Pervasive biases in proxy GWAS based on parental history of Alzheimer's disease.

Almost every recent Alzheimer's disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current AD GWAX provide highly misleading genetic correlations between AD risk and higher education which subsequently affects a variety of genetic epidemiologic applications involving AD and cognition. Our study sheds important light on the design and analysis of mid-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.

The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC50) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC50 ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic.

Recent advances of ß-catenin small molecule inhibitors for cancer therapy: Current development and future perspectives.

The Wnt/ß-catenin signaling pathway is involved in many cellular physiological processes, including embryonic development, cell proliferation and differentiation, tissue homeostasis and regeneration, etc. Aberrant activation of Wnt/ß-catenin signaling is one of the most typical features in the development and progression of cancer. Abnormal accumulation of ß-catenin, a core component of the Wnt/ß-catenin signaling pathway, is one of the main factors leading to abnormal activation of the Wnt/ß-catenin signaling pathway. Therefore, ß-catenin has become an important target for the development of anticancer drugs. Some ß-catenin small molecule inhibitors have been shown to have the potential to treat cancer, such as the specific ß-catenin/CBP antagonist PRI-724, which has entered phase I/II clinical trials. However, the development and application of ß-catenin inhibitors are still challenging due to their selectivity, specificity and physicochemical properties, etc. This review introduces the Wnt/ß-catenin signaling pathway, focuses on the research progress of ß-catenin small molecule inhibitors, and prospects for the development of drug in the future.

Medicinal chemistry strategies targeting PRMT5 for cancer therapy.

Protein arginine methyltransferases 5 (PRMT5), a therapeutic target whose main physiological function is mono- and symmetric dimethylation of arginine, has drawn significant attention from researchers in the field. PRMT5 has been reported to participate in many cellular functions including cell growth, migration, and development. Upregulation of PRMT5 occurs in different kinds of tumors and is strongly associated with poor prognosis. In recent years, several PRMT5 inhibitors have entered clinical trials for the treatment of various cancers, such as advanced or recurrent solid tumors with MTAP deletion. Herein, we reviewed the binding modes and structure-activity relationships of novel PRMT5 inhibitors and discussed prospects of PRMT5 inhibitors in cancer therapy, aiming to provide insights on drug development of PRMT5 inhibitors.

Recent research and development of inhibitors targeting sentrin-specific protease 1 for the treatment of cancers.

Small ubiquitin-like modifier (SUMO)/sentrin-specific protease 1 (SENP1), is a cysteine protease that promotes SUMO maturation and deSUMOylation of target proteins and regulates transcription factors or co-regulatory factors to mediate gene transcription. Many studies have shown that SENP1 is the driving factor for a multitude of cancers including prostate cancer, liver cancer, and breast cancer. Inhibition of SENP1 activity has been proved to inhibit the survival, proliferation, invasion, and migration of cancer cells, and increase their chemical and radiation sensitivity. Therefore, SENP1 is a promising anti-tumor target. At present, peptide inhibitors of SENP1 have entered clinical trials. Recently, many small molecule compounds and natural products were synthesized and identified as SENP1 inhibitors, and showed good tumor inhibitory activity in vitro and in vivo. This review summarizes the structure, physiological function, and role of SENP1 in tumorigenesis and development, focusing on the design and discovery of small molecule inhibitors of SENP1 from the perspective of medicinal chemistry, providing ideas for the development and research of small molecule inhibitors of SENP1 in the future.

Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy.

Neurodegenerative diseases (NDs) are currently incurable diseases that cause progressive degeneration of nerve cells. Many of the disease-causing proteins of NDs are "undruggable" for traditional small-molecule inhibitors (SMIs). None of the compounds that attenuated the amyloid-ß (Aß) accumulation process have entered clinical practice, and many phase III clinical trials of SMIs for Alzheimer's disease (AD) have failed. In recent years, emerging targeted protein degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimaeras (LYTACs), and autophagy-targeting chimeras (AUTACs) with TPD-assistive technologies such as click-formed proteolysis-targeting chimeras (CLIPTACs) and deubiquitinase-targeting chimera (DUBTAC) have developed rapidly. In vitro and in vivo experiments have also confirmed that TPD technology can target the degradation of ND pathogenic proteins, bringing hope for the treatment of NDs. Herein, we review the latest TPD technologies, introduce their targets and technical characteristics, and discuss the emerging TPD technologies with potential in ND research, with the hope of providing a new perspective for the development of TPD technology in the NDs field.

Compact 3D Metal Collectors Enabled by Roll-to-Roll Nanoimprinting for Improving Capacitive Energy Storage.

Reducing the contact resistance between active materials and current collectors is of engineering importance for improving capacitive energy storage. 3D current collectors have shown extraordinary promise for reducing the contact resistance, however, there is a major obstacle of being bulky or inefficient fabrication before they become viable in practice. Here a roll-to-roll nanoimprinting method is demonstrated to deform flat aluminum foils into 3D current collectors with hierarchical microstructures by combining soft matter-enhanced plastic deformation and template-confined local surface nanocracks. The generated 3D current collectors are inserted by and interlocked with active electrode materials such as activated carbon, decreasing the contact resistance by at least one order of magnitude and quadrupling the specific capacitance at high current density of 30 A g-1 for commercial-level mass loading of 5 mg cm-2 . The 3D current collectors are so compact that they have a low volume percentage of 7.8% in the entire electrode film, resulting in energy and power density of 29.1 Wh L-1 and 12.8 kW L-1 , respectively, for stack cells in organic electrolyte. Furthermore, roll-to-roll nanoimprinting of metal microstructures is low-cost, high-throughput, and can be extended to other systems that involve the microstructured metal interface, such as batteries and thermal management.

An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment.

Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of IgG1+ plasma cells, CD8+ T cells, CD103+ DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumor-associated antigen-specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector CD8+ T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of IgG1+ memory B cells in tumors could improve immunotherapy outcomes.

Tetrameric Neuraminidase of Influenza A Virus Is Required to Induce Protective Antibody Responses in Mice.

Influenza neuraminidase (NA) is able to induce cross-subtype immunity and is considered as a promising target for the development of universal influenza vaccines. However, commercial influenza vaccines only induced low NA-specific immune responses due to the low amounts and the denatured conformation of NA proteins in current inactivated or split influenza vaccines. Here we investigated the protective efficacy of recombinant tetrameric and monomeric NA proteins to determine whether the conformation contributed to induce protective immunity. We found that H1N1 P R 8NA tetramer (NA tet ) could provide complete homologous protection against A/PR8 (H1N1) virus infection in mice, while the protection of H1N1 P R 8NA monomer (NA mono ) was moderate. Higher levels of NA-reactive binding and inhibition antibodies and less weight loss were observed in the H1N1 P R 8NA tet -vaccinated group. Similarly, H5N1 V N NA tet immunization exhibited a preferable heterologous protection than H5N1 V N NA mono , but neither H7N9 S H NA tet nor H7N9 S H NA mono vaccination showed heterosubtypic protection. We also compared the effect of three adjuvants, aluminum, 3'3'-cGAMP (cGAMP), and Poly(I:C), on the humoral response and protective efficacy induced by H1N1 P R 8NA tet . H1N1 P R 8NA tet protein adjuvanted with aluminum was observed to exhibited better capacity in inducing NA-specific humoral immunity and preventing weight loss than with cGAMP or Poly(I:C). In conclusion, our data demonstrate that tetrameric NA with natural conformation is required to induce protective anti-NA immunity. The NA tetramer could provide homologous protection and subtype-specific cross-protection. In addition, the aluminum adjuvant is preferable in recombinant NA protein vaccination.

An amphipathic peptide targeting the gp41 cytoplasmic tail kills HIV-1 virions and infected cells.

HIV-associated morbidity and mortality have markedly declined because of combinational antiretroviral therapy, but HIV readily mutates to develop drug resistance. Developing antivirals against previously undefined targets is essential to treat existing drug-resistant HIV strains. Some peptides derived from HIV-1 envelope glycoprotein (Env, gp120-gp41) have been shown to be effective in inhibiting HIV-1 infection. Therefore, we screened a peptide library from HIV-1 Env and identified a peptide from the cytoplasmic region, designated F9170, able to effectively inactivate HIV-1 virions and induce necrosis of HIV-1-infected cells, and reactivated latently infected cells. F9170 specifically targeted the conserved cytoplasmic tail of HIV-1 Env and effectively disrupted the integrity of the viral membrane. Short-term monoadministration of F9170 controlled viral loads to below the limit of detection in chronically SHIV-infected macaques. F9170 can enter the brain and lymph nodes, anatomic reservoirs for HIV latency. Therefore, F9170 shows promise as a drug candidate for HIV treatment.