Bidirectional two-sample Mendelian randomization analysis identifies causal associations between oxidative stress and Parkinson's disease.

Background: Observational studies have shown that oxidative stress (OS) is associated with Parkinson's disease (PD). However, whether such observations reflect cause-effect remains largely unknown. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal-effects between OS biomarkers and PD. Methods: We selected summary statistics data for single-nucleotide polymorphisms (SNPs) associated with catalase (n = 13), glutathione peroxidases (n = 12), superoxide dismutase (n = 13), vitamin A (n = 7), vitamin C (n = 10), vitamin E (n = 12), vitamin B12 (n = 8), folate (n = 14), copper (n = 6), Zinc (n = 7), and iron (n = 23) levels, and the corresponding data for PD from the International Parkinson Disease Genomics Consortium (IPDGC, 33,674 cases and 449,056 controls). Inverse-variance weighted (IVW) MR analyses were conducted to estimate associations of OS with PD. Reverse MR analysis was further performed to predict the causal effects of PD on the above OS biomarkers. Results: As for PD, the IVW method suggested that the Zinc (Zn) levels was significantly associated with PD (OR = 1.107, 95% CI 1.013-1.211; p = 0.025), which is consistent with results from the weighted median analyses. Moreover, the results remained consistent and robust in the sensitivity analysis. However, there were no significant associations of catalase, glutathione peroxidases, superoxide dismutase, vitamin A, vitamin C, vitamin E, vitamin B12, folate, copper, or iron with PD. As for OS, our reverse MR analysis also did not support a causal effect of liability to PD on OS. Conclusion: The MR study supported the causal effect of Zn on PD. These findings may inform prevention strategies and interventions directed toward OS and PD.

Recent Progress in Solar-Blind Photodetectors Based on Ultrawide Bandgap Semiconductors.

Ultrawide bandgap (UWBG) semiconductors, including Ga2O3, diamond, Al x Ga1-x N/AlN, featuring bandgaps greater than 4.4 eV, hold significant promise for solar-blind ultraviolet photodetection, with applications spanning in environmental monitoring, chemical/biological analysis, industrial processes, and military technologies. Over recent decades, substantial strides in synthesizing high-quality UWBG semiconductors have facilitated the development of diverse high-performance solar-blind photodetectors (SBPDs). This review comprehensively examines recent advancements in UWBG semiconductor-based SBPDs across various device architectures, encompassing photoconductors, metal-semiconductor-metal photodetectors, Schottky photodiodes, p-n (p-i-n) photodiodes, phototransistors, etc., with a systematic introduction and discussion of their operational principles. The current state of device performance for SBPDs employing these UWBG semiconductors is evaluated across different device configurations. Finally, this review outlines key challenges to be addressed, aiming to steer future research endeavors in this critical domain.

LncRNA AFAP1-AS1 Promotes Oral Squamous Cell Carcinoma Development by Ubiquitin-Mediated Proteolysis.

BACKGROUND AND PURPOSE: Long noncoding RNA (lncRNA) dysregulation has been reported to play a pivotal role in the development of cancers. In this study, we aimed to screen the key lncRNA in oral squamous cell carcinoma (OSCC) via bioinformatics analysis and further validate the function of lncRNA in vitro and in vivo. METHODS: Bioinformatics analysis was conducted to identify differentially expressed lncRNAs between control and OSCC samples. Quantitative real-time-polymerase chain reaction was employed to detect the expression of differentially expressed lncRNAs in human tongue squamous cell carcinoma and human oral keratinocytes cell lines. The biological function of lncRNA and its mechanism were examined via the experimental assessment of the cell lines with the lncRNA overexpressed and silenced. Additionally, to further explore the function of lncRNA in the progression of OSCC, xenograft tumour mouse models were established using 25 mice (5 groups, each with 5 mice). Tumour formation was observed at 2 weeks after the cell injection, and the tumours were resected at 5 weeks post-implantation. RESULTS: Two lncRNAs, LINC00958 and AFAP1-AS1, were found to be correlated with the prognosis of OSCC. The results of the quantitative real-time-polymerase chain reaction indicated that the 2 lncRNAs were highly expressed in OSCC. In combination with the previous literature, we found AFAP1-AS1 to be a potentially important biomarker for OSCC. Thus, we further investigated its biological function and found that AFAP1-AS1 silencing inhibited cell proliferation, migration, and invasion whereas AFAP1-AS1 overexpression reversed the effect of AFAP1-AS1 silencing (P < .05). Mechanism analysis revealed that AFAP1-AS1 regulated the development of OSCC through the ubiquitin-mediated proteolysis pathway. CONCLUSIONS: AFAP1-AS1 is an oncogene that aggravates the development of OSCC via the ubiquitin-mediated proteolysis pathway. It also provides a novel potential therapy for OSCC.

Acoustofluidic-based microscopic examination for automated and point-of-care urinalysis.

Urinalysis is a heavily used diagnostic test in clinical laboratories; however, it is chronically held back by urine sediment microscopic examination. Current instruments are bulky and expensive to be widely adopted, making microscopic examination a procedure that still relies on manual operations and requires large time and labor costs. To improve the efficacy and automation of urinalysis, this study develops an acoustofluidic-based microscopic examination system. The system utilizes the combination of acoustofluidic manipulation and a passive hydrodynamic mechanism, and thus achieves a high throughput (1000 µL min-1) and a high concentration factor (95.2 ± 2.1 fold) simultaneously, fulfilling the demands for urine examination. The concentrated urine sample is automatically dispensed into a hemocytometer chamber and the images are then analyzed using a machine learning algorithm. The whole process is completed within 3 minutes with detection accuracies of erythrocytes and leukocytes of 94.6 ± 3.5% and 95.1 ± 1.8%, respectively. The examination outcome of urine samples from 50 volunteers by this device shows a correlation coefficient of 0.96 compared to manual microscopic examination. Our system offers a promising tool for automated urine microscopic examination, thus it has potential to save a large amount of time and labor in clinical laboratories, as well as to promote point-of-care urine testing applications in and beyond hospitals.

GnRH-mediated suppression of S100A4 expression inhibits endometrial epithelial cell proliferation in sheep via GNAI2/MAPK signaling.

Background: Gonadotrophin-releasing hormone (GnRH) administration significantly decreases the pregnancy rate of recipient ewes after embryo transfer, possibly because GnRH affects endometrial epithelial cell function. Therefore, this study investigated the effect of GnRH on endometrial epithelial cells. Methods: Transcriptome sequencing was used to determine the regulatory effect of GnRH on the ewe endometrium, and the S100A4 gene, which showed altered transcription, was screened as a candidate regulator of this effect. Endometrial epithelial cells were further isolated, the S100A4 protein was immunoprecipitated, and host proteins that interacted with S100A4 were identified by mass spectrometry. We further verified the effects of S100A4 and GNAI2 on the proliferation of endometrial epithelial cells via overexpression/knockdown experiments and subsequent CCK-8 and EdU assays. The effect of S100A4 deletion in endometrial cells on reproduction was verified in mice with S100A4 knockout. Results: Our results showed that S100A4 gene transcription in endometrial cells was significantly inhibited after GnRH administration. GNAI2 was identified as a downstream interacting protein of S100A4, and S100A4 was confirmed to activate the MAPK signaling pathway to promote cell proliferation by targeting GNAI2. Conclusion: GnRH can suppress the expression of S100A4 in the endometrium, consequently inhibiting the proliferation of endometrial cells through the S100A4/GNAI2/MAPK signaling pathway. These findings suggest a potential explanation for the limited efficacy of GnRH in promoting embryo implantation.

Enhancing ASPP2 promotes acute liver injury via an inflammatory immunoregulatory mechanism.

Background: Acute liver injury (ALI), which is a type of inflammation-mediated hepatocellular injury, is a clinical syndrome that results from hepatocellular apoptosis and hemorrhagic necrosis. Apoptosis stimulating protein of p53-2 (ASPP2) is a proapoptotic member of the p53 binding protein family. However, the role of ASPP2 in the pathogenesis of ALI and its regulatory mechanisms remain unclear. Methods: The expression of ASPP2 were compared between liver biopsies derived from patients with CHB, patients with ALI, and normal controls. Acute liver injury was modelled in mice by administration of D-GalN/LPS. Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. ASPP2-knockdown mice (ASPP2+/-) were used to determine its role in acute liver injury. Mouse bone marrow macrophages (BMMs) were isolated from wildtype and ASPP2+/- mice and stimulated with LPS, and the supernatant was collected to incubate with the primary hepatocytes. Quantitative real-time PCR and western blot were used to analyze the expression level of target. Results: The expression of ASPP2 was significantly upregulated in the liver tissue of ALI patients and acute liver injury mice. ASPP2+/- mice significantly relieved liver injury through reducing liver inflammation and decreasing hepatocyte apoptosis. Moreover, the conditioned medium (CM) of ASPP2+/- bone marrow-derived macrophages (BMMs) protected hepatocytes against apoptosis. Mechanistically, we revealed that ASPP2 deficiency in BMMs specifically upregulated IL-6 through autophagy activation, which decreased the level of TNF-α to reduce hepatocytes apoptosis. Furthermore, up-regulation of ASPP2 sensitizes hepatocytes to TNF-α-induced apoptosis. Conclusion: Our novel findings show the critical role of ASPP2 in inflammatory immunoregulatory mechanism of ALI and provide a rationale to target ASPP2 as a refined therapeutic strategy to ameliorate acute liver injury.

Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer.

The mediator kinases CDK8 and CDK19 control the dynamic transcription of selected genes in response to various signals and have been shown to be hijacked to sustain hyperproliferation by various solid and liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic target. Here, we report the discovery of compound 12, a novel small molecule CDK8/19 inhibitor. This molecule demonstrated not only decent enzymatic and cellular activities but also remarkable selectivity in CDK and kinome panels. Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition, acceptable clearance, and high oral bioavailability in multiple preclinical species. Robust in vivo PD and efficacy studies in mice models further demonstrated its potential use as mono- and combination therapy for the treatment of cancers.

Systematic Research and Application of a 5G Medical Unmanned Aerial Vehicle to Deliver COVID-19 Nucleic Acid Samples.

The purpose of this study was to investigate the feasibility and effectiveness of COVID-19 throat swab samples delivered by medical drones in epidemic prevention and control. This study was carried out in both southern and northern hospital districts of the Affiliated Hospital of Jiangnan University from May to October 2022. The main participants were the Affiliated Hospital of Jiangnan University and Zhejiang Antwork Technology Co., Ltd. We first constructed an urban medical unmanned aerial vehicle (UAV) delivery system and developed a UAV-specific storage box for COVID-19 samples. The UAV system was used to transport COVID-19 throat swab samples from the northern hospital district to the southern hospital district, and the following indexes were obtained: (1) flight time of COVID-19 samples delivered by UAV, (2) real-time temperature of COVID-19 nucleic acid samples during transportation, and (3) the time of distribution of COVID-19 nucleic acid samples by road traffic as measured using the Baidu Maps application, compared with the flight time of UAV. The COVID-19 sample delivery system for urban medical UAV mainly consists of intelligent logistics UAV, low-temperature COVID-19 throat swab sample storage box, unmanned logistics hub, and cloud operation control platform. The flight distance between the northern and southern districts of the Affiliated Hospital of Jiangnan University was 10 km, and the ground distance was 24 km. From May 11 to October 28, 2022, a total of 1,190 UAV flights occurred. The average flight time was 13 minutes, which was 40 to 70 minutes faster than the average road travel time required for manual delivery of COVID-19 throat swab samples. At different time points in the day, UAV delivery efficiency increased by 67.5% to 82%. The use of 5G with the Internet of Things and UAV technology to deliver nucleic acid samples has the characteristics of fast speed, being unaffected by ground traffic conditions, and the ability to ensure the safety of nucleic acid samples in the transportation process, which is worthy of further study.

Polymer-based cascaded waveguide Bragg grating for blood glucose sensing.

Waveguide Bragg grating (WBG) blood glucose sensing, as a biological sensing technology with broad application prospects, plays an important role in the fields of health management and medical treatment. In this work, a polymer-based cascaded WBG is applied to glucose detection. We investigated photonic devices with two different grating structures cascaded-a crossed grating and a bilateral grating-and analyzed the effects of the crossed grating period, bilateral grating period, and number of grating periods on the sensing performance of the glucose sensor. Finally, the spectral reflectance characteristics, response time, and sensing specificity of the cascaded WBG were evaluated. The experimental results showed that the glucose sensor has a sensitivity of 175 nm/RIU in a glucose concentration range of 0-2 mg/ml and has the advantages of high integration, a narrow bandwidth, and low cost.

Preparation of NIR-II Polymer Nanoprobe Through Twisted Intramolecular Charge Transfer and Förster Resonance Energy Transfer of NIR-I Dye.

Near-infrared-II (NIR-II) fluorescence imaging is pivotal in biomedical research. Organic probes exhibit high potential in clinical translation, due to advantages such as precise structure design, low toxicity, and post-modifications convenience. In related preparation, enhancement of NIR-II tail emission from NIR-I dyes is an efficient method. In particular, the promotion of twisted intramolecular charge transfer (TICT) of relevant NIR-I dyes is a convenient protocol. However, present TICT-type probes still show disadvantages in relatively low emission, large particle sizes, or limited choice of NIR-I dyes, etc. Herein, the synthesis of stable small-sized polymer NIR-II fluoroprobes (e.g., 7.2 nm), integrating TICT and Förster resonance energy transfer process to synergistically enhance the NIR-II emission is reported. Strong enhanced emissions can be obtained from various NIR-I dyes and lanthanide elements (e.g., twelvefold at 1250 nm from Nd-DTPA/IR-808 sample). The fluorophore provides high-resolution angiography, with high-contrast imaging on middle cerebral artery occlusion model mice for distinguishing occlusion. The fluorophore can be rapidly excreted from the kidney (urine ≈65% within 4 h) in normal mice and exhibits long-term renal retention on acute kidney injury mice, showing potential applications in the prognosis of kidney diseases. This development provides an effective strategy to design and synthesize effective NIR-II fluoroprobes.

TNIK's emerging role in cancer, metabolism, and age-related diseases.

Traf2- and Nck-interacting kinase (TNIK) has emerged as a key regulator of pathological metabolic signaling in several diseases and is a promising drug target. Originally studied for its role in cell migration and proliferation, TNIK possesses several newly identified functions that drive the pathogenesis of multiple diseases. Specifically, we evaluate TNIK's newfound roles in cancer, metabolic disorders, and neuronal function. We emphasize the implications of TNIK signaling in metabolic signaling and evaluate the translational potential of these discoveries. We also highlight how TNIK's role in many biological processes converges upon several hallmarks of aging. We conclude by discussing the therapeutic landscape of TNIK-targeting drugs and the recent success of clinical trials targeting TNIK.

Effect of probiotics and synbiotics on complications of wound infection after colorectal surgery: A meta-analysis.

Wound infection is a serious complication that impacts the prognosis of patients after colorectal surgery (CS). Probiotics and synbiotics (Pro and Syn) are live bacteria that produce bacteriostatic agents in the intestinal system and have a positive effect on postoperative wound infections. The purpose of this study was to evaluate the effect of Pro and Syn on complications of wound infection after CS. In November 2023, we searched relevant clinical trial reports from Pubmed, Cochrane Library, and Embase databases and screened the retrieved reports, extracted data, and finally analysed the data by using RevMan 5.3. A total of 12 studies with 1567 patients were included in the study. Pro and Syn significantly reduced total infection (OR, 0.44; 95% CI, 0.35, 0.56; p < 0.00001), surgical incision site infection (SSI) (OR, 0.61; 95% CI, 0.45, 0.81; p = 0.002), pneumonia (OR, 0.43; 95% CI, 0.25, 0.72; p = 0.001), urinary tract infection (OR, 0.28; 95% CI, 0.14, 0.56; p = 0.0003), and Pro and Syn did not reduce anastomotic leakage after colorectal surgery (OR, 0.84; 95% CI, 0.50, 1.41; p = 0.51). Pro and Syn can reduce postoperative wound infections in patients with colorectal cancer, which benefits patients' postoperative recovery.

Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors.

Protein tyrosine phosphatases PTPN2 and PTPN1 (also known as PTP1B) have been implicated in a number of intracellular signaling pathways of immune cells. The inhibition of PTPN2 and PTPN1 has emerged as an attractive approach to sensitize T cell anti-tumor immunity. Two small molecule inhibitors have been entered the clinic. Here we report the design and development of compound 4, a novel small molecule PTPN2/N1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy.

Diagnostic Value of Stimulated Urine Luteinizing Hormone After Triptorelin Stimulation Test in Girls with Central Precocious Puberty.

OBJECTIVE: To investigate the diagnostic value of urine luteinizing hormone (ULH) after the triptorelin stimulation test detected by immunochemiluminometric assay (ICMA) in girls with central precocious puberty (CPP). METHODS: The girls with precocious puberty were included. The triptorelin stimulation test at 8:30 a.m. was performed. Two consecutive 12-hour urine samples were collected after the test, defined as the first 12-hour and second 12-hour urine, respectively. ICMA measured ULH. Urine creatinine (Cr) concentration was measured. CPP and peripheral precocious puberty (PPP) were diagnosed by the same pediatric endocrinologist based on clinical symptoms, signs, and progression of clinical development. RESULTS: A total of 97 cases (CPP n=69; PPP n=28) were included, with 12 cases not meeting the receiver operating characteristic analysis criteria. The first and second 12-hour ULH/Cr in the CPP group were higher than those in the PPP group. When the first 12-hour ULH/Cr was≥287.252 IU/mol, the sensitivity and specificity for diagnosing CPP were 87.3% and 90.9%, respectively. When the second 12-hour ULH/Cr was≥152.769 IU/mol, the sensitivity and specificity for diagnosing CPP were 92.1% and 90.9%, respectively. The area under the curve of the first and second 12-hour ULH/Cr were 0.933 and 0.954, respectively. CONCLUSION: The ULH detection method after the triptorelin stimulation test has clinical significance for diagnosing CPP in girls. When blood sampling compliance in girls with precocious puberty is poor, the first 12-hour ULH/Cr≥288 IU/mol (or second 12-hour≥153 IU/mol) after the triptorelin stimulation test can serve as a laboratory indicator for diagnosis of CPP.

Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Morphology and Compressive Properties of Extruded Polyethylene Terephthalate Foam.

The cell structure and compressive properties of extruded polyethylene terephthalate (PET) foam with different densities were studied. The die of the PET foaming extruder is a special multi-hole breaker plate, which results in a honeycomb-shaped foam block. The SEM analysis showed that the aspect ratio and cell wall thickness of the strand border is greater than that of the strand body. The cells are elongated and stronger in the extruding direction, and the foam anisotropy of the structure and compressive properties decrease with increasing density. The compression results show typical stress-strain curves even though the extruded PET foam is composed of multiple foamed strands. The compression properties of PET foam vary in each of the three directions, with the best performing direction (i.e., extrusion direction) showing stretch-dominated structures, while the other two directions show bending-dominated structures. Foam mechanics models based on both rectangular and elongated Kelvin cell geometries were considered to predict the compressive properties of PET foams in terms of relative density, structure anisotropy, and the properties of the raw polymer. The results show that the modulus and strength anisotropy of PET foam can be reasonably predicted by the rectangular cell model, but more accurate predictions were obtained with an appropriately assumed elongated Kelvin model.

Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors.

Inhibition of the low fidelity DNA polymerase Theta (Polθ) is emerging as an attractive, synthetic-lethal antitumor strategy in BRCA-deficient tumors. Here we report the AI-enabled development of 3-hydroxymethyl-azetidine derivatives as a novel class of Polθ inhibitors featuring central scaffolding rings. Structure-based drug design first identified A7 as a lead compound, which was further optimized to the more potent derivative B3 and the metabolically stable deuterated compound C1. C1 exhibited significant antiproliferative properties in DNA repair-compromised cells and demonstrated favorable pharmacokinetics, showcasing that 3-hydroxymethyl-azetidine is an effective bio-isostere of pyrrolidin-3-ol and emphasizing the potential of AI in medicinal chemistry for precise molecular modifications.

Nanoarchitectonics of Bimetallic Cu-/Co-Doped Nitrogen-Carbon Nanozyme-Functionalized Hydrogel with NIR-Responsive Phototherapy for Synergistic Mitigation of Drug-Resistant Bacterial Infections.

Superbug infections and transmission have become major challenges in the contemporary medical field. The development of novel antibacterial strategies to efficiently treat bacterial infections and conquer the problem of antimicrobial resistance (AMR) is extremely important. In this paper, a bimetallic CuCo-doped nitrogen-carbon nanozyme-functionalized hydrogel (CuCo/NC-HG) has been successfully constructed. It exhibits photoresponsive-enhanced enzymatic effects under near-infrared (NIR) irradiation (808 nm) with strong peroxidase (POD)-like and oxidase (OXD)-like activities. Upon NIR irradiation, CuCo/NC-HG possesses photodynamic activity for producing singlet oxygen(1O2), and it also has a high photothermal conversion effect, which not only facilitates the elimination of bacteria but also improves the efficiency of reactive oxygen species (ROS) production and accelerates the consumption of GSH. CuCo/NC-HG shows a lower hemolytic rate and better cytocompatibility than CuCo/NC and possesses a positive charge and macroporous skeleton for restricting negatively charged bacteria in the range of ROS destruction, strengthening the antibacterial efficiency. Comparatively, CuCo/NC and CuCo/NC-HG have stronger bactericidal ability against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AmprE. coli) through destroying the cell membranes with a negligible occurrence of AMR. More importantly, CuCo/NC-HG plus NIR irradiation can exhibit satisfactory bactericidal performance in the absence of H2O2, avoiding the toxicity from high-concentration H2O2. In vivo evaluation has been conducted using a mouse wound infection model and histological analyses, and the results show that CuCo/NC-HG upon NIR irradiation can efficiently suppress bacterial infections and promote wound healing, without causing inflammation and tissue adhesions.

Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform.

Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.