A program for one-time assistance to undocumented workers affected by the pandemic is a start, but California must do much more.

THE QUEEN addressed the nation as part of VE Day celebrations today, and Her Majesty wore her Aquamarine Clip Brooches, making a sweet nod to her father, who gave her the jewellery.

strataconf: Humans as nodes, pills & electronic tattoo password authenticators & hiding data in temporal cloaks http://t.co/vRgkRtTTKe #strataconf

Node.js is used by many companies for building performant backend services without sacrificing developer efficiency. In this hands-on guide, author Thomas Hunter II proves that Node.js is just as capable as traditional enterprise platforms for building services that are observable, scalable, and resilient. Intermediate to advanced Node.js developers will find themselves integrating application code with a breadth of tooling from each layer of a modern service stack.

Luis Spencer Freitas, digital marketing director at Pernod Ricard USA, explains what will drive greater innovation in display advertising next year.

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.

Introduction: The aim of this study was to analyze patterns of persistent versus recurrent or new PET lesions in a selected patient cohort with PSA persistence following salvage lymph node dissection (SLND) and pre/post procedure prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET). Material and Methods: 16 patients were included in this multicenter study. Inclusion criteria were: a) PSMA-PET performed for biochemical recurrence before SLND (pre-SLND PET) and b) repeat PSMA-PET performed for persistently elevated PSA level (≥0.1 ng/mL) ≥6 weeks after SLND (post-SLND PET). Image analysis was performed by three independent nuclear medicine physicians applying the molecular imaging TNM system PROMISE. Lesions were confirmed by histopathology, presence on correlative CT/MRI/bone scan or PSA response after focal therapy. Results: post-SLND PET identified PCa-lesions in 88% (14/16) of patients with PSA persistence after SLND. Median PSA was 1.2 ng/mL (IQR, 0.6-2.8 ng/mL). Disease was confined to the pelvis in 56% of patients (9/16) and most of these men had common iliac (6/16, 38%) and internal iliac lymph node metastases (6/16, 38%). Extrapelvic disease was detected in 31% of patients (5/16). In pre- and post-SLND PET comparison, 10/16 had at least one lesion already detected at baseline (63% PET persistence); 4/16 had new lesions only (25% PET recurrence); 2 had no disease on post-SLND PET. All validated regions (11 regions in 9 patients) were true positive. 9/14 (64%) patients underwent repeat local therapies after SLND (7/14 radiotherapy, 2/14 surgery). Conclusion: SLND of pelvic nodal metastases was often not complete according to PSMA-PET. About two thirds of patients had PET positive nodal disease after SLND already seen on pre-SLND PSMA-PET. Notably, about one quarter of patients had new lesions, not detected by pre-surgical PSMA-PET.

Introduction: To use positron emission tomography coupled with computed tomography (¹⁸FDG-PET/CT) to identify a high-risk subgroup requiring therapeutic intensification among patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) involvement. Methods: In this retrospective multicentric study, patients with LACC and PALN involvement concurrently treated with chemoradiotherapy and extended-field radiotherapy (EFR) between 2006 and 2016 were included. A senior nuclear medicine specialist in PET for gynaecologic oncology reviewed all ¹⁸FDG-PET/CT scans. Metabolic parameters including maximum standardised uptake value (SUV_max), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were determined for the primary tumour, pelvic lymph nodes and PALN. Associations between these parameters and overall survival (OS) were assessed with Cox's proportional hazards model. Results: Sixty-eight patients were enrolled in the study. Three-year OS was 55.5% (95% CI (40.8-68.0)). When adjusted for age, stage and histology, pelvic lymph node TLG, PALN TLG and PALN SUV_max were significantly associated with OS (p<0.005). Conclusion: FDG-PET/CT was able to identify predictors of survival in the homogeneous subgroup of patients with LACC and PALN involvement, thus allowing therapeutic intensification to be proposed.

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.

Our objective was to determine the diagnostic capabilities of combined prostate-specific membrane antigen (PSMA) PET/CT and sentinel node (SN) biopsy in PSMA PET/CT–negative patients for primary lymph node (LN) staging in prostate cancer (PCa) patients. Methods: Between January 2017 and March 2019, retrospectively, all consecutive patients with diagnosed intermediate- or high-risk primary PCa who underwent preoperative PSMA PET/CT (⁶⁸Ga or ¹⁸F-DCFPyL) followed by robot-assisted radical prostatectomy and extended pelvic LN dissection (ePLND) were included. All patients without suspected LN metastases on PSMA PET/CT were considered candidates for SN biopsy with indocyanine green–^99mTc-nanocolloid or ^99mTc-nanocolloid with free indocyanine green used as tracers. The ePLND was used as a reference standard. Results: Of 53 patients, 22 had positive PSMA PET/CT results and 31 underwent subsequent SN biopsy after negative PSMA PET/CT results. In total, 23 patients (43%) were pN1, of whom 6 (26%) had negative PSMA PET/CT results and underwent subsequent SN biopsy. The combined use of SN biopsy and PSMA PET/CT identified all pN1 patients (100% sensitivity; 95% confidence interval, 86%–100%) and performed correct nodal staging in 50 of 53 patients (94% diagnostic accuracy; 95% confidence interval, 84%–99%). SN biopsy identified significantly smaller LN metastases (median diameter, 2.0 mm; interquartile range, 1.0–3.8 mm) than PSMA PET/CT (median diameter, 5.5 mm; interquartile range, 2.6–9.3 mm; P = 0.007). Conclusion: Combining both modalities led to a 94% accuracy for nodal staging in diagnosed intermediate- and high-risk primary PCa. Adding SN biopsy in patients with negative PSMA PET/CT results increased the combined sensitivity to 100% for detecting nodal metastases at ePLND. This diagnostic accuracy may provide valuable information for directing further treatment in PCa patients, such as the use of PSMA PET/CT and SN biopsy rather than ePLND as the preferred approach for staging before radiotherapy.

The international group SNOMED International honored ADA member dentist Dr. Mark Jurkovich with the Award of Excellence for spearheading the important work the ADA has done on SNODENT, the group announced Jan. 16.

The American Dental Association is seeking qualified individuals to join a canvass committee to consider approval of the 2020 revision of the Systemized Nomenclature of Dentistry.

Accountability is in the air in Washington. At one end of Pennsylvania Avenue, Paul Wolfowitz is struggling to save his job as president of the World Bank after getting caught arranging a sweetheart deal for his, well, sweetheart. A few blocks down the road, President Bush faces endless questions...

We consider the skill rating problem for multiplayer games, that is how to infer player skills from game outcomes in multiplayer games. We formulate the problem as a minimization problem $arg min_{s} s^T Delta s$ where $Delta$ is a positive semidefinite matrix and $s$ a real-valued function, of which some entries are the skill values to be inferred and other entries are constrained by the game outcomes. We leverage graph-based semi-supervised learning (SSL) algorithms for this problem. We apply our algorithms on several data sets of multiplayer games and obtain very promising results compared to Elo Duelling (see Elo, 1978) and TrueSkill (see Herbrich et al., 2006).. As we leverage graph-based SSL algorithms and because games can be seen as relations between sets of players, we then generalize the approach. For this aim, we introduce a new finite model, called hypernode graph, defined to be a set of weighted binary relations between sets of nodes. We define Laplacians of hypernode graphs. Then, we show that the skill rating problem for multiplayer games can be formulated as $arg min_{s} s^T Delta s$ where $Delta$ is the Laplacian of a hypernode graph constructed from a set of games. From a fundamental perspective, we show that hypernode graph Laplacians are symmetric positive semidefinite matrices with constant functions in their null space. We show that problems on hypernode graphs can not be solved with graph constructions and graph kernels. We relate hypernode graphs to signed graphs showing that positive relations between groups can lead to negative relations between individuals.

The paper focuses on a novel approach for false-positive reduction (FPR) of nodule candidates in Computer-aided detection (CADe) system after suspicious lesions proposing stage. Unlike common decisions in medical image analysis, the proposed approach considers input data not as 2d or 3d image, but as a point cloud and uses deep learning models for point clouds. We found out that models for point clouds require less memory and are faster on both training and inference than traditional CNN 3D, achieves better performance and does not impose restrictions on the size of the input image, thereby the size of the nodule candidate. We propose an algorithm for transforming 3d CT scan data to point cloud. In some cases, the volume of the nodule candidate can be much smaller than the surrounding context, for example, in the case of subpleural localization of the nodule. Therefore, we developed an algorithm for sampling points from a point cloud constructed from a 3D image of the candidate region. The algorithm guarantees to capture both context and candidate information as part of the point cloud of the nodule candidate. An experiment with creating a dataset from an open LIDC-IDRI database for a feature of the FPR task was accurately designed, set up and described in detail. The data augmentation technique was applied to avoid overfitting and as an upsampling method. Experiments are conducted with PointNet, PointNet++ and DGCNN. We show that the proposed approach outperforms baseline CNN 3D models and demonstrates 85.98 FROC versus 77.26 FROC for baseline models.

A competition-record crowd of 32,510 watched Krasnodar take Real Madrid to penalties in their UEFA Youth League play-off, the Spanish side eventually winning 3-0 on spot-kicks.

"A natural-born striker" according to his coach at Krasnodar, ex-USSR star Igor Shalimov, Ivan Ignatyev is top scorer in this season's UEFA Youth League.

The kit 'DiAGSure nCOV-19 Detection Assay' can meet the growing demand for testing equipment across the country to a certain extent.

Deferasirox binds to iron and removes it from the bloodstream. It is used to treat iron overload caused by blood transfusions in adults and children who are at least two years old.

We are into consulting on non-banking financial services. The candidate must have strong drafting skills for business agreements involving complicated financial transactions. Very strong understanding of the law of secured lending - mortgages, assignment, transfer of security interests, pledges, NBFC regulations, etc - will be essentialNo phone calls please. Only emails.

  In this article I will be demonstrating how to create a basic Node.js application using Intel Mashery's JamBase API with Intel Edison and XDK. You will find accompanying GitHub source in the provi...

Jagdishan and Bharucha are the internal candidates and have been serving the bank for many years each, while Garg is working with American bank Citi at present.

The CSIR has already tied up with Cadila Pharmaceuticals Ltd to evaluate Mycobacterium W (Mw) for faster recovery of hospitalised COVID-19 patients and minimise the spread of disease.

Test chips are becoming more widespread and more complex at advanced process nodes as design teams utilize early silicon to diagnose problems prior to production. But this approach also is spurring questions about whether this approach is viable at 7nm and 5nm, due to the rising cost of prototyping advanced technology, such as mask tooling and wafer costs.

Semiconductor designers have long been making test chips to validate test structures, memory bit cells, larger memory blocks, and precision analog circuits like current mirrors, PLLs, temperature sensors, and high-speed I/Os. This has been done at 90nm, 65nm, 40nm, 32nm, 28nm, etc., so having test chips at 16nm, 7nm, or finer geometries should not be a surprise. Still, as costs rise, there is debate about whether those chips are over-used given advancements in tooling, or whether they should be utilized even more, with more advanced diagnostics built into them.

Modern EDA tools are very good. You can simulate and validate almost anything with certain degree of accuracy and correctness. The key to having good and accurate tools and accurate results (for simulation) is the quality of the foundry data provided. The key to having good designs (layouts) is that the DRC deck must be of high quality and accurate and must catch all the things you are not supposed to do in the layout. Most of the challenges in advanced node is in the FEOL where semiconductor physics and lithography play outsize roles. Issues that were not an issue at more mature nodes can manifest themselves as big problems at 7nm or 5nm. Process variation across the wafer and variation across a large die also present problems that were of no consequence in more mature nodes.

The real questions to be asked are as follows:

What is the role of test chips in SoC designs?

1. Do all hard IP require test chips for validation?
2. Are test chips more important at advanced nodes compared to more mature nodes?
3. Is the importance of test chip validation relative to the type of IP protocols?
4. What are the risks if I do not validate in silicon?

In complex SoC designs, there are many high-performance protocols such as LPDDR4/4x PHY, PCIe4 PHY, USB3.0 PHY, 56G/112G SerDes, etc. Each one of these IP are very complex in and by itself. If there is any chance of failure that is not detected prior to SoC (tapeout) integration, the cost of retrofit is huge. This is why the common practice is to validate each one of these complex IP in silicon before committing to use such IP in chip integration. The test chips are used to validate that the IP are properly designed and meet the functional specifications of the protocols. They are also used to validate if sufficient margins are designed into the IP to mitigate variances due to process tolerances. All high-performance hard IP go through this test chip/silicon validation process. Oftentimes, marginality is detected at this stage. In advanced nodes, it is also important to have the test chips built under different process corners. This is intended to simulate process variations in production wafers so as to maximize yields. Advanced protocols such as 112G, GDDR6, HBM2, and PCIe4 are incredibly complex and sensitive to process variations. It is almost impossible to design these circuits and try to guarantee their performance without going through the test chip route.

Besides validating performance of the IP protocols, test silicon is also used to validate robustness of ESD structures, sensitivity to latch up, and performance degradation over wide temperature ranges. All these items are more critical in advanced nodes than more mature modes. Test chips are vehicles to guarantee design integrity in bite-size chunks. It is better to deal with any potential issues in smaller blocks than to try to fix them in the final integrated SoC.

Test chips will continue to play a vital role in helping IP and SoC teams lower the risk of their designs, and assuring optimal quality and performance in the foreseeable future. They are not going away!

To read more, please visit https://semiengineering.com/test-chips-play-larger-role-at-advanced-nodes/

Howdy,

            In the netlist generated after parasitic extraction, nodes have been added at fracture points to add parasitic devices. For example, in the image below, I'm referring to the nodes IN#1 and IN#2. Is there a way to determine their co-ordinates relative to the layout co-ordinate system? I could not find them in the Skill command reference and when I query the parasitic elements in the extracted view, it gives the graphical pin locations of the elements rather than the physical.

Thanks

Audi

Case C-260/17, Anodiki Services EPE1: interpreting the scope of the “employment contracts” exemption under EU procurement legislation Introduction The judgment relates to a request for a preliminary ruling made by Greece’s Council ...

Title: Thyroid Nodules
Category: Diseases and Conditions
Created: 2/23/2005 12:00:00 AM
Last Editorial Review: 10/25/2019 12:00:00 AM

Title: Radiation May Equal Surgery, With Easier Recovery, for Cancerous Lymph Nodes
Category: Health News
Created: 4/30/2014 2:36:00 PM
Last Editorial Review: 5/1/2014 12:00:00 AM

Title: Human Immunodeficiency Virus (HIV)
Category: Diseases and Conditions
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 3/5/2020 12:00:00 AM

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.

ABSTRACT

Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K. pneumoniae, Escherichia coli, and Salmonella. TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa. In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniae. tmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning.

IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings—especially carbapenem-resistant K. pneumoniae. Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a "One Health" perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.

ABSTRACT

Many HIV prevention strategies are currently under consideration where it is highly informative to know the study participants’ times of infection. These can be estimated using viral sequence data sampled early in infection. However, there are several scenarios that, if not addressed, can skew timing estimates. These include multiple transmitted/founder (TF) viruses, APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)-mediated mutational enrichment, and recombination. Here, we suggest a pipeline to identify these problems and resolve the biases that they introduce. We then compare two modeling strategies to obtain timing estimates from sequence data. The first, Poisson Fitter (PF), is based on a Poisson model of random accumulation of mutations relative to the TF virus (or viruses) that established the infection. The second uses a coalescence-based phylogenetic strategy as implemented in BEAST. The comparison is based on timing predictions using plasma viral RNA (cDNA) sequence data from 28 simian-human immunodeficiency virus (SHIV)-infected animals for which the exact day of infection is known. In this particular setting, based on nucleotide sequences from samples obtained in early infection, the Poisson method yielded more accurate, more precise, and unbiased estimates for the time of infection than did the explored implementations of BEAST.

IMPORTANCE The inference of the time of infection is a critical parameter in testing the efficacy of clinical interventions in protecting against HIV-1 infection. For example, in clinical trials evaluating the efficacy of passively delivered antibodies (Abs) for preventing infections, accurate time of infection data are essential for discerning levels of the Abs required to confer protection, given the natural Ab decay rate in the human body. In such trials, genetic sequences from early in the infection are regularly sampled from study participants, generally prior to immune selection, when the viral population is still expanding and genetic diversity is low. In this particular setting of early viral growth, the Poisson method is superior to the alternative approach based on coalescent methods. This approach can also be applied in human vaccine trials, where accurate estimates of infection times help ascertain if vaccine-elicited immune protection wanes over time.

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.

Simian-human immunodeficiency virus (SHIV) infection of rhesus monkeys is an important preclinical model for human immunodeficiency virus type 1 (HIV-1) vaccines, therapeutics, and cure strategies. SHIVs have been optimized by incorporating HIV-1 Env residue 375 mutations that mimic the bulky or hydrophobic residues typically found in simian immunodeficiency virus (SIV) Env to improve rhesus CD4 binding. We applied this strategy to three SHIV challenge stocks (SHIV-SF162p3, SHIV-AE16, and SHIV-325c) and observed three distinct outcomes. We constructed six Env375 variants (M, H, W, Y, F, and S) for each SHIV, and we performed a pool competition study in rhesus monkeys to define the optimal variant for each SHIV prior to generating large-scale challenge stocks. We identified SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH as the optimal variants. SHIV-SF162p3S could not be improved, as it already contained the optimal Env375 residue. SHIV-AE16W exhibited a similar replicative capacity to the parental SHIV-AE16 stock. In contrast, SHIV-325cH demonstrated a 2.6-log higher peak and 1.6-log higher setpoint viral loads than the parental SHIV-325c stock. These data demonstrate the diversity of potential outcomes following Env375 modification in SHIVs. Moreover, the clade C SHIV-325cH challenge stock may prove useful for evaluating prophylactic or therapeutic interventions against clade C HIV-1.

IMPORTANCE We sought to enhance the infectivity of three SHIV stocks by optimization of a key residue in human immunodeficiency virus type 1 (HIV-1) Env (Env375). We developed the following three new simian-human immunodeficiency virus (SHIV) stocks: SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH. SHIV-SF162p3S could not be optimized, SHIV-AE16W proved comparable to the parental virus, and SHIV-325cH demonstrated markedly enhanced replicative capacity compared with the parental virus.

During human immunodeficiency virus type 1 (HIV-1) entry into cells, the viral envelope glycoprotein (Env) trimer [(gp120/gp41)₃] binds the receptors CD4 and CCR5 and fuses the viral and cell membranes. CD4 binding changes Env from a pretriggered (state-1) conformation to more open downstream conformations. BMS-378806 (here called BMS-806) blocks CD4-induced conformational changes in Env important for entry and is hypothesized to stabilize a state-1-like Env conformation, a key vaccine target. Here, we evaluated the effects of BMS-806 on the conformation of Env on the surface of cells and virus-like particles. BMS-806 strengthened the labile, noncovalent interaction of gp120 with the Env trimer, enhanced or maintained the binding of most broadly neutralizing antibodies, and decreased the binding of poorly neutralizing antibodies. Thus, in the presence of BMS-806, the cleaved Env on the surface of cells and virus-like particles exhibits an antigenic profile consistent with a state-1 conformation. We designed novel BMS-806 analogues that stabilized the Env conformation for several weeks after a single application. These long-acting BMS-806 analogues may facilitate enrichment of the metastable state-1 Env conformation for structural characterization and presentation to the immune system.

IMPORTANCE The envelope glycoprotein (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) mediates the entry of the virus into host cells and is also the target for antibodies. During virus entry, Env needs to change shape. Env flexibility also contributes to the ability of HIV-1 to evade the host immune response; many shapes of Env raise antibodies that cannot recognize the functional Env and therefore do not block virus infection. We found that an HIV-1 entry inhibitor, BMS-806, stabilizes the functional shape of Env. We developed new variants of BMS-806 that stabilize Env in its natural state for long periods of time. The availability of such long-acting stabilizers of Env shape will allow the natural Env conformation to be characterized and tested for efficacy as a vaccine.

Legumes tend to be nodulated by competitive rhizobia that do not maximize nitrogen (N2) fixation, resulting in suboptimal yields. Rhizobial nodulation competitiveness and effectiveness at N2 fixation are independent traits, making their measurement extremely time-consuming with low experimental throughput. To transform the experimental assessment of rhizobial competitiveness and effectiveness, we...

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.

Of four genotypes of Encephalitozoon cuniculi, E. cuniculi genotype II is considered to represent a parasite that occurs in many host species in a latent asymptomatic form, whereas E. cuniculi genotype III seems to be more aggressive, and infections caused by this strain can lead to the death of even immunocompetent hosts. Although albendazole has been considered suitable for treatment of Encephalitozoon species, its failure in control of E. cuniculi genotype III infection has been reported. This study determined the effect of a 100x recommended daily dose of albendazole on an Encephalitozoon cuniculi genotype III course of infection in immunocompetent and immunodeficient mice and compared the results with those from experiments performed with a lower dose of albendazole and E. cuniculi genotype II. The administration of the regular dose of abendazole during the acute phase of infection reduced the number of affected organs in all strains of mice and absolute counts of spores in screened organs. However, the effect on genotype III was minor. Surprisingly, no substantial effect was recorded after the use of a 100x dose of albendazole, with larger reductions seen only in the number of affected organs and absolute counts of spores in all strains of mice, implying variations in albendazole resistance between these Encephalitozoon cuniculi genotypes. These results imply that differences in the course of infection and the response to treatment depend not only on the immunological status of the host but also on the genotype causing the infection. Understanding how microsporidia survive in hosts despite targeted antimicrosporidial treatment could significantly contribute to research related to human health.

To date, more than 200 monogenic, often devastating, skin diseases have been described. Because of unmet medical needs, development of long-lasting and curative therapies has been consistently attempted, with the aim of correcting the underlying molecular defect. In this review, we will specifically address the few combined cell and gene therapy strategies that made it to the clinics. Based on these studies, what can be envisioned for the future is a patient-oriented strategy, built on the specific features of the individual in need. Most likely, a combination of different strategies, approaches, and advanced therapies will be required to reach the finish line at the end of the long and winding road hampering the achievement of definitive treatments for genodermatoses.

Some of this year's Oscar nominees, including Andrew Garfield and Michael Shannon, react to news of their nomination.

Fans can check out the event, which kicks off at 8.30am PT each day, on 320 Festival's Facebook Live and YouTube Live pages.

A Banksy mural in Bristol has been given a face mask in a coronavirus-themed makeover.

West Ham midfielder Robert Snodgrass has launched a scathing criticism of Matt Hancock, warning the health secretary to "do his homework" before calling out footballers over their wages.