Biological characterization of AB-343, a novel and potent SARS-CoV-2 M inhibitor with pan-coronavirus activity.

Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main protease (M) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 M with potent activity in both cell-based (EC = 0.

Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants.

The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M inhibitor was the first such approved therapy.

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma.

Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study.

Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.

Background: There is an urgent need to better understand the mechanisms associated with the development, progression, and onset of recurrence after initial surgery in glioblastoma (GBM). The use of integrative phenotype-focused -omics technologies such as proteomics and lipidomics provides an unbiased approach to explore the molecular evolution of the tumor and its associated environment.

Methods: We assembled a cohort of patient-matched initial (iGBM) and recurrent (rGBM) specimens of resected GBM.

Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis.

Background: Glioblastoma multiforme (GBM) is characterized by an unfavorable prognosis for patients affected. During standard-of-care chemotherapy using temozolomide (TMZ), tumors acquire resistance thereby causing tumor recurrence. Thus, deciphering essential molecular pathways causing TMZ resistance are of high therapeutic relevance.

Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation.

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD.

The Long-Term Efficacy Study of Multiple Allogeneic Canine Adipose Tissue-Derived Mesenchymal Stem Cells Transplantations Combined With Surgery in Four Dogs With Lumbosacral Spinal Cord Injury.

Severe lumbosacral pain, paraparesis or paraplegia, and urinary incontinence are common but frustrating problems in dogs with lumbosacral spinal cord injury (SCI). The surgical interventions including stabilization and decompression may not restore satisfying neurological functions in severe SCI. Adipose tissue-derived mesenchymal stem cells (Ad-MSCs) show benefits in immunomodulation, anti-inflammation, and promotion of axonal growth and remyelination, and also display efficacy in several diseases in veterinary medicine.

HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice.

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth.

Reflex and habituation behavior of Caenorhabditis elegans assessed by a mechanical vibration system and image analysis.

Background: The nematode Caenorhabditis elegans is an emerging invertebrate animal model for investigating neuronal functions in behavioral assays. C. elegans mechanosensation was characterized by the use of a constant mechanical stimulation transmitter followed by quantitative imaging.

N-Terminomics identifies HtrA1 cleavage of thrombospondin-1 with generation of a proangiogenic fragment in the polarized retinal pigment epithelial cell model of age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population. Variants in the HTRA1-ARMS2 locus have been linked to increased AMD risk. In the present study we investigated the impact of elevated HtrA1 levels on the retina pigment epithelial (RPE) secretome using a polarized culture system.

HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss. The protein HtrA1 is enriched in retinal pigment epithelial (RPE) cells isolated from AMD patients and in drusen deposits. However, it is poorly understood how increased levels of HtrA1 affect the physiological function of the RPE at the intracellular level.

Proteome profiling of clear cell renal cell carcinoma in von Hippel-Lindau patients highlights upregulation of Xaa-Pro aminopeptidase-1, an anti-proliferative and anti-migratory exoprotease.

Patients of the von Hippel-Lindau (VHL) disease frequently develop clear cell renal cell carcinoma (ccRCC). Using archived, formalin-fixed, paraffin-embedded (FFPE) samples, we sought to determine global proteome alterations that distinguish ccRCC tissue from adjacent, non-malignant kidney tissue in VHL-patients. Our quantitative proteomic analysis clearly discriminated tumor and non-malignant tissue.

HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication.

The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes. Among these, HtrA1 is implicated in several cancers, cerebrovascular disease and age-related macular degeneration. Currently, HtrA1 activation is not fully characterized and relevant for drug-targeting this protease.

Profiling of Protease Cleavage Sites by Proteome-Derived Peptide Libraries and Quantitative Proteomics.

Biochemical profiling of active site specificity is a crucial step to characterize proteases, which play key roles in health and disease. Here, we present a protocol using proteome-derived peptide libraries in combination with quantitative proteomics to simultaneously identify cleavage motifs N- and C-terminal to the scissile peptide bond. First, bacterial or eukaryotic cell lysate is used to generate peptide libraries.

The influences of perceived social support and personality on trajectories of subsequent depressive symptoms in Taiwanese youth.

Little is known about the combined effect of personality and social support on trajectories of depressive symptoms among youth. This study aims to investigate the influence of social support in different contexts on the development of depressive symptoms during adolescence and whether the association is moderated by adolescents' personality. The data using in this study is selected from the Taiwan Educational Panel Survey (TEPS), a longitudinal panel study since the year 2000 (at age 13) and three more waves (at ages 15, 17, and 18).

The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance.

Proteolysis by aspartyl intramembrane proteases such as presenilin and signal peptide peptidase (SPP) underlies many cellular processes in health and disease. Saccharomyces cerevisiae encodes a homolog that we named yeast presenilin fold 1 (Ypf1), which we verify to be an SPP-type protease that localizes to the endoplasmic reticulum (ER). Our work shows that Ypf1 functionally interacts with the ER-associated degradation (ERAD) factors Dfm1 and Doa10 to regulate the abundance of nutrient transporters by degradation.

Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u.

Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of signal peptides at the endoplasmic reticulum (ER), but has also been suggested to play a role in ER-associated degradation (ERAD). Here, we show that SPP forms a complex with the ERAD factor Derlin1 and the E3 ubiquitin ligase TRC8 to cleave the unfolded protein response (UPR) regulator XBP1u. Cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an SPP substrate through specific sequence features.

Two-way lightwave subcarrier transmission system.

This Letter proposes and demonstrates a two-way lightwave subcarrier transmission system employing interleavers to deliver intensity-modulated CATV/phase-modulated RoF/intensity-remodulated 16-QAM-OFDM signals over two 20 km SMF links. To the best of our knowledge, it is the first time that interleavers have been employed in two-way lightwave subcarrier transmission systems. The downstream light is successfully intensity-remodulated with a 16-QAM-OFDM signal for uplink transmission.

A multiple-input-multiple-output visible light communication system based on VCSELs and spatial light modulators.

A multiple-input-multiple-output (MIMO) visible light communication (VLC) system employing vertical cavity surface emitting laser (VCSEL) and spatial light modulators (SLMs) with 16-quadrature amplitude modulation (QAM)-orthogonal frequency-division multiplexing (OFDM) modulating signal is proposed and experimentally demonstrated. The transmission capacity of system is significantly increased by space-division demultiplexing scheme. With the assistance of low noise amplifier (LNA) and data comparator, good bit error rate (BER) performance, clear constellation map, and clear eye diagram are achieved for each optical channel.

A 10-Gbps optical WiMAX transport system.

A 10-Gbps optical worldwide interoperability for microwave access (WiMAX) transport system employing vertical cavity surface emitting laser (VCSEL) and spatial light modulator (SLM) with 16-quadrature amplitude modulation (QAM)-orthogonal frequency-division multiplexing (OFDM) modulating signal is proposed. With the assistance of equalizer and low noise amplifier (LNA) at the receiving site, good bit error rate (BER) performance, clear constellation map, and clear eye diagram are achieved in the proposed systems. An optical WiMAX transport system, transmitting 16-QAM-OFDM signal over a 6-m free-space link, with a data rate of 10 Gbps is successfully demonstrated.

Optical free-space wavelength-division-multiplexing transport system.

An optical free-space wavelength-division-multiplexing (WDM) transport system employing vertical cavity surface emitting lasers and spatial light modulators with 16-quadrature amplitude modulation orthogonal frequency-division multiplexing modulating signals over a 17.5 m free-space link is proposed and demonstrated. With the help of a low-noise amplifier and data comparator, good bit error rate performance is obtained for each optical channel.

Hybrid lightwave subcarrier CATV/16-QAM/16-QAM OFDM transmission system.

A hybrid lightwave subcarrier CATV/16-QAM/16-QAM orthogonal frequency-division multiplexing (OFDM) transmission system employing light injection/optoelectronic feedback techniques and photonic crystal fiber (PCF) is proposed and demonstrated. Good performance of carrier-to-noise ratio (CNR), composite second order, and composite triple beat were obtained for the CATV band, and high CNR and low bit error rate values were achieved for the 16-QAM and 16-QAM OFDM bands over a combination of 80 km single-mode fiber (SMF) and 2.86 km PCF transport.

Full-duplex lightwave transport systems based on long-haul SMF and optical free-space transmissions.

A full-duplex lightwave transport system employing wavelength-division-multiplexing (WDM) and optical add-drop multiplexing techniques, as well as optical free-space transmission scheme is proposed and experimentally demonstrated. Over an 80-km single-mode fiber (SMF) and 2.4 m optical free-space transmissions, impressive bit error rate (BER) performance is obtained for long-haul fiber link and finite free-space transmission distance.

Bidirectional 16-QAM OFDM in-building network over SMF and free-space VLC transport.

A bidirectional 16-quadrature amplitude modulation (QAM) orthogonal frequency-division multiplexing (OFDM) in-building network over 20 km single-mode fiber (SMF) and 15 m free-space visible light communication (VLC) transport is proposed and experimentally demonstrated. Good bit error rate performances and clear constellation maps are obtained for 16-QAM OFDM applications in our proposed in-building networks.

Bidirectional phase-modulated hybrid cable television/radio-over-fiber lightwave transport systems.

A bidirectional phase-modulated hybrid cable television/radio-over-fiber lightwave transport system employing fiber Bragg grating tilt filter as a phase modulation-to-intensity modulation conversion scheme is proposed and demonstrated. Impressive performances of carrier-to-noise ratio, composite second-order, composite triple-beat, and bit-error rate are obtained in our proposed systems over a combination of 40 km single-mode fiber-and 1.43 km photonic crystal fiber transmission.