The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

/pdf/ampk-and-mtor-regulate-autophagy-through-direct-14wqsz16ke.pdf

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Autophagy: Renovation of Cells and Tissues

This paper deals with the optimal filtering problem of discrete-time systems, the objective is to find a filter such that an upper bound on the H/sub 2/ norm criterion of the estimation error is minimized while a prescribed noise attenuation level is guaranteed. A procedure to designing the optimal H/sub 2//H/sub /spl infin// filter is presented by formulating and solving a certain convex optimization problem with linear matrix inequality constraints.

http://ieeexplore.ieee.org/iel5/9294/29544/01340921.pdf

H/sub 2//H/sub /spl infin// optimal filter design for linear discrete-time systems

With further research on dual-polarized antennas and reconfigurable intelligent surface (RIS), dual-polarized RIS has become the focus of research attention in recent years. It retains the advantage of being programmable, cost- and energy-effective and expands the freedom of polarization domain. Meanwhile, the ever-increasing growth in the size of wireless connections poses a significant challenge to system performance, such as system spectral efficiency (SE). To this end, we investigate the application of dual-polarized RIS in far-field multi-user multi-input multi-output (MIMO) uplink transmission. We first establish a dual-polarized model of the system and formulate the corresponding optimization problem for SE maximization. Due to the presence of dual polarization, the channel dimension is doubled and the system is influenced by the cross-polarization interference. To handle the above issues, a low-complexity joint optimization algorithm is proposed in this paper, which takes the cross-polarization interference into account. The effectiveness of the proposed algorithm for enhancing the system SE is demonstrated by numerical results.

Low-Complexity Multi-User MIMO Uplink Transmission Assisted by Dual-Polarized Reconfigurable Intelligent Surface

In this paper, the symbol error rate (SER) per-formance of sparse vector coding (SVC) for the short packet transmission over independent and identically distributed (i. i. d.) k - u shadowed fading channels is studied. We firstly analyze the signal to interference plus noise ratio (SINR) of the SVC scheme and show that the corresponding signal to noise ratio (SNR) performance can be improved with the increasing number of resource blocks compared to the conventional baseline, which indicates that the reliability of the system is improved. Then, we derive the simple SER analytical expression over the $\kappa-\mu$ fading scenario with low computational complexity. The versatility of the $\kappa-\mu$ fading model determines that the other well-known fading distributions and their inclusive ones can be derived as special cases. Simulation results indicate the validness of our derivations, and that the SVC scheme can greatly improve the system reliability with longer spreading sequences.

Performance Analysis of Sparse Vector Coding over $\kappa-\mu$ Fading Channel

This paper proposes a grant-free massive access scheme based on the millimeter wave (mmWave) extra-large-scale multiple-input multiple-output (XL-MIMO) to support massive Internet-of-Things (IoT) devices with low latency, high data rate, and high localization accuracy in the upcoming sixth-generation (6G) networks. The XL-MIMO consists of multiple antenna subarrays that are widely spaced over the service area to ensure line-of-sight (LoS) transmissions. First, we establish the XL-MIMO-based massive access model considering the near-field spatial non-stationary (SNS) property. Then, by exploiting the block sparsity of subarrays and the SNS property, we propose a structured block orthogonal matching pursuit algorithm for efficient active user detection (AUD) and channel estimation (CE). Furthermore, different sensing matrices are applied in different pilot subcarriers for exploiting the diversity gains. Additionally, a multi-subarray collaborative localization algorithm is designed for localization. In particular, the angle of arrival (AoA) and time difference of arrival (TDoA) of the LoS links between active users and related subarrays are extracted from the estimated XL-MIMO channels, and then the coordinates of active users are acquired by jointly utilizing the AoAs and TDoAs. Simulation results show that the proposed algorithms outperform existing algorithms in terms of AUD and CE performance and can achieve centimeter-level localization accuracy.

Sensing User's Activity, Channel, and Location with Near-Field Extra-Large-Scale MIMO

/pdf/correction-protac-mediated-fkbp12-degradation-enhances-2opjalfm.pdf

Li Yu

Papers

H/sub 2//H/sub /spl infin// optimal filter design for linear discrete-time systems

Low-Complexity Multi-User MIMO Uplink Transmission Assisted by Dual-Polarized Reconfigurable Intelligent Surface

Performance Analysis of Sparse Vector Coding over $\kappa-\mu$ Fading Channel

Sensing User's Activity, Channel, and Location with Near-Field Extra-Large-Scale MIMO

Correction: PROTAC mediated FKBP12 degradation enhances Hepcidin expression via BMP signaling without immunosuppression activity