and closing of the display. Impacted notebooks can exhibit uneven lighting at the bottom of the screen, which has been described as a "stage light" effect, and the backlighting system can eventually fail entirely.

Since the issue often takes time to manifest, the affected ‌MacBook Pro‌ units can be outside of Apple's one-year warranty period when they start exhibiting symptoms, resulting in an out-of-warranty repair fee of up to $850.

"Imagine spending more than $2,500 on a laptop only for it to fail shortly after the manufacturer's warranty expires," said PARRIS Law Firm attorney R. Rex Parris. "What's even more appalling is Apple requiring customers to spend an additional $600 to $850 to replace the screen."

Apple seemingly fixed the issue by extending the length of the flex cable by 2mm in the 2018 MacBook Pro. It also launched a free repair program in May 2019, but the program only applies to 13-inch MacBook Pro models released in 2016.

iFixit found the 2018 MacBook Pro flex cable on the left to be 2mm longer
The class action lawsuit seeks restitution for all costs attributable to replacing or replacing the affected MacBook Pro units, and calls for Apple to expand its repair program to cover the 15-inch MacBook Pro. The proposed class is defined as all persons within the United States who purchased a 2016 or newer MacBook Pro.

Related Guide: "Flexgate" Display Issues Affecting 2016 MacBook Pro and Later
This article, "Apple Faces Class Action Lawsuit Over 'Flexgate' Issue With MacBook Pro Displays" first appeared on MacRumors.com

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Apple will begin reopening its retail stores in the United States next week, reports CNBC, starting with locations in Idaho, South Carolina, Alabama, and Alaska.


Apple plans to limit the number of customers in the store at a time, and temperature checks will be performed at the door. Apple also has a number of other measures in place to keep customers and employees safe, as we outlined this morning.

"We're excited to begin reopening stores in the US next week, starting with some stores in Idaho, South Carolina, Alabama and Alaska. Our team is constantly monitoring local heath data and government guidance, and as soon as we can safely open our stores, we will."

"Our new social distance protocol allows for a limited number of visitors in the store at one time so there may be a delay for walk-in customers. We recommend, where possible, customers buy online for contactless delivery or in-store pick up."

Reopened Apple Stores will operate on reduced hours and will primarily focus on repairs, with Apple encouraging customers to purchase online where possible.

Most stores are not listing hours at this time with the exception of Apple Boise Towne Square, which reopens Monday at 11:00 a.m.

During last week's earnings call, Apple CEO Tim Cook said that Apple planned to start reopening some stores in the United States in May. Store reopenings are done on a city by city, county by county basis, with Apple taking into account local data and guidelines.

Apple has already reopened stores in South Korea, Austria, and Australia, with plans to also reopen stores in Germany next week.
This article, "Apple to Start Reopening U.S. Stores Next Week" first appeared on MacRumors.com

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New experience reports published by Erowid on May 01 2020

New experience reports published by Erowid on May 02 2020

New experience reports published by Erowid on May 04 2020

New experience reports published by Erowid on May 05 2020

New experience reports published by Erowid on May 06 2020

New experience reports published by Erowid on May 08 2020

Glenn Greenwald predicts over the next four years that "it's all going to get much worse", with President Obama shifting politically more to the right while the Democratic base continues to support him. Continue reading →

I am still holding on a call to the Internal Revenue Service, even though I called (800) 829-0115 two hours ago. This telephone number is the one often included in notices from the Internal Revenue Service for overdue business taxes. … Continue reading →

There's got to be a reason for the Democrats to suppose to exist. And the reason the Democrats are supposed to exist is to be an opposition party to the Republicans. If you're in bed with the same people, taking money from the same people, you're no longer an opposition party. There's no reason for you to exist. And guess what? Don't be surprised that people don't vote for you. Continue reading →

Donald Trump sold out his supporters and the 99% by selecting Wall Streeters and war mongers for his top cabinet positions. Continue reading →

Вокалист EXODUS Steve "Zetro" Souza сказал, что болезнь Gary Holt'a повлияла на работу группы над новым альбомом:

«По состоянию на текущий момент мы все вместе работаем где-то месяц. У Gary полно риффов, и многое ещё нужно собрать воедино. Всё начинается с него и Tom'a обычно. Все знают, что сначала барабаны и гитара — так всегда поступали EXODUS. Но из-за всего этого дистанцирования всё сделать просто нереально, так что работа несколько подпорчена. Но я могу гарантировать вам, что то, что я слышал на саундчеке, когда они играли перед шоу в рамках "The Bay Strikes Back", очень порадует фанатов EXODUS. Ещё раз скажу: я не слышал целых песен — я слышал лишь риффы и фрагменты — и я такой: "Вау!" Это просто охренеть как тяжело!» #Exodus #ThrashMetal #Thrash_Metal

With only 37 days until Britain leaves the EU, its biggest foreign and trade policy shift in more than 40 years, divisions over Brexit are redrawing the political landscape.

European Union leaders have offered Britain a Brexit extension until May 22.

Undone by Blood #3 is now due out June 10.

The post EXCLUSIVE: More meta revenge in UNDONE BY BLOOD #3 appeared first on The Beat.

IBM today announced its Health Cloud and Watson cognitive computing capabilities will support health data entered by customers in iOS apps using Apple's ResearchKit and HealthKit frameworks. The move, which complements IBM’s new Watson Health business unit, will arm medical researchers with a secure, open data storage solution, as well as access to IBM’s most sophisticated data analytics capabilities.

I'm getting so very tired of safety/accident researchers claiming that root cause analysis is an invalid, blame-focused practice that ignores systems and complexity. Most root cause investigators that I know are pretty well oriented towards process, organization, and system issues as the fundamental sources underlying problems and accidents... and even some of our simplest analysis […]

My previous post about root causes in complex systems, in retrospect, looks a little bit like a rant. That doesn't bother me too much, really... but I wish I had included the following info: it is one way to go about resolving the mess that complex systems can make of your root cause analysis. Basically, when […]

IBM today announced an expansion of its mobile portfolio for enterprises as it continues to create analytics-driven and cognitive enabled enterprise iOS apps that enable organizations to accelerate digital reinvention and transform how businesses engage across industries.

Pets at Home, the UK’s leading pet specialist retailer and IBM today announced the launch of Sales Assist, an IBM MobileFirst for iOS app for iPad which will be used across 440 stores nationwide to make it easier and simpler for customers to purchase the products they need.

IBM today announced that it will help deliver a tailored fan experience through the IBM Cloud at Atlanta’s new Mercedes-Benz Stadium, scheduled to open later this month.

IBM today unveiled a number of major additions to its Flex System portfolio. The offerings combine the latest server technology with new virtualization, networking and management tools, allowing clients to consolidate their existing IT infrastructures and reduce operating costs. This will help clients use smaller data center environments to quickly deploy, manage and secure increasingly larger clouds.

Today IBM and Eurobank announced the first cloud-based digital platform for online international commercial trading. Using IBM's industry-leading Digital Experience software, with advanced cloud capabilities and social offerings, Eurobank is uniting exporters and importers from around the globe to enhance international trade operations and increase transactions.

IBM today announced the opening of IBM Studio Groningen, where IBM design, digital and industry experts will work with clients to help them engage with their customers using big data, mobile, cloud and social innovations.

IBM today announced that Joanne Wright, Vice President, IBM Watson Supply Chain and Jeanette Barlow, Vice President of Offering Management and Strategy for IBM Watson Supply Chain will be participating in the “Industry Value Chain Exchange Series,” part of the Gartner Supply Chain Management Executive Conference. The conference takes place from May 23-25 in Phoenix, Arizona.

IBM today announced new offerings to its Watson Data Platform, including data cataloging and data refining, which is designed to make it easier for developers and data scientists to analyze and prepare enterprise data for AI applications, regardless of its structure or where it resides. By improving data visibility and helping to better enforce data security policies, users can now connect and share data across public and private cloud environments.

I was skeptical of an email asking for a lung cancer link

If your timing is just exactly right, you can experience a Disneyland ghost town

IBM today announced it is teaming up with Toronto-based FinTech company Dream Payments to bring new revenue generating mobile payment offerings to financial institutions and merchants in the United States via the IBM Cloud.

Digital video consumption is viral and, according to a new study released today by IBM and International Broadcasting Convention (IBC), more than half of the 21,000 consumers surveyed are using mobiles every day to watch streaming videos, and that number is expected to grow 45 percent in the next three years.

IBM is bringing its expertise in sports venue infrastructure design and implementation to the practice field for newly formed Major League Soccer Club, Atlanta United, providing a year-round, state-of-the art technological experience for the players and staff.

IBM anunció hoy que un 40% de los principales bancos e instituciones financieras en el país cuentan con protección de fraudes en línea que se sustentan en la solución Trusteer de IBM, con la cual la seguridad de los clientes está respaldada al realizar transacciones electrónicas.

IBM es y ha sido un jugador clave en el progreso de México, liderando en el transcurso de 90 años a diferentes generaciones a través de la transformación de industrias y profesiones, e impactando el panorama económico, académico y social del país gracias a la estrecha colaboración con todos los actores de la sociedad.

IBM anuncia el lanzamiento de IBM Cloud Private, una plataforma de software creada para los clientes que requieren la flexibilidad y capacidad de una nube pública en un ambiente privado. IBM Cloud Private transforma los sistemas de TI (Tecnologías de la Información) en un ambiente de nube flexible para crear un puente hasta las nubes públicas y acelerar el desarrollo de aplicativos.

The University of Canterbury (UC) is upgrading its centralised IT storage system with the IBM XIV and SONAS network attached storage arrays, to protect valuable research data and better meet user long term needs, while reducing operational costs.

Unitec today announced that the number of people employed in two Delivery Centres at its Mount Albert campus now exceeds 500, and continue to drive benefits for Unitec students and the Auckland economy.

Durante la conferencia mundial VMworld® 2016, VMware e IBM anunciaron la disponibilidad de los primeros servicios de nube para industrias que permiten a las organizaciones mover rápida y fácilmente, archivos a la nube. Con más de 500 clientes comprometidos ya, la alianza global entre IBM y VMware está ayudando a más organizaciones a extender sus archivos a la nube en horas, en comparación de semanas o meses.

CEMEX, S.A.B. de C.V. (BMV: CEMEXCPO), una de las compañías de materiales para la industria de la construcción líder en el mundo, e IBM (NYSE: IBM) anunciaron hoy que CEMEX llevará a cabo una importante transformación tecnológica diseñada para optimizar sus operaciones, mejorar notablemente la experiencia de sus clientes y aumentar la eficiencia del negocio.

IBM y Crown Holdings, Inc., proveedor global líder en productos de empaques metálicos, anunciaron hoy la firma de un contrato de varios años que incluye servicios de TI y servicios administrados corriendo en la robusta plataforma de cómputo en la nube de clase empresarial de IBM.

La empresa se afianza como líder de Proveedores Autorizados de Certificación (PAC) y logra procesar grandes volúmenes de transacciones de manera sencilla