Datsun’s Go as well as Go+ models have now received a CVT option. These come in the top trim and boast a slightly higher fuel efficiency compared to their manual counterparts or at par. How are they to drive? Take a look at our video.

A one-of-the-kind Russian website has enabled anyone to pay vocal tribute to the 75th anniversary of Nazi Germany’s defeat – by performing a beloved Russian Victory Day song with lyrics available in multiple languages.
Read Full Article at RT.com

Hot summer days may finally rid humanity of the Covid-19 scourge as the virus becomes almost non-infectious at air temperatures of over 30 degrees Celsius (86 degrees Fahrenheit), according to the Russian consumer watchdog.
Read Full Article at RT.com

  When developing an Android* application, you usually need to test, optimize, and debug on many different platforms. While basically every hardware and chip manufacturer provides a set of custom tools...

Assam has 'temporarily' shut down the Guwahati Medical College and Hospital (GMCH) - the biggest medical college of the northeast and the B Borooah Cancer Institute in Guwahati after four coronavirus...

When it comes to flagship chipsets for Android phones, Qualcomm is typically regarded as being the top contender with its 800-series processors. That being said, MediaTek has been playing an incredible catchup game as of late with the Dimensity 1000 in late 2019 which put it within a striking range of the new Snapdragon 865 ...

Once while eating dinner in Montreal, our friendly, intoxicated waitress plopped herself in my lap and proceeded to tell us about how obsessed she was with the CD that was playing - singing out the lyrics at an ungodly volume and flinging her arms about. Wow, I thought to myself, people who listen to Morcheeba sure seem to have a lot of fun, and promised to check them out.

Several CDs later, they are firmly one of my favorites. And their trip hop meditation, 2003’s Charango remains one of my most played CDs.

Morcheeba (Mor = more, Cheeba = pot) are brothers Ross and Paul Godfrey with singer Skye Edwards (who has since been replaced). Part trance, part ambience, Charango is full of smooth, snogworthy jams. And just as you surrender to its seductive groove, Slick Rick shows up with a rap called “Women Lose Weight”.

Lamenting his wife putting on weight after having kids and stalled by his mistress who wants a clean break before she shacks up with him, he decides the easiest way out of it all is to kill the spouse. Considering different ways to do the deed, he finally rams his car into her Chevy over a long lunch break one fine day. It is an unexpected, stunning, tongue-in-cheek social commentary that makes it a CD you won’t forget easily.

Rave Out © 2007 IndiaUncut.com. All rights reserved.
India Uncut * The IU Blog * Rave Out * Extrowords * Workoutable * Linkastic

In 1985, as a relatively new editor at Computer Design magazine, I was asked to go forth and cover a new business called CAE (computer-aided engineering). I knew nothing about it, but I had been writing about design for test, so there seemed to be somewhat of a connection. Little did I know that “CAE” would turn into “EDA” and that I’d write about it for the next 30 years, for Computer Design, EE Times, Cadence, and a few others.

Now that I’m about to retire, I’m looking back over those 30 years. What a ride it has been! By the numbers I covered 31 Design Automation Conferences (DACs), hundreds of new products, dozens of acquisitions and startups, dozens of lawsuits, and some blind alleys that didn’t work out (like “silicon compilation”). Chip design went from gate arrays and PLDs with a few thousand gates to processors and SoCs with billions of transistors.

In 1985 there were three big CAE vendors – Daisy Systems, Mentor Graphics, and Valid Logic. All sold bundled packages that included workstations and CAE software; in fact, Daisy and Valid designed and manufactured their own workstations. In the early 1980s a workstation with schematic capture and gate-level logic simulation might have set you back $120,000. In 1985 OrCAD, now part of Cadence, came out with a $500 schematic capture package running on IBM PCs.

Cadence and Synopsys emerged in the late 1980s, and by the 1990s the EDA industry was pretty much a software-only business (apart from specialized machines like simulation accelerators). Since the early 1990s the “big three” EDA vendors have been Cadence, Synopsys, and Mentor, giving the industry stability but allowing for competition and innovation.

Here, in my view, are some of the highlights that occurred during the past 30 years of EDA.

EDA is a Highlight

The biggest highlight in EDA is the existence of a commercial EDA industry! Marching hand in hand with the fabless semiconductor revolution, commercial EDA made it possible for hundreds of companies to design semiconductors, as opposed to a small handful that could afford large internal CAD operations and fabs. With hundreds of semiconductor companies as opposed to a half-dozen, there’s a lot more creativity, and you get the level of sophistication and intelligence that you see in your smartphone, video camera, tablet, gaming console, and car today.

CAE + CAD = EDA. This is not just a terminology issue. By the mid-1980s it became clear that front-end design (CAE) and physical design (CAD) belonged together. The big CAE vendors got involved in IC and PCB CAD, and presented increasingly integrated solutions. People got tired of writing “CAE/CAD” and “EDA” was born.

The move from gate-level design to RTL. This move happened around 1990, and in my view this is EDA’s primary technology success story during the past 30 years. Moving up in abstraction made the design and verification of much larger chips possible. Going from gate-level schematics to a hardware description language (HDL) revolutionized logic design and verification. Which would you rather do – draw all the gates that form an adder, or write a few lines of code and let a synthesis tool find an adder in your chosen technology?

Two developments made this shift in design possible. One was the emergence of commercial RTL synthesis (or “logic synthesis”) tools from Synopsys and other companies, which happened around 1990. Another was the availability of Verilog, developed by Gateway Design Automation and purchased by Cadence in 1989, as a standard RTL HDL. Although most EDA vendors at the time were pushing VHDL, designers wanted Verilog and that’s what most still use (with SystemVerilog coming on strong in the verification space).

IC functional verification underwent huge changes in the late 1990s and early 2000s, largely due to new technology developed by Verisity, which was acquired by Cadence in 2005. Before Verisity, verification engineers were writing and running directed tests in an ad-hoc manner. Verisity introduced or improved technologies such as pseudo-random test generation, coverage metrics, reusable verification IP, and semi-automated verification planning. The Verisity “e” language became a widely used hardware verification language (HVL).

The biggest way that EDA has expanded its focus has been through semiconductor IP. Today Synopsys and Cadence are leading providers in this area. Thanks to the availability of design and verification IP, many SoC designs today reuse as much as 80% of previous content. This makes it much, much faster to design the remaining portion. While IP began with fairly simple elements, today commercially available IP can include whole subsystems along with the software that runs on them. With IP, EDA vendors are providing not only design tools but design content.

Finally, the EDA industry has done an amazing job of keeping up with SoC complexity and with advanced process nodes. Thanks to intense and early collaboration between foundries, IP, and EDA providers, tools and IP have been ready for process nodes going down to 10nm.

Where Does ESL Fit?

In some ways, electronic system level (ESL) design is both a lowlight and a highlight. It’s a lowlight because people have been talking about it for 30 years and the acceptance and adoption have come very slowly. ESL is a highlight because it’s finally starting to happen, and its impact on design and verification flows could be dramatic. Still, ESL is vaguely defined and can be used to describe almost anything that happens at a higher abstraction level than RTL.

High-level synthesis (HLS) is an ESL technology that is seeing increasing use in production environments. Current HLS tools are not restricted to datapaths, and they produce RTL code that gives better quality of results than hand-written RTL. Another ESL methodology that’s catching on is virtual prototyping, which lets software developers write software pre-silicon using SystemC models. Both HLS and virtual prototyping are made possible by the standardization of SystemC and transaction-level modeling (TLM). However, it’s still not easy to use the same SystemC code for HLS and virtual prototyping.

And Now, Some Lowlights

Every new industry has some twists and turns, and EDA is no exception. For example, the EDA industry in the 1980s and 1990s sparked a lot of lawsuits. At EE Times my colleagues and I wrote a number of articles about EDA legal disputes, mostly about intellectual property, trade secrets, or patent issues. Over the past decade, fortunately, there have been far fewer EDA lawsuits than we had before the turn of the century.

Another issue that was troublesome in the 1980s and 1990s was so-called “standards wars.” These would occur as EDA vendors picked one side or the other in a standards dispute. For example, power intent formats were a point of conflict in the early 2000s, but the Common Power Format (CPF) and the Unified Power Format (UPF) are on the road to convergence today with the IEEE 1801 effort. As mentioned previously, Verilog and VHDL were competing for adoption in the early 1990s. For the most part, Verilog won, showing that the designer community makes the final decision about which standards will be used.

How on earth did there get to be something like 30 DFM (design for manufacturability) companies 10-12 years ago? To my knowledge, none of these companies are around today. A few were acquired, but most simply faded away. A lot of investors lost money. Today, VCs and angel investors are funding very few EDA or IP startups. There are fewer EDA startups than there used to be, and that’s too bad, because that’s where a lot of the innovation comes from.

Here’s another current lowlight -- not enough bright engineering or computer science students are joining EDA companies. They’re going to Google, Apple, Facebook, and the like. EDA is perceived as a mature industry that is still technically very difficult. We need to bring some excitement back into EDA.

Where Is EDA Headed?

Now we come to what you might call “headlights” and look at what’s coming. My list includes:

• System Design Enablement. This term has been coined by Cadence to describe a focus on whole systems or end products including chips, packages, boards, embedded software, and mechanical components. There are far more systems companies than semiconductor companies, leaving a large untapped market that’s looking for solutions.
• New frontiers for EDA. At a 2015 Design Automation Conference speech, analyst Gary Smith suggested that EDA can move into markets such as embedded software, mechanical CAD, biomedical, optics, and more.
• Vertical markets. EDA has until now been “horizontal,” providing the same solution for all market segments. Going forward, markets like consumer, automotive, and industrial will have differing needs and will need optimized tools and IP.
• Internet of Things. This is a current buzzword, but the impact on EDA remains uncertain. Many IoT devices will be heavily analog, use mature process nodes, and be dirt cheap. Lip-Bu Tan, Cadence CEO, recently pointed out that the silicon percentage of IoT revenue will be small and that a lot of the profits will be on the service side.

Moving On

For the past six years I’ve been writing the Industry Insights blog at Cadence.com. All things change, and with this post comes a farewell – I am retiring in late June and will be pursuing a variety of interests other than EDA. I’ll be watching, though, to see what happens next in this small but vital industry. Thanks for reading!

Richard Goering

Hello,

I would like to simulate the PSSR+/PSSR- and the CMMR using xf for the attached test bench.

Normally, I do the AC analysis and using the post-processing capability of cadence spectre I do 20log(vdd/vout) for PSSR+

and 20*log(vss/vout) for PSSR-. 

looked online from an old post that I do:

PSRR-
db20(1/DATA("/Vn/PLUS" "xf-xf"))

PSRR+
db20(1/DATA("/Vp/MINUS" "xf-xf"))

How about the for the CMRR?

Thanks a lot in advance.  

Botan is a C++ library of cryptographic algorithms, including AES, DES, SHA-1, RSA, DSA, Diffie-Hellman, and many others. It also supports X.509 certificates and CRLs, and PKCS #10 certificate requests, and has a high level filter/pipe message processing system. The library is easily portable to most systems and compilers, and includes a substantial tutorial and API reference. This is the current stable release.

Botan is a C++ library of cryptographic algorithms, including AES, DES, SHA-1, RSA, DSA, Diffie-Hellman, and many others. It also supports X.509 certificates and CRLs, and PKCS #10 certificate requests, and has a high level filter/pipe message processing system. The library is easily portable to most systems and compilers, and includes a substantial tutorial and API reference. This is the current stable release.

Botan is a C++ library of cryptographic algorithms, including AES, DES, SHA-1, RSA, DSA, Diffie-Hellman, and many others. It also supports X.509 certificates and CRLs, and PKCS #10 certificate requests, and has a high level filter/pipe message processing system. The library is easily portable to most systems and compilers, and includes a substantial tutorial and API reference. This is the current stable release.

Botan is a C++ library of cryptographic algorithms, including AES, DES, SHA-1, RSA, DSA, Diffie-Hellman, and many others. It also supports X.509 certificates and CRLs, and PKCS #10 certificate requests, and has a high level filter/pipe message processing system. The library is easily portable to most systems and compilers, and includes a substantial tutorial and API reference. This is the current stable release.

Botan is a C++ library of cryptographic algorithms, including AES, DES, SHA-1, RSA, DSA, Diffie-Hellman, and many others. It also supports X.509 certificates and CRLs, and PKCS #10 certificate requests, and has a high level filter/pipe message processing system. The library is easily portable to most systems and compilers, and includes a substantial tutorial and API reference. This is the current stable release.

Managed DSLS Service will be upgraded on Feb, 29th (starting Saturday Feb, 29th 2020 - 3AM - UTC+1)

47 bytes small Linux/x86 (NOT|ROT+8 Encoded) execve(/bin/sh) null free shellcode.

114 bytes small Linux/x86 random bytes encoder and XOR/SUB/NOT/ROR execve(/bin/sh) shellcode.

155 bytes small Linux/x86 shellcode that has a MMX stub decoder that dynamically decodes the payload in memory. The FPU GetPC technique is used to determine the offset from EIP dynamically in running memory. Once decoded. this shellcode adds the user 'ctl' with the password 'ctl' to the /etc/passwd file with the UID and GID of 0 (root). This shellcode uses legacy passwd functionality. Therefore the /etc/shadow file does not need to be accessed or modified.

Netis E1+ version 1.2.32533 suffers from having a hardcoded backdoor root account.

Linux futex+VFS suffers from an improper inode reference in get_futex_key() that causes a use-after-free if the superblock goes away.

NSClient++ version 0.5.2.35 suffers from an authenticated remote code execution vulnerability.

Netis E1+ version 1.2.32533 suffers from an unauthenticated wifi password disclosure vulnerability.

The FLIR Brickstream 3D+ sensor is vulnerable to unauthenticated config download and file disclosure vulnerability when calling the ExportConfig REST API (getConfigExportFile.cgi). This will enable the attacker to disclose sensitive information and help her in authentication bypass, privilege escalation and/or full system access.

devolo dLAN 550 duo+ version 3.1.0-1 suffers from a remote code execution vulnerability. The devolo firmware has what seems to be a 'hidden' services which can be enabled by authenticated attacker via the the htmlmgr CGI script. This allows the attacker to start services that are deprecated or discontinued and achieve remote arbitrary code execution with root privileges.

On July 1, Public Service of New Mexico filed a plan with regulators in the state for how it plans to get to a 100 percent emission-free power by 2040. The utility reviewed four scenarios, all of which involved the early retirement of the San Juan Coal Plant, to arrive at its recommended path forward.

After announcing nearly a gigawatt of new clean-energy projects in February, APS is now seeking proposals to build two of them in different parts of the state. The first request for proposals (RFP) seeks partners to add batteries to existing APS solar plants in rural Arizona, storing their power for use after the panels stop producing each day. A second partner is being sought to develop a large (100-MW) solar plant paired with an equal amount of storage, to bring more clean energy to customers after dark. Both of these projects will provide APS customers with more solar after sunset, serving their evening energy needs with an even cleaner resource mix.

On July 1, Public Service of New Mexico filed a plan with regulators in the state for how it plans to get to a 100 percent emission-free power by 2040. The utility reviewed four scenarios, all of which involved the early retirement of the San Juan Coal Plant, to arrive at its recommended path forward.

Last week, Sunrun announced that its bid to supply 20 MW of residential solar + storage capacity into the New England ISO Forward Capacity Market for 2022-2023 was approved. According to Chris Rauscher, Director of Policy and Storage Market Strategy for Sunrun, this is not a pilot project or an experiment in any way.

After announcing nearly a gigawatt of new clean-energy projects in February, APS is now seeking proposals to build two of them in different parts of the state. The first request for proposals (RFP) seeks partners to add batteries to existing APS solar plants in rural Arizona, storing their power for use after the panels stop producing each day. A second partner is being sought to develop a large (100-MW) solar plant paired with an equal amount of storage, to bring more clean energy to customers after dark. Both of these projects will provide APS customers with more solar after sunset, serving their evening energy needs with an even cleaner resource mix.

This week, Duke Energy announced that regulators have approved two projects involving energy storage worth about $30 million.

On July 1, Public Service of New Mexico filed a plan with regulators in the state for how it plans to get to a 100 percent emission-free power by 2040. The utility reviewed four scenarios, all of which involved the early retirement of the San Juan Coal Plant, to arrive at its recommended path forward.

On July 1, Public Service of New Mexico filed a plan with regulators in the state for how it plans to get to a 100 percent emission-free power by 2040. The utility reviewed four scenarios, all of which involved the early retirement of the San Juan Coal Plant, to arrive at its recommended path forward.

ABSTRACT

Arthritogenic alphaviruses such as Ross River and Chikungunya viruses cause debilitating muscle and joint pain and pose significant challenges in the light of recent outbreaks. How host immune responses are orchestrated after alphaviral infections and lead to musculoskeletal inflammation remains poorly understood. Here, we show that myositis induced by Ross River virus (RRV) infection is driven by CD11b^hi Ly6C^hi inflammatory monocytes and followed by the establishment of a CD11b^hi Ly6C^lo CX₃CR1⁺ macrophage population in the muscle upon recovery. Selective modulation of CD11b^hi Ly6C^hi monocyte migration to infected muscle using immune-modifying microparticles (IMP) reduced disease score, tissue damage, and inflammation and promoted the accumulation of CX₃CR1⁺ macrophages, enhancing recovery and resolution. Here, we detail the role of immune pathology, describing a poorly characterized muscle macrophage subset as part of the dynamics of alphavirus-induced myositis and tissue recovery and identify IMP as an effective immunomodulatory approach. Given the lack of specific treatments available for alphavirus-induced pathologies, this study highlights a therapeutic potential for simple immune modulation by IMP in infected individuals in the event of large alphavirus outbreaks.

IMPORTANCE Arthritogenic alphaviruses cause debilitating inflammatory disease, and current therapies are restricted to palliative approaches. Here, we show that following monocyte-driven muscle inflammation, tissue recovery is associated with the accumulation of CX₃CR1⁺ macrophages in the muscle. Modulating inflammatory monocyte infiltration using immune-modifying microparticles (IMP) reduced tissue damage and inflammation and enhanced the formation of tissue repair-associated CX₃CR1⁺ macrophages in the muscle. This shows that modulating key effectors of viral inflammation using microparticles can alter the outcome of disease by facilitating the accumulation of macrophage subsets associated with tissue repair.

ABSTRACT

The posttranslational Ca²⁺-dependent "clip-and-link" activity of large repeat-in-toxin (RTX) proteins starts by Ca²⁺-dependent structural rearrangement of a highly conserved self-processing module (SPM). Subsequently, an internal aspartate-proline (Asp-Pro) peptide bond at the N-terminal end of SPM breaks, and the liberated C-terminal aspartyl residue can react with a free -amino group of an adjacent lysine residue to form a new isopeptide bond. Here, we report a solution structure of the calcium-loaded SPM (Ca-SPM) derived from the FrpC protein of Neisseria meningitidis. The Ca-SPM structure defines a unique protein architecture and provides structural insight into the autocatalytic cleavage of the Asp-Pro peptide bond through a "twisted-amide" activation. Furthermore, in-frame deletion of the SPM domain from the ApxIVA protein of Actinobacillus pleuropneumoniae attenuated the virulence of this porcine pathogen in a pig respiratory challenge model. We hypothesize that the Ca²⁺-dependent clip-and-link activity represents an unconventional strategy for Gram-negative pathogens to adhere to the host target cell surface.

IMPORTANCE The Ca²⁺-dependent clip-and-link activity of large repeat-in-toxin (RTX) proteins is an exceptional posttranslational process in which an internal domain called a self-processing module (SPM) mediates Ca²⁺-dependent processing of a highly specific aspartate-proline (Asp-Pro) peptide bond and covalent linkage of the released aspartyl to an adjacent lysine residue through an isopeptide bond. Here, we report the solution structures of the Ca²⁺-loaded SPM (Ca-SPM) defining the mechanism of the autocatalytic cleavage of the Asp414-Pro415 peptide bond of the Neisseria meningitidis FrpC exoprotein. Moreover, deletion of the SPM domain in the ApxIVA protein, the FrpC homolog of Actinobacillus pleuropneumoniae, resulted in attenuation of virulence of the bacterium in a pig infection model, indicating that the Ca²⁺-dependent clip-and-link activity plays a role in the virulence of Gram-negative pathogens.

ABSTRACT

Reversible repression of HIV-1 5' long terminal repeat (5'-LTR)-mediated transcription represents the main mechanism for HIV-1 to maintain latency. Identification of host factors that modulate LTR activity and viral latency may help develop new antiretroviral therapies. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are known to regulate gene expression and possess multiple physiological functions. hnRNP family members have recently been identified as the sensors for viral nucleic acids to induce antiviral responses, highlighting the crucial roles of hnRNPs in regulating viral infection. A member of the hnRNP family, X-linked RNA-binding motif protein (RBMX), has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5'-LTR-driven transcription of viral genome in CD4⁺ T cells. Mechanistically, RBMX binds to HIV-1 proviral DNA at the LTR downstream region and maintains the repressive trimethylation of histone H3 lysine 9 (H3K9me3), leading to a blockage of the recruitment of the positive transcription factor phosphorylated RNA polymerase II (RNA pol II) and consequential impediment of transcription elongation. This RBMX-mediated modulation of HIV-1 transcription maintains viral latency by inhibiting viral reactivation from an integrated proviral DNA. Our findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

IMPORTANCE HIV-1 latency featuring silence of transcription from HIV-1 proviral DNA represents a major obstacle for HIV-1 eradication. Reversible repression of HIV-1 5'-LTR-mediated transcription represents the main mechanism for HIV-1 to maintain latency. The 5'-LTR-driven HIV gene transcription can be modulated by multiple host factors and mechanisms. The hnRNPs are known to regulate gene expression. A member of the hnRNP family, RBMX, has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5'-LTR-driven transcription of viral genome in CD4⁺ T cells and maintains viral latency. These findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

ABSTRACT

Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4⁺ T cells (CD4) and macrophages (Ms) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4⁺ memory T cells (Br-mCD4), brain-Ms (Br-Ms), and brain B cells (Br-B cells). Both Br-mCD4s and Br-Ms harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-Ms. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain.

IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4⁺ T cells harbor replication-competent SIV DNA; however, only brain CD4⁺ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.

Key Points

Key Points

Key Points

Brucella spp. are facultative intracellular bacteria notorious for their ability to induce a chronic, and often lifelong, infection known as brucellosis. To date, no licensed vaccine exists for prevention of human disease, and mechanisms underlying chronic illness and immune evasion remain elusive. We and others have observed that B cell-deficient mice challenged with Brucella display reduced bacterial burden following infection, but the underlying mechanism has not been clearly defined. Here, we show that at 1 month postinfection, B cell deficiency alone enhanced resistance to splenic infection ~100-fold; however, combined B and T cell deficiency did not impact bacterial burden, indicating that B cells only enhance susceptibility to infection when T cells are present. Therefore, we investigated whether B cells inhibit T cell-mediated protection against Brucella. Using B and T cell-deficient Rag1^–/– animals as recipients, we demonstrate that adoptive transfer of CD4⁺ T cells alone confers marked protection against Brucella melitensis that is abrogated by cotransfer of B cells. Interestingly, depletion of CD4⁺ T cells from B cell-deficient, but not wild-type, mice enhanced susceptibility to infection, further confirming that CD4⁺ T cell-mediated immunity against Brucella is inhibited by B cells. In addition, we found that the ability of B cells to suppress CD4⁺ T cell-mediated immunity and modulate CD4⁺ T cell effector responses during infection was major histocompatibility complex class II (MHCII)-dependent. Collectively, these findings indicate that B cells modulate CD4⁺ T cell function through an MHCII-dependent mechanism which enhances susceptibility to Brucella infection.

High magnetic fields have revealed a surprisingly small Fermi surface in underdoped cuprates, possibly resulting from Fermi-surface reconstruction due to an order parameter that breaks translational symmetry of the crystal lattice. A crucial issue concerns the doping extent of such a state and its relationship to the principal pseudogap and...

Dynamic regulation of the mitochondrial network by mitofusins (MFNs) modulates energy production, cell survival, and many intracellular signaling events, including calcium handling. However, the relative importance of specific mitochondrial functions and their dependence on MFNs vary greatly among cell types. Osteoclasts have many mitochondria, and increased mitochondrial biogenesis and oxidative phosphorylation enhance bone resorption, but little is known about the mitochondrial network or MFNs in osteoclasts. Because expression of each MFN isoform increases with osteoclastogenesis, we conditionally deleted MFN1 and MFN2 (double conditional KO (dcKO)) in murine osteoclast precursors, finding that this increased bone mass in young female mice and abolished osteoclast precursor differentiation into mature osteoclasts in vitro. Defective osteoclastogenesis was reversed by overexpression of MFN2 but not MFN1; therefore, we generated mice lacking only MFN2 in osteoclasts. MFN2-deficient female mice had increased bone mass at 1 year and resistance to Receptor Activator of NF-κB Ligand (RANKL)-induced osteolysis at 8 weeks. To explore whether MFN-mediated tethering or mitophagy is important for osteoclastogenesis, we overexpressed MFN2 variants defective in either function in dcKO precursors and found that, although mitophagy was dispensable for differentiation, tethering was required. Because the master osteoclastogenic transcriptional regulator nuclear factor of activated T cells 1 (NFATc1) is calcium-regulated, we assessed calcium release from the endoplasmic reticulum and store-operated calcium entry and found that the latter was blunted in dcKO cells. Restored osteoclast differentiation by expression of intact MFN2 or the mitophagy-defective variant was associated with normalization of store-operated calcium entry and NFATc1 levels, indicating that MFN2 controls mitochondrion–endoplasmic reticulum tethering in osteoclasts.

As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3⁺ Treg-cell expansion in the spleen of wild-type mice but not in Gitr^–/– mice. G3C/cps also induced the expansion of nonconventional Cd4⁺Cd25^–/lowFoxp3^lowGitr^int/high (GITR single-positive [sp]) Tregs. Both Cd4⁺Cd25⁺Gitr^highFoxp3⁺ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.