The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) constitute a nuclear NAD ؉ salvage pathway which regulates the functions of NAD ؉ -dependent enzymes such as the protein deacetylase SIRT1. One of the major functions of SIRT1 is to regulate target gene transcription through modification of chromatin-associated proteins. However, little is known about the molecular mechanisms by which NAD ؉ biosynthetic enzymes regulate SIRT1 activity to control gene transcription in the nucleus. In this study we show that stable short hairpin RNA-mediated knockdown of NAMPT or NMNAT-1 in MCF-7 breast cancer cells reduces total cellular NAD ؉ levels and alters global patterns of gene expression. Furthermore, we show that SIRT1 plays a key role in mediating the gene regulatory effects of NAMPT and NMNAT-1. Specifically, we found that SIRT1 binds to the promoters of genes commonly regulated by NAMPT, NMNAT-1, and SIRT1 and that SIRT1 histone deacetylase activity is regulated by NAMPT and NMNAT-1 at these promoters. Most significantly, NMNAT-1 interacts with, and is recruited to target gene promoters by SIRT1. Collectively, our results reveal a mechanism for the direct control of SIRT1 deacetylase activity at a set of target gene promoters by NMNAT-1. This mechanism, in collaboration with NAMPT-dependent regulation of nuclear NAD ؉ production, establishes an important pathway for transcription regulation by NAD ؉ .Nicotinamide adenine dinucleotide (NAD ϩ ), a coenzyme in metabolic processes and redox reactions, is an important signaling molecule. NAD ϩ is (i) a substrate for mono-and poly-ADP-ribosylation of proteins, (ii) required for NAD ϩ -dependent protein deacetylation, and (iii) a precursor for calcium mobilizing agents (1). As a signaling molecule, NAD ϩ is consumed as a donor of ADP-ribose, releasing nicotinamide (NAM) 2 as a byproduct. Consequently, resynthesis of NAD ϩ is crucial for maintaining the functions of a wide variety of NAD ϩ -dependent enzymes in the cytoplasm and nucleus. In mammalian cells the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase (NMNAT) constitute an NAD ϩ salvage/ recycling pathway using NAM as the precursor (see Fig. 1A) (2). NAMPT, a unique enzyme encoded by a single gene, catalyzes the conversion of NAM to nicotinamide mononucleotide (NMN). NAMPT localizes to both the cytosol and nucleus (3, 4).3 Interestingly, an extracellular form of NAMPT has also been described, although controversy exists regarding its function (5, 6). NMN produced by NAMPT is further converted into NAD ϩ by NMNAT. Three NMNAT enzymes encoded by distinct genes are found in mammals (7-10). Among them, NMNAT-1 is localized exclusively in the nucleus, whereas NMNAT-2 and NMNAT-3 are found in the Golgi and mitochondria, respectively (11). In the nucleus, NAMPT and NMNAT-1 form a nuclear NAD ϩ salvage pathway that supplies NAD ϩ as a substrate for a variety of NAD ϩ -dependent enzymes, including th...

IntroductionT cells, especially cytotoxic T cells (CTLs), play important roles in antitumor immunity. 1 Adoptive transfer of tumor-specific T cells into patients provides a promising means to treat cancer. 2 However, the traditional approaches for obtaining large numbers of tumorspecific T cells are time consuming, laborious, and sometimes difficult because the average frequency of antigen-specific T cells in the periphery is extremely low. [3][4][5] In addition, isolation and expansion of T cells that retain their antigen specificity and function can also be a challenging task. 2 Genetic modification of primary T cells with tumor-specific immunoreceptors, such as full-length T-cell receptors (flTCRs) or chimeric TCR (chTCR) molecules provides a novel way for redirecting T cells against tumor cells. 6-9 This strategy avoids the limitation of low frequency of antigen-specific T cells, allowing for facilitated expansion of tumor-specific T cells to therapeutic doses. Although some success has been reported using flTCR-or chTCR-transduced T cells, several factors, such as incorrect pairing between endogenous and exogenous TCR molecules, variable signaling capacity, and potential immunogenecity of chTCR molecules, may limit the therapeutic efficiency of these approaches. 2,10,11 Therefore, investigation of novel immunoreceptors besides flTCR or chTCR molecules remains an important goal.Natural killer (NK) cells attack tumor and virally infected cells in the absence of major histocompatibility complex (MHC) restriction, using a combination of signals from activating and inhibitory receptors. 12 One of these activating receptors is NKG2D, which is expressed on all NK cells, NKT cells, ␥␦ T cells, and some CD8 ϩ ␣␤ T cells. 12,13 Ligands for mouse NKG2D are Retinoic acid early inducible protein 1 (Rae-1), Murine UL-16-binding proteinlike transcript (Mult-1), and minor histocompatibility antigen H60 (H60), and ligands for human NKG2D include MHC class I chain-related A (MICA), MICB, and several UL-16-binding proteins (ULBPs). 13,14 It has been found that NKG2D ligands are primarily expressed on tumor cells but not on most normal tissues. 13,14 Thus, the NKG2D receptor-NKG2D ligand system provides a relatively specific system for immune cells to recognize tumor cells. Recent data show that Rae-1-and H60-expressing tumor cells can induce robust antitumor effects in an NK cell-mediated and CD8 ϩ T-cell-mediated fashion. 15 However, NKG2D expression on T cells does not induce direct activation of T cells after NKG2D crosslinking, but NKG2D enhances T-cell signaling initiated by TCR crosslinking. 16 This is probably due to the distinct signaling pathway of NKG2D in different cell types. T cells express the adaptor protein Dap10 but lack expression of Dap12, whereas NK cells express both adaptor proteins. 16,17 Dap12 contains an immunoreceptor tyrosine-based activation motif (ITAM) capable of providing primary signals for cell activation. 18 In contrast, Dap10 only contains a Tyr-X-X-Met (YXXM) motif that transduces costimula...

Thyroid nodules are very common all over the world, and China is no exception. Ultrasound plays an important role in determining the risk stratification of thyroid nodules, which is critical for clinical management of thyroid nodules. For the past few years, many versions of TIRADS (Thyroid Imaging Reporting and Data System) have been put forward by several institutions with the aim to identify whether nodules require fine-needle biopsy or ultrasound follow-up. However, no version of TIRADS has been widely adopted worldwide till date. In China, as many as ten versions of TIRADS have been used in different hospitals nationwide, causing a lot of confusion. With the support of the Superficial Organ and Vascular Ultrasound Group of the Society of Ultrasound in Medicine of the Chinese Medical Association, the Chinese-TIRADS that is in line with China's national conditions and medical status was established based on literature review, expert consensus, and multicenter data provided by the Chinese Artificial Intelligence Alliance for Thyroid and Breast Ultrasound.