HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV ...infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV− individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression.
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•Methylome-wide analysis of HIV chronically infected, cART treated individuals•HIV+ individuals have an epigenetic age 4.9 years older than healthy controls•HLA locus is hypomethylated in HIV+ individuals•HIV methylation aging signature is validated in purified cells
Gross et al. investigate the impact of chronic HIV infection by profiling the DNA methylomes of HIV+ individuals and matched HIV− controls. Using epigenetic models of aging, they observe that HIV+ individuals show an age advancement of 4.9 years in whole blood and validate these results in pure cell samples.
HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor ...cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy.
The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining.
258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC.
This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.
Endoplasmic reticulum (ER)-associated degradation (ERAD) removes misfolded proteins from the ER membrane and lumen by the ubiquitin-proteasome pathway. Retrotranslocation of ubiquitinated substrates ...to the cytosol is a universal feature of ERAD that requires the Cdc48 AAA-ATPase. Despite intense efforts, the mechanism of ER exit, particularly for integral membrane (ERAD-M) substrates, has remained unclear. Using a self-ubiquitinating substrate (SUS), which undergoes normal retrotranslocation independently of known ERAD factors, and the new SPOCK (single plate orf compendium kit) micro-library to query all yeast genes, we found the rhomboid derlin Dfm1 was required for retrotranslocation of both HRD and DOA ERAD pathway integral membrane substrates. Dfm1 recruited Cdc48 to the ER membrane with its unique SHP motifs, and it catalyzed substrate extraction through its conserved rhomboid motifs. Surprisingly, dfm1Δ can undergo rapid suppression, restoring wild-type ERAD-M. This unexpected suppression explained earlier studies ruling out Dfm1, and it revealed an ancillary ERAD-M retrotranslocation pathway requiring Hrd1.
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•Retrotranslocation of integral membrane ERAD (ERAD-M) substrates requires Dfm1•Dfm1 provides this function in both the Hrd and Doa pathways•Dfm1 binds Cdc48 at the ER surface and moves ERAD-M substrates to the cytosol•dfm1Δ-null mutants are rapidly suppressed by amplified Hrd1 when ERAD-M substrates are strongly expressed
ER-associated degradation (ERAD) is a conserved pathway of protein quality control. All ERAD pathways require the retrotranslocation of ubiquitinated ERAD substrates from the ER to the cytoplasm for degradation. Neal et al. show that Dfm1 protein is a critical component of a dedicated retrotranslocation pathway for integral membrane ERAD substrates.
Sequence preferences of DNA binding proteins are a primary mechanism by which cells interpret the genome. Despite the central importance of these proteins in physiology, development, and evolution, ...comprehensive DNA binding specificities have been determined experimentally for only a few proteins. Here, we used microarrays containing all 10-base pair sequences to examine the binding specificities of 104 distinct mouse DNA binding proteins representing 22 structural classes. Our results reveal a complex landscape of binding, with virtually every protein analyzed possessing unique preferences. Roughly half of the proteins each recognized multiple distinctly different sequence motifs, challenging our molecular understanding of how proteins interact with their DNA binding sites. This complexity in DNA recognition may be important in gene regulation and in the evolution of transcriptional regulatory networks.
Roads pose an imminent threat to wildlife directly through mortality and changes in individual behavior, and also indirectly through modification of the amount and configuration of wildlife habitat. ...However, few studies have addressed how these mechanisms interact to determine species response to roads. We used structural equation modeling to assess direct and indirect effects (via landscape modification) of roads on space use by jaguars in Brazil, using radio-tracking data available from the literature. We fit path models that directly link jaguars' space use to roads and to land cover, and indirectly link jaguars' space use to roads through the same land cover categories. Our findings show that space use by jaguars was not directly affected by roads, but indirect effects occurred through reductions in natural areas on which jaguars depend, and through urban sprawl. Males´ space use, however, was not negatively influenced by urban areas. Since jaguars seem to ignore roads, mitigation should be directed to road fencing and promoting safe crossings. We argue that planners and managers need to much more seriously take into account the deforestation and the unbridled urban expansion from roads to ensure jaguar conservation in Brazil.
Silicon-on-insulator racetrack resonators can be used as multiplexers in wavelength division multiplexing applications. The free spectral range should be comparable to the span of the C-band so that ...a maximum number of channels can be multiplexed. However, the free spectral range is inversely proportional to the length of the resonator and, therefore, bending losses can become non-negligible. A viable alternative to increase the free spectral range is to use the Vernier effect. In this work, we present the theory of series-coupled racetrack resonators exhibiting the Vernier effect. We demonstrate the experimental performance of the device using silicon-on-insulator strip waveguides. The extended free spectral range is 36 nm and the interstitial peak suppression is from 9 dB to 17 dB.
Most homeodomains are unique within a genome, yet many are highly conserved across vast evolutionary distances, implying strong selection on their precise DNA-binding specificities. We determined the ...binding preferences of the majority (168) of mouse homeodomains to all possible 8-base sequences, revealing rich and complex patterns of sequence specificity and showing that there are at least 65 distinct homeodomain DNA-binding activities. We developed a computational system that successfully predicts binding sites for homeodomain proteins as distant from mouse as
Drosophila and
C. elegans, and we infer full 8-mer binding profiles for the majority of known animal homeodomains. Our results provide an unprecedented level of resolution in the analysis of this simple domain structure and suggest that variation in sequence recognition may be a factor in its functional diversity and evolutionary success.
We experimentally demonstrate compact broadband directional couplers using subwavelength gratings for silicon-on-insulator wafers with silicon layers of 220 nm. The dispersion properties of the ...optical modes are engineered using subwavelength gratings, which allow broadband operation. Finite-difference time-domain (FDTD)-based band structure calculations, with significantly reduced simulation time, were used to analyze the design, which included both the structure and material dispersions. Compact broadband direction couplers, with device lengths shorter than 14 <inline-formula> <tex-math notation="LaTeX">\mu\text{m}</tex-math></inline-formula>, which cover a bandwidth of 100 nm for power splitting ratios of 50/50, 40/60, 30/70, and 20/80, are designed and fabricated for the fundamental transverse electric mode with a central operating wavelength of 1550 nm.
We design and demonstrate a wideband silicon photonic polarization beamsplitter on a silicon-on-insulator platform. The device consists of two 3 dB broadband couplers cascaded in a point-symmetric ...network. The transverse electric (TE) and transverse magnetic (TM) modes are coupled to different output ports due to a large difference between their coupling strengths. The device exhibits large isolation at both the two output ports, of more than 20 dB over a large bandwidth of 125 nm, and a small excess loss, of less than 0.5 dB for the entire C-band.
Wavelength-division-multiplexing (WDM) networks with wide channel grids and bandwidths are promising for low-cost, low-power optical interconnects. Wide-bandwidth, single-band (i.e., no free-spectral ...range) add-drop filters have been developed on silicon using anti-reflection contra-directional couplers with out-of-phase Bragg gratings. Using such filter components, we demonstrate a 4-channel, coarse-WDM demultiplexer with flat passbands of up to 13 nm and an ultra-compact size of 1.2 × 10(-3) mm(2).
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