Homotopy, symmetry, and non-Hermitian band topology.

Non-Hermitian matrices are ubiquitous in the description of nature ranging from classical dissipative systems, including optical, electrical, and mechanical metamaterials, to scattering of waves and open quantum many-body systems. Seminal line-gap and point-gap classifications of non-Hermitian systems using K-theory have deepened the understanding of many physical phenomena. However, ample systems remain beyond this description; reference points and lines do not in general distinguish whether multiple non-Hermitian bands exhibit intriguing exceptional points, spectral braids and crossings. To address this we consider two different notions: non-Hermitian band gaps and separation gaps that crucially encompass a broad class of multi-band scenarios, enabling the description of generic band structures with symmetries. With these concepts, we provide a unified and comprehensive classification of both gapped and nodal systems in the presence of physically relevant parity-time (PT) and pseudo-Hermitian symmetries using homotopy theory. This uncovers new stable topology stemming from both eigenvalues and wave functions, and remarkably also implies distinct fragile topological phases. In particular, we reveal different Abelian and non-Abelian phases inPT-symmetric systems, described by frame and braid topology. The corresponding invariants are robust to symmetry-preserving perturbations that do not induce (exceptional) degeneracy, and they also predict the deformation rules of nodal phases. We further demonstrate that spontaneousPTsymmetry breaking is captured by Chern-Euler and Chern-Stiefel-Whitney descriptions, a fingerprint of unprecedented non-Hermitian topology previously overlooked. These results open the door for theoretical and experimental exploration of a rich variety of novel topological phenomena in a wide range of physical platforms.

Supramolecular interactions in cocrystals of benzoic acid derivatives with selective COX-2 inhibitor etoricoxib.

The structures of three 1:1 cocrystal forms of etoricoxib {ETR; systematic name: 5-chloro-2-(6-methylpyridin-3-yl)-3-[4-(methylsulfonyl)phenyl]pyridine, C18H15ClN2O2S} have been synthesized and characterized by single-crystal X-ray diffraction; these are etoricoxib-benzoic acid (1/1), C18H15ClN2O2S·C7H6O2 (ETR-Bz), etoricoxib-4-fluorobenzoic acid (1/1), C18H15ClN2O2S·C7H5FO2 (ETR-PFB), and etoricoxib-4-nitrobenzoic acid (1/1), C18H15ClN2O2S·C7H5NO4 (ETR-PNB). Powder X-ray diffraction and thermal differential scanning calorimetry-thermogravimetry (DSC-TG) techniques were also used to characterize these multicomponent systems. Due to the influence of the corresponding acids, ETR shows different conformations. Furthermore, the energetic contributions of the supramolecular motifs have been established by energy framework studies of the stabilizing interaction forces and are consistent with the thermal stability of the cocrystals.

Nitrite induces hepatic glucose and lipid metabolism disorders in zebrafish through mitochondrial dysfunction and ERs response.

Nitrite, a highly toxic environmental contaminant, induces various physiological toxicities in aquatic animals. Herein, we investigate the in vivo effects of nitrite exposure at concentrations of 0, 0.2, 2, and 20 mg/L on glucose and lipid metabolism in zebrafish. Our results showed that exposure to nitrite induced mitochondrial oxidative stress in zebrafish liver and ZFL cells, which were evidenced by increased levels of malondialdehyde (MDA) and reactive oxygen species (ROS) as well as decreased mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP). Changes in these oxidative stress markers were accompanied by alterations in the expression levels of genes involved in HIF-1α pathway (hif1α and phd), which subsequently led to the upregulation of glycolysis and gluconeogenesis-related genes (gk, pklr, pdk1, pepck, g6pca, ppp1r3cb, pgm1, gys1 and gys2), resulting in disrupted glucose metabolism. Moreover, nitrite exposure activated ERs (Endoplasmic Reticulum stress) responses through upregulating of genes (atf6, ern1 and xbp1s), leading to increased expression of lipolysis genes (pparα, cpt1aa and atgl) and decreased expression of lipid synthesis genes (srebf1, srebf2, fasn, acaca, scd, hmgcra and hmgcs1). These results were also in consistent with the observed changes in glycogen, lactate and decreased total triglyceride (TG) and total cholesterol (TC) in the liver of zebrafish. Our in vitro results showed that co-treatment with Mito-TEMPO and nitrite attenuated nitrite-induced oxidative stress and improved mitochondrial function, which were indicated by the restorations of ROS, MMP, ATP production, and glucose-related gene expression recovered. Co-treatment of TUDCA and nitrite prevented nitrite-induced ERs response and which was proved by the levels of TG and TC ameliorated as well as the expression levels of lipid metabolism-related genes. In conclusion, our study suggested that nitrite exposure disrupted hepatic glucose and lipid metabolism through mitochondrial dysfunction and ERs responses. These findings contribute to the understanding of the potential hepatotoxicity for aquatic animals in the presence of ambient nitrite.

Corrigendum to "Hypoxia-triggered degradable porphyrinic covalent organic framework for synergetic photodynamic and photothermal therapy of cancer" [Mater. Today Bio 25, 2024, 100981].

[This corrects the article DOI: 10.1016/j.mtbio.2024.100981.].

Robust Spectral π Pairing in the Random-Field Floquet Quantum Ising Model.

Motivated by an experiment on a superconducting quantum processor [X. Mi et al., Science 378, 785 (2022).SCIEAS0036-807510.1126/science.abq5769], we study level pairings in the many-body spectrum of the random-field Floquet quantum Ising model. The pairings derive from Majorana zero and π modes when writing the spin model in Jordan-Wigner fermions. Both splittings have log-normal distributions with random transverse fields. In contrast, random longitudinal fields affect the zero and π splittings in drastically different ways. While zero pairings are rapidly lifted, the π pairings are remarkably robust, or even strengthened, up to vastly larger disorder strengths. We explain our results within a self-consistent Floquet perturbation theory and study implications for boundary spin correlations. The robustness of π pairings against longitudinal disorder may be useful for quantum information processing.

Prognostic value of the systemic immune-inflammation index in critically ill elderly patients with hip fracture: evidence from MIMIC (2008-2019).

Background: The systemic immune-inflammation index (SII) showed an extensive link between immunological dysfunction and the activation of systemic inflammation. Several studies have confirmed the application of SII to orthopedic diseases. However, the significance of SII in critically ill elderly individuals with hip fracture who require intensive care unit (ICU) admission is not yet known. This study centered on exploring the relationship between SII and clinical outcomes among critically ill elderly hip fracture individuals. Methods: The study centered around elderly patients experiencing severe illness following hip fractures and requiring admission to the ICU. These patients from the MIMIC-IV database formed the basis of this study's cohort. We stratified them into quartiles according to their SII levels. The results involved the mortality at 30 days and 1 year post-admission. Then we employ Cox proportional hazards regression analysis as well as restricted cubic splines to explore the association between the SII and clinical results in critically ill elderly patients with hip fracture. Results: The study encompassed 991 participants, among whom 63.98% identified as females. Notably, the mortality rates attributed to any cause within 30 days and 1 year after hospitalization stood at 19.68 and 33.40%, respectively. The multivariate Cox proportional hazards model disclosed a significant correlation between an elevated SII and all-cause mortality. Following adjustments for confounding variables, individuals with a high SII showed a notable correlation with 30-day mortality [adjusted hazard ratio (HR), 1.065; 95% confidence interval (CI), 1.044-1.087; p < 0.001] and 1-year mortality (adjusted HR, 1.051; 95% CI, 1.029-1.074; p < 0.001). Furthermore, the analysis of restricted cubic splines demonstrated a progressive increase in the risk of all-cause death as the SII value rose. Conclusion: Among critically ill elderly patients with hip fracture, the SII exhibits a non-linear association that positively correlates with both 30-day and 1-year all-cause mortality rates. The revelation indicates that the SII may play a vital role in identifying patients with hip fractures who face an escalated risk of mortality due to any cause.

Chemical profiling of principle active and toxic constituents in herbs containing aristolochic acids.

Objective: To clear the amounts of the principal active/toxic components in herbs containing aristolochic acids (HCAAs), which are still used as medicine and/or seasoning in many ethnic minority areas of China. Methods: In this study, six major active and toxic components in HCAAs were extracted with ultrasonic extraction. With 6-O-methyl guanosine as internal standard, the target compounds were analyzed qualitatively and quantitatively by using ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) with multiple reaction monitoring-information dependent acquisition-enhanced production ion scanning mode (MRM-IDA-EPI) combined with dynamic background subtraction (DBS) function. Results: The method showed good linearity in the linear range of the six analytes. The limit range of detection was from 0.01 ng/mL to 0.27 ng/mL. All of the detection repeatability, extraction repeatability and accuracy of the method were good. After extraction, the samples remained stable at 15 °C within 24 h. Six analytes were all found in samples except aristolactam (AL) in sample 2, and the contents varied greatly. The contents of these compounds decreased in fruits, leaves and stems of Aristolochia delavayi successively. Conclusion: This method has the advantages of less sample dosage, simple operation, short analysis cycle, high sensitivity, specificity and accuracy. It laid a good foundation for guiding the safety of HCAAs, the in-depth study of pharmacological and toxicological effects and the scientific and standardized processing and compatibility of HCAAs.

Combined use of Panax notoginseng and leech provides new insights into renal fibrosis: Restoration of mitochondrial kinetic imbalance.

In this study, we aimed to investigate the protective effects of Panax notoginseng and leech (PL) on renal fibrosis and explore the mechanisms underlying their actions. For this study, we created an adenine-induced renal fibrosis model in SD rats to investigate the protective effect of PL on renal fibrosis and explore its underlying mechanism. Initially, we assessed the renal function in RF rats and found that Scr, BUN, and urine protein content decreased after PL treatment, indicating the protective effect of PL on renal function. Histological analysis using HE and Masson staining revealed that PL reduced inflammatory cell infiltration and decreased collagen fiber deposition in renal tissue. Subsequently, we analyzed the levels of α-SMA, Col-IV, and FN, which are the main components of the extracellular matrix (ECM), using IHC, RT-qPCR, and WB. The results demonstrated that PL was effective in reducing the accumulation of ECM, with PL1-2 showing the highest effectiveness. To further understand the underlying mechanisms, we conducted UPLC-MS/MS analysis on the incoming components of the PL1-2 group. The results revealed several associations between the differential components and antioxidant and mitochondrial functions. This was further confirmed by enzyme-linked immunosorbent assay and biochemical indexes, which showed that PL1-2 ameliorated oxidative stress by reducing ROS and MDA production and increasing GSH and SOD levels. Additionally, transmission electron microscopy results indicated that PL1-2 promoted partial recovery of mitochondrial morphology and cristae. Finally, using RT-qPCR and WB, an increase in the expression of mitochondrial fusion proteins Mfn1, Mfn2, and Opa1 after PL1-2 treatment was observed, coupled with a decline in the expression and phosphorylation of mitochondrial cleavage proteins Fis and Drp1. These findings collectively demonstrate that PL1-2 ameliorates renal fibrosis by reducing oxidative stress and restoring mitochondrial balance.

Advancing treatment strategies for posterior malleolar malunion: The ankle dislocation method.

BACKGROUND: This study aimed to assess the radiological and clinical outcomes of treatment using the ankle dislocation method for posterior malleolar malunion. METHOD: Thirty-one patients with posterior malleolar malunion who underwent treatment using the ankle dislocation method from May 2015 to October 2021 were retrospectively analyzed. Key outcome measures were radiographic parameters (articular step-off, tibiofibular clear space, fibular length, tibial lateral surface angle, and ankle osteoarthritis), clinical scores (American Orthopaedic Foot and Ankle Society ankle-hindfoot scale and Visual Analogue Scale), and patient satisfaction rate. RESULT: Preoperative computed tomography revealed that Bartoní cek types 3 and 4 accounted for 64.5 % (n = 20) of total cases. Most posterior malleolar malunions were accompanied by depressed intercalary fragments (61.2 % [n = 19]). At the final follow-up, radiographic parameters and clinical scores showed significant improvements postoperatively (P < 0.05), with a high patient satisfaction rate of 77.4 %. Subgroup analysis revealed that the posterior malleolar fracture morphology significantly affected postoperative pain, particularly in more complex fractures (P < 0.001). CONCLUSION: The ankle dislocation method effectively exposes the distal tibial articular surface and facilitates the anatomical restoration of joint congruity under direct vision. This approach substantially improves the clinical and imaging outcomes in patients with complex posterior malleolar malunion. LEVELS OF EVIDENCE: Level IV, retrospective case series.

A novel homozygous CLN6 Tyr142Cys variant in a nonconsanguineous family with Kufs disease.

BACKGROUND: Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it's rare and challenging to diagnose. CASE DESCRIPTION: The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic-clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband's younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G. CONCLUSION: Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene.

Tumor targeted porphyrin-based metal-organic framework for photodynamic and checkpoint blockade immunotherapy.

Photodynamic therapy (PDT) has become a promising approach and non-invasive modality for cancer treatment, however the therapeutic effect of PDT is limited in tumor metastasis and local recurrence. Herein, a tumor targeted nanomedicine (designated as PCN@HA) is constructed for enhanced PDT against tumors. By modified with hyaluronic acid (HA), which could target the CD44 receptor that expressed on the cancer cells, the targeting ability of PCN@HA has been enhanced. Under light irradiation, PCN@HA can produce cytotoxic singlet oxygen (1O2) and kill cancer cells, then eliminate tumors. Furthermore, PCN@HA exhibits fluorescence (FL)/ photoacoustic (PA) effects for multimodal imaging-guided cancer treatment. And PCN@HA-mediated PDT also can induce immunogenic cell death (ICD) and stimulate adaptive immune responses by releasing of tumor antigens. By combining with anti-PD-L1 checkpoint blockade therapy, it can not only effectively suppress the growth of primary tumor, but also inhibit the metastatic tumor growth.

Engineering Properties and Microstructure of Soils Stabilized by Red-Mud-Based Cementitious Material.

Red mud (RM) is an industrial waste generated in the process of aluminum refinement. The recycling and reusing of RM have become urgent problems to be solved. To explore the feasibility of using RM in geotechnical engineering, this study combined magnesium oxide (MgO) (or calcium oxide (CaO)) with RM as an RM-based binder, which was then used to stabilize the soil. The physical, mechanical, and micro-structural properties of the stabilized soil were investigated. As the content of MgO or CaO in the mixture increased, the unconfined compressive strength (UCS) of the RM-based cementitious materials first increased and then decreased. For the soils stabilized with RM-MgO or RM-CaO, the UCS increased and then decreased, reaching a maximum at RM:MgO = 5:5 or RM:CaO = 8:2. The addition of sodium hydroxide (NaOH) promoted the hydration reaction. The UCS enhancement ranged from 8.09% to 66.67% for the RM-MgO stabilized soils and 204.6% to 346.6% for the RM-CaO stabilized soils. The optimum ratio of the RM-MgO stabilized soil (with NaOH) was 2:8, while that of the RM-CaO stabilized soil (with NaOH) was 4:6. Freeze-thaw cycles reduced the UCS of the stabilized soil, but the resistance of the stabilized soil to freeze-thaw erosion was significantly improved by the addition of RM-MgO or RM-CaO, and the soil stabilized with RM-MgO had better freeze-thaw resistance than that with RM-CaO. The hydrated magnesium silicate generated by the RM-MgO stabilized soil and the hydrated calcium silicate generated by the RM-CaO stabilized soil helped to improve the UCS of the stabilized soil. The freeze-thaw cycles did not weaken the formation of hydration products in the stabilized soil but could result in physical damage to the stabilized soils. The decrease in the UCS of the stabilized soil was mainly due to physical damage.

Vegetation restoration in an alpine meadow: Insights from soil microbial communities and resource limitation across soil depth.

Aboveground vegetation restoration shapes the soil microbial community structure and affects microbial resource acquisition. However, the changes in soil microbial resource limitation in subsoil during vegetation restoration are still unclear. In this study, the microbial community structure and resource limitation in an alpine meadow soil profile that had undergone natural restoration for short-term (4-year) and long-term (10-year) restoration in response to vegetation restoration were explored through high-throughput sequencing analysis and extracellular enzyme stoichiometry (EES). There was no significant difference in microbial composition and α diversity between short- and long-term restoration soils. Soil microorganisms in this alpine meadow were mainly limited by phosphorus. Carbon limitation of soil microorganisms was significantly decreased in each layer (0-15, 15-30, 30-45, 45-60, and 60-80 cm corresponding to L1, L2, L3, L4, and L5, respectively) of long-term restoration soils when compared to that of the short-term restoration soil layers, while phosphorus limitation of microorganisms in subsoil (60-80 cm) was significantly increased by 17.38%. Soil nutrients, pH, moisture content, and microbial composition are the main drivers of microbial resource limitation in restoration, and their effects on microbial resource limitation were different in short- and long-term restoration. Meanwhile, key microbial taxa have a significant impact on microbial resource limitation, especially in short-term restoration soils. This study suggested that vegetation restoration significantly affected soil microbial resource limitation, and could alleviate microbial resource limitations by adding nutrients, thus accelerating the process of vegetation restoration in alpine ecosystems.

A ferroptosis-related signature predicts the clinical diagnosis and prognosis, and associates with the immune microenvironment of lung cancer.

Targeting ferroptosis-related pathway is a potential strategy for treatment of lung cancer (LC). Consequently, exploration of ferroptosis-related markers is important for treating LC. We collected LC clinical data and mRNA expression profiles from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained through FerrDB database. Expression analysis was performed to obtain differentially expressed FRGs. Diagnostic and prognostic models were constructed based on FRGs by LASSO regression, univariate, and multivariate Cox regression analysis, respectively. External verification cohorts GSE72094 and GSE157011 were used for validation. The interrelationship between prognostic risk scores based on FRGs and the tumor immune microenvironment was analyzed. Immunocytochemistry, Western blotting, and RT-qPCR detected the FRGs level. Eighteen FRGs were used for diagnostic models, 8 FRGs were used for prognostic models. The diagnostic model distinguished well between LC and normal samples in training and validation cohorts of TCGA. The prognostic models for TCGA, GSE72094, and GSE157011 cohorts significantly confirmed lower overall survival (OS) in high-risk group, which demonstrated excellent predictive properties of the survival model. Multivariate Cox regression analysis further confirmed risk score was an independent risk factor related with OS. Immunoassays revealed that in high-risk group, a significantly higher proportion of Macrophages_M0, Neutrophils, resting Natural killer cells and activated Mast cells and the level of B7H3, CD112, CD155, B7H5, and ICOSL were increased. In conclusion, diagnostic and prognostic models provided superior diagnostic and predictive power for LC and revealed a potential link between ferroptosis and TIME.

Self-Assembly Study of Block Copolypeptoids in Response to pH and Temperature Stimulation.

Polypeptoids with well-designed structures have the ability to self-assemble into nanomaterials, which have wide potential applications. In this study, a series of diblock copolypeptoids were synthesized via ring-opening polymerization followed by click chemistry and exhibited both temperature and pH stimulation responsiveness. Under specific temperature and pH conditions, the responsive blocks in the copolypeptoids became hydrophobic and aggregated to form micelles. The self-assembly process was monitored using the UV-Vis and DLS methods, which suggested the reversible transition of free molecules to micelles and bigger aggregates upon instituting temperature and pH changes. By altering the length and proportion of each block, the copolypeptoids displayed varying self-assembly characteristics, and the transition temperature could be tuned. With good biocompatibility, stability, and no cytotoxicity, the polypeptoids reported in this study are expected to be applied as bionanomaterials in fields including drug delivery, tissue engineering, and intelligent biosensing.

Bioinspired construction of petal-like regenerated PVDF/cellulose fibers for efficient fog harvesting.

Water collection from atmospheric fog was deemed to be an efficient and sustainable strategy to defuse the freshwater scarcity crisis. Fog harvesting and trapping fibers, therefore, has aroused extensive interest due to their ease of preparation, weave, and use. However, the traditional fibers used in fog collector usually have a low fog collection capacity and efficiency because of their unreasonable morphology and structure design. Herein, we proposed a simple process to construct advanced fibers using a one-step wet spinning of hydrophobic polyvinylidene fluoride (PVDF) and hydrophilic cellulose mixture fiber for fog harvesting. The as-prepared fibers featured a petaloid structure and surface hydrophobic gradient, thus facilitating fog deposition, water droplet formation, and drainage. The unique longitudinal groove structure above enabled the hybrid fiber to achieve an excellent fog collection efficiency of 2750.26 mg/cm2/h per monofilament, which outstripped most of other fiber materials. When woven these fibers were in a longitudinal array network with an interval of 1 mm, and the fog collection efficiency can maintain at 10.30 L/m2/h. Therefore, this work provided a new strategy for further exploration of effective fog collection by cellulose-based fiber materials.

Would Combination Be Better: Swimming Exercise and Intermittent Fasting Improve High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Obese Rats via the miR-122-5p/SREBP-1c/CPT1A Pathway.

Background: Swimming and intermittent fasting can both improve obesity-induced NAFLD, but which of the two is more effective and whether the combination of the two has a superimposed effect is inconclusive. Methods: The model of NAFLD in obese rats was established by a high-fat diet and performed swimming, intermittent fasting, and a combination of both interventions for 8 weeks. Serum lipids and enzyme activity were measured by an automatic biochemical analyzer. Liver morphostructural analysis was observed by transmission electron microscopy, and morphology was observed by HE staining. RT‒PCR was used to detect the mRNA level. Results: Morphology and microstructure of the liver of model rats were impaired, with the upregulation of miR-122-5p, SREBP-1c, FASN and ACC1. Eight weeks of swimming exercise, intermittent fasting and the combination of both attenuate these effects, manifested by the downregulation of miR-122-5p and upregulation of CPT1A mRNA levels. There was no significant stacking effect of the combination of the swimming and intermittent fasting interventions. Conclusion: NAFLD leads to pathology in model rats. Eight weeks of swimming exercise, intermittent fasting and the combination of both can inhibit miR-122-5p and improve hepatic lipid metabolism, while no significant additive effects of combining the interventions were found.

Preparation of Peptoid Antifreeze Agents and Their Structure-Property Relationship.

The development of nontoxic and efficient antifreeze agents for organ cryopreservation is crucial. However, the research remains highly challenging. In this study, we designed and synthesized a series of peptoid oligomers using the solid-phase submonomer synthesis method by mimicking the amphiphilic structures of antifreeze proteins (AFPs). The obtained peptoid oligomers showed excellent antifreeze properties, reducing the ice crystal growth rate and inhibiting ice recrystallization. The effects of the hydrophobicity and sequence of the peptoid side chains were also studied to reveal the structure-property relationship. The prepared peptoid oligomers were detected as non-cytotoxic and considered to be useful in the biological field. We hope that the peptoid oligomers presented in this study can provide effective strategies for the design of biological cryoprotectants for organ preservation in the future.

Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors.

The duality of function (cell cycle regulation and gene transcription) of cyclin-dependent kinase 7 (CDK7) makes it an attractive oncology target and the discovery of CDK7 inhibitors has been a long-term pursuit by academia and pharmaceutical companies. However, achieving selective leading compounds is still difficult owing to the similarities among the ATP binding pocket. Herein, we detail the design and synthesis of a series of macrocyclic derivatives with pyrazolo[1,5-a]-1,3,5-triazine core structure as potent and selective CDK7 inhibitors. The diverse manners of macrocyclization led to distinguished selectivity profiles of the CDK family. Molecular dynamics (MD) simulation explained the binding difference between 15- and 16-membered macrocyclic compounds. Further optimization generated compound 37 exhibiting good CDK7 inhibitory activity and high selectivity over other CDKs. This work clearly demonstrated macrocyclization is a versatile method to finely tune the selectivity profile of small molecules and MD simulation can be a valuable tool in prioritizing designs of the macrocycle.