Cell-type-specific 3D epigenomes in the developing human cortex.

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone1,2. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.

Auditory change detection and visual selective attention: association between MMN and N2pc.

While the auditory and visual systems each provide distinct information to our brain, they also work together to process and prioritize input to address ever-changing conditions. Previous studies highlighted the trade-off between auditory change detection and visual selective attention; however, the relationship between them is still unclear. Here, we recorded electroencephalography signals from 106 healthy adults in three experiments. Our findings revealed a positive correlation at the population level between the amplitudes of event-related potential indices associated with auditory change detection (mismatch negativity) and visual selective attention (posterior contralateral N2) when elicited in separate tasks. This correlation persisted even when participants performed a visual task while disregarding simultaneous auditory stimuli. Interestingly, as visual attention demand increased, participants whose posterior contralateral N2 amplitude increased the most exhibited the largest reduction in mismatch negativity, suggesting a within-subject trade-off between the two processes. Taken together, our results suggest an intimate relationship and potential shared mechanism between auditory change detection and visual selective attention. We liken this to a total capacity limit that varies between individuals, which could drive correlated individual differences in auditory change detection and visual selective attention, and also within-subject competition between the two, with task-based modulation of visual attention causing within-participant decrease in auditory change detection sensitivity.

Automatic sensory change processing in adults with attention deficit and hyperactivity disorder: a visual mismatch negativity study.

In addition to higher-order executive functions, underlying sensory processing ability is also thought to play an important role in Attention-Deficit/Hyperactivity Disorder (AD/HD). An event-related potential feature, the mismatch negativity, reflects the ability of automatic sensory change processing and may be correlated with AD/HD symptoms and executive functions. This study aims to investigate the characteristics of visual mismatch negativity (vMMN) in adults with AD/HD. Twenty eight adults with AD/HD and 31 healthy controls were included in this study. These two groups were matched in age, IQ and sex. In addition, both groups completed psychiatric evaluations, a visual ERP task used to elicit vMMN, and psychological measures about AD/HD symptoms and day-to-day executive functions. Compared to trols, the late vMMN (230-330 ms) was significantly reduced in the AD/HD group. Correlation analyses showed that late vMMN was correlated with executive functions but not AD/HD symptoms. However, further mediation analyses showed that different executive functions had mediated the relationships between late vMMN and AD/HD symptoms. Our findings indicate that the late vMMN, reflecting automatic sensory change processing ability, was impaired in adults with AD/HD. This impairment could have negative impact on AD/HD symptoms via affecting day-to-day executive functions.

The neurovascular couplings between electrophysiological and hemodynamic activities in anticipatory selective attention.

Selective attention is thought to involve target enhancement and distractor inhibition processes. Here, we recorded simultaneous electroencephalographic (EEG) and functional near-infrared spectroscopy (fNIRS) data from human adults when they were pre-cued by the visual field of coming target, distractor, or both of them. From the EEG data, we found alpha power relatively decreased contralaterally to the to-be-attended target, as reflected by the positive-going alpha modulation index. Late alpha power relatively increased contralaterally to the to-be-suppressed distractor, as reflected by the negative-going alpha modulation index. From the fNIRS data, we found enhancements of hemodynamic activity over the contralateral hemisphere in response to both the target and the distractor anticipation but within nonoverlapping posterior brain regions. More importantly, we described the specific neurovascular modulation between alpha power and oxygenated hemoglobin signal, which showed a positive coupling effect during target anticipation and a negative coupling effect during distractor anticipation. Such flexible neurovascular couplings between EEG oscillation and hemodynamic activity seem to play an essential role in the final behavioral outcomes. These results provide unique neurovascular evidence for the dissociation of the mechanisms of target enhancement and distractor inhibition. Individual behavioral differences can be related to individual differences in neurovascular coupling.

Association between subtalar articular surface typing and flat foot deformity: which type is more likely to cause flat foot deformity.

BACKGROUND: Previous studies have shown a wide range of anatomical classifications of the subtalar joint (STJ) in the population and this is related to the different force line structures of the foot. Different subtalar articular surface morphology may affect the occurrence and development of flat foot deformity, and there are fewer studies in this area. The main objective of our study was to determine the association of different subtalar articular surface with the occurrence and severity of flat foot deformity. METHODS: We analyzed the imaging data of 289 cases of STJ. The articular surface area, Gissane's angle and Bohler's angle of subtalar articular surface of different types were counted. The occurrence and severity of flat foot deformity in different subtalar articular surface were judged by measuring the Meary angle of foot. RESULTS: We classified 289 cases of subtalar articular surface into five types according to the morphology. According to Meary angle, the flat foot deformity of Type I and Type IV are significantly severer than Type II (P < 0.05). Type II (7.65 ± 1.38 cm2) was significantly smaller than Type I (8.40 ± 1.79 cm2) in the total joint facet area(P < 0.05). Type III (9.15 ± 1.92 cm2) was smaller than Type I (8.40 ± 1.79 cm2), II (7.65 ± 1.38 cm2) and IV (7.81 ± 1.74 cm2) (P < 0.05). Type II (28.81 ± 7.44∘) was significantly smaller than Type I (30.80 ± 4.61 degrees), and IV (32.25 ± 5.02 degrees) in the Bohler's angle (P < 0.05). Type II (128.49 ± 6.74 degrees) was smaller than Type I (131.58 ± 7.32 degrees), and IV (131.94 ± 5.80 degrees) in the Gissane's angle (P < 0.05). CONCLUSIONS: After being compared and analyzed the measurement of morphological parameters, joint facet area and fusion of subtalar articular surface were closely related to the severity of flat foot deformity and Type I and IV were more likely to develop severer flat foot deformity. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Predictive factors of stone-free rate and complications in patients undergoing minimally invasive percutaneous nephrolithotomy under local infiltration anesthesia.

PURPOSE: To evaluate predictive factors affecting the stone-free rates (SFR) and complications of minimally invasive percutaneous nephrolithotomy (MPCNL) under local infiltration anesthesia (LIA) METHODS: A retrospective analysis was conducted on 976 consecutive patients who underwent MPCNL under LIA from January 2015 to June 2018. Postoperative complications were classified according to modified Clavien classification system. Univariate and multivariate logistic regression analyses were used to determine factors affecting SFR and complications. RESULTS: The pain was acceptable with postoperative visual analog scale (VAS) scores being 3.58, 2.99, 2.25, and 2.07 after 0, 6, 24, and 48 h, respectively. The SFR after primary MPCNL reached 85.7%. Postoperative complications were recorded in 77 patients (7.9%). In the univariate logistic analysis, larger stone size, staghorn stone, and multiple calyxes were significantly associated with lower SFR. The higher American Society of Anesthesiologists (ASA) score, staghorn stone, positive urine culture, multiple tracts, and longer operation time were associated with occurrence of complications. However, hydronephrosis was associated with lower complication rate. Multivariate analysis indicated that larger stone size (P < 0.001) and staghorn stone (P < 0.001) were associated with lower SFR, while development of complications was independently influenced by higher ASA score (P = 0.002), multiple tract (P = 0.004), and staghorn stone (P = 0.028). CONCLUSIONS: MPCNL can be safely and effectively performed under LIA. Stone size and staghorn stone are factors associated with SFR while ASA score, multiple tracts, and staghorn stone are associated with the development of complications. For the first time, we developed a model to predict the SFR and complications in MPCNL under LIA.

Acute exposure to triphenyl phosphate inhibits the proliferation and cardiac differentiation of mouse embryonic stem cells and zebrafish embryos.

Attention has recently paid to the interaction of triphenyl phosphate (TPHP) and body tissues, particularly within the reproductive and development systems, due to its endocrine-disrupting properties. However, the acute effects of TPHP on early embryonic development remain unclear. Here, we used mouse embryonic stem cells (mESC) and zebrafish embryos to investigate whether TPHP is an embryo toxicant. First, we found that continuous exposure of TPHP decreased the proliferation and increased the apoptotic populations of mESCs in a concentration-dependent manner. Results of mass spectrometry showed that the intracellular concentration of TPHP reached 39.45 ± 7.72 µg/g w/w after 3 hr of acute exposure with TPHP (38.35 µM) but gradually decreased from 3 hr to 48 hr. Additionally, DNA damage was detected in mESCs after a short-term treatment with TPHP, which in turn, activated DNA damage responses, leading to cell cycle arrest by changing the expression levels of p53, proliferating cell nuclear antigen, and Y15-phosphorylated Cdk I. Furthermore, our results revealed that short-term treatment with TPHP disturbed cardiac differentiation by decreasing the expression levels of Oct4, Sox2, and Nanog and transiently reduced the glycolysis capacity in mESCs. In zebrafish embryos, exposure to TPHP resulted in broad, concentration-dependent developmental defects and coupled with heart malformation and reduced heart rate. In conclusion, the two models demonstrate that acute exposure to TPHP affects early embryonic development and disturbs the cardiomyogenic differentiation.

Characteristics and Prognosis of Talaromyces marneffei Infection in Non-HIV-Infected Children in Southern China.

Knowledge about the clinical and laboratory characteristics and prognosis of Talaromyces marneffei infection in children is limited. A retrospective study was conducted on pediatric patients with disseminated T. marneffei infection in a clinical setting. Extracted data included demographic information (age and sex), clinical features, laboratory findings, treatment, and prognosis. Eleven HIV-negative children were enrolled. The male/female ratio was 8:3. The median age of onset was 17.5 months (3.5-84 months). The mortality rate in these children was 36.36% (4/11). Seven children had underlying diseases. All of the children had multiple immunoglobulin abnormalities and immune cell decline. Ten children received voriconazole treatment, and most of the children (7/10) had a complete response to therapy at primary and long-term follow-up assessment; only three children died of talaromycosis. One patient recovered from talaromycosis but died of leukemia. The child who received itraconazole treatment also showed clinical improvement. No adverse events associated with antifungal therapies were recorded during and after the treatment. Talaromycosis is an indicator disease for undiagnosed severe immunodeficiencies in children. Awareness of mycoses in children by pediatricians may prompt diagnosis and timely treatment. Voriconazole is an effective, well-tolerated therapeutic option for disseminated T. marneffei infection in non-HIV-infected children.

[Video endosopic inguinal lymphadenectomy for penile cancer].

Inguinal lymph node metastasis is one of the important factors affecting the prognosis of penile cancer. Conventional open inguinal lymphadenectomy, with a high rate of complications, seriously affects the effect of surgery and the patient's quality of life, and therefore is rarely employed nowadays as a treatment option. Video endosopic inguinal lymphadenectomy (VEIL), however, can significantly reduce the incidence rate of surgery-related complications, achieve a desirable control of the tumor, and markedly improve the prognosis. This review focuses on the application, development, indications, effectiveness and complications of VEIL in the treatment of penile cancer.

Ligation-free technique for dorsal vascular complex control during laparoscopic radical prostatectomy: a single-center experience from China.

OBJECTIVE: To illustrate a ligation-free technique and compare perioperative and postoperative outcomes of this technique versus the standard suture method. PATIENTS AND METHODS: This study is a retrospective review of 233 consecutive patients with localized prostate cancer who underwent ligation-free technique (n = 180, Group 1) or standard ligation (n = 53, Group 2) at an academic institution from February 2010 to January 2014. RESULTS AND LIMITATIONS: Operative time was significantly shorter in Group 1 than in Group 2 (148.47 vs. 164.25 min, p = 0.000). No difference in EBL was noted between the groups (191.11 vs. 185.06 mL, p = 0.055). Postoperative continence rates at 3, 6, and 12 months in Groups 1 and 2 were 40.0 versus 24.5, 54.4 versus 37.7, and 73.9 versus 71.7 %, respectively. These differences were statistically significant. No patient in either group had a positive apical surgical margin. During follow-up, tumor recurrence or metastasis was not observed in any patient. Limitations of the study include this retrospective study of a single-center experience and lack of potency appraisal. CONCLUSIONS: This present ligation-free technique showed a statistically significant shorter interval to recovery of continence and higher continence rates in short-term postoperative results by contrast to conventional suture ligation, but no significant difference was revealed in long-term urinary control. We offer this technique and the correlative data to provide more information for deeply understanding the precise construction of the dorsal vascular complex and the mechanism of urinary control.

A convenient and effective strategy for the enrichment of tumor-initiating cell properties in prostate cancer cells.

Stem-like prostate cancer (PrCa) cells, also called PrCa stem cells (PrCSCs) or PrCa tumor-initiating cells (PrTICs), are considered to be involved in the mediation of tumor metastasis and may be responsible for the poor prognosis of PrCa patients. Currently, the methods for PrTIC sorting are mainly based on cell surface marker or side population (SP). However, the rarity of these sorted cells limits the investigation of the molecular mechanisms and therapeutic strategies targeting PrTICs. For PrTIC enrichment, we induced cancer stem cell (CSC) properties in PrCa cells by transducing three defined factors (OCT3/4, SOX2, and KLF4), followed by culture with conventional serum-containing medium. The CSC properties in the transduced cells were evaluated by proliferation, cell cycle, SP assay, drug sensitivity technology, in vivo tumorigenicity, and molecular marker analysis of PrCSCs compared with parental cells and spheroids. After culture with serum-containing medium for 8 days, the PrCa cells transduced with the three factors showed significantly enhanced CSC properties in terms of marker gene expression, sphere formation, chemoresistance to docetaxel, and tumorigenicity. The percentage of CD133+/CD44+ cells was ninefold higher in the transduced cell population than in the adherent PC3 cell population (2.25 ± 0.62 vs. 0.25 ± 0.12 %, respectively), and the SP increased to 1.22 ± 0.18 % in the transduced cell population, but was undetectable in the adherent population. This method can be used to obtain abundant PrTIC material and enables a complete understanding of PrTIC biology and development of novel therapeutic agents targeting PrTICs.

IgG silencing induces apoptosis and suppresses proliferation, migration and invasion in LNCaP prostate cancer cells.

Immunoglobulin G (IgG) has been implicated in the progression of various cancers. This study explored the role of IgG in the proliferation, apoptosis, cell cycle and in vitro invasive properties of LNCaP prostate cancer cells. We used IGHG1 small interfering RNA to silence IgG1 expression in LNCaP cells. The efficacy of IgG1 gene knockdown was confirmed using qPCR and western blotting. The colony formation, proliferation, migration and invasion abilities of LNCaP cells after transfection were assessed using colony-forming, flow cytometry and transwell assays. The expressions of PCNA and caspase-3 proteins in LNCaP cells after transfection were detected with immunofluorescence staining and western blotting. IgG1 silencing significantly decreased the colony formation, survival, cell cycle progression, migration and invasion of LNCaP cells (p < 0.05). IgG1 silencing also reduced the amount of the proliferation marker PCNA and induced formation of the apoptotic marker caspase-3 (p < 0.05). Our results show that IgG1 produced by LNCaP cells confers advantages for tumor cell survival, proliferation, migration and invasion, suggesting that IgG1 is a potential target for prostate cancer treatment.

Construction of a three-dimensional model of renal stones: comprehensive planning for percutaneous nephrolithotomy and assistance in surgery.

OBJECTIVES: To construct a three-dimensional (3D) model of renal stones to facilitate comprehensive planning for percutaneous nephrolithotomy (PCNL) and to assist in surgery. METHODS: Fifteen patients with complex renal stones, including one patient with a horseshoe kidney, eight patients with partial/complete staghorn, and six patients with multiple renal stones, participated in our study. Computed tomography images of the unenhanced, arterial, venous, and excretory phases were obtained before surgery. Image segmentation and 3D reconstruction of the renal stones were performed using Mimics 12.1 software. A virtual safe and reliable percutaneous renal access route were established for each patient by comprehensive planning based on the 3D model of renal stones. PCNL was subsequently performed with the assistance of the 3D model. Patient demographics, surgical details, and postoperative treatment parameters were recorded. RESULTS: The 3D models of renal stones accurately represented the interrelationships between the intrarenal arteries and veins, collecting system, stones, and adjacent anatomical structures. PCNL was completed successfully in all 15 patients. The mean operating time was 75.6 ± 13.4 min. The change in hemoglobin concentration was 1.2 ± 0.3 g/l. The one-stage stone-free rate was 93.3%, and the final stone-free rate was 100%. No major postoperative complications were noted, except for postoperative pain in one case. CONCLUSION: Construction of a 3D model of renal stones with the aim of minimizing the risks of percutaneous procedures and achieving higher one-stage stone-free rates is feasible for comprehensive PCNL planning and assistance in patients with complex renal stones.

Urethral reconstruction using allogenic frozen-thawed bladder mucosa: an experimental study.

OBJECTIVE: To determine the feasibility and effectivity of allogenic frozen-thawed bladder mucosa for urethroplasty. METHODS: Bladder mucosa was harvested from 6 New Zealand rabbits. Changes in the bladder mucosa as seen by histological and electron microscope examination were compared between the frozen-thawed and fresh groups. Twelve urethral stricture models were established and randomly divided into two groups. In the test group, we performed urethroplasty with allogenic frozen-thawed bladder mucosa, and the same operation was done in the control group, but using fresh bladder mucosa. The result of retrograde urethrography and histological changes of the urethral sample were compared postoperatively. RESULTS: No obvious changes on histological and electron microscope examination were observed in the frozen-thawed bladder mucosa. Inflammation reaction of the surgical site in the test group was milder than that of the controls 2 weeks after surgery. The urethral epithelial cells grew well 2 weeks after surgery, but lots of epithelia were necrotic in the control group. The urethra of all rabbits in the test group had good continuity and the urethral lumen was large in the test group 2 months after surgery. There was a layer of urethral epithelium in the test group 2 months after surgery, whereas scar tissue was found in the control group. CONCLUSIONS: The freeze-thaw technique can maintain bladder mucosa structure and biological function. Frozen-thawed allogenic bladder mucosa may be a potential material for urethroplasty.

The next generation of EGFR inhibitors: a patenting perspective of PROTACs based EGFR degraders.

INTRODUCTION: Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials. AREAS COVERED: This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs. EXPERT OPINION: By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.

Abnormal Reactivity of Brain Oscillations to Visual Search Target in Children With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Previous studies have shown that impaired goal-directed alpha lateralization and functional disconnection within attention networks during the cue period are significant features of attention-deficit/hyperactivity disorder (ADHD). This study aimed to explore the role of brain oscillations in the visual search process, focusing on target-induced posterior alpha lateralization, midfrontal theta synchronization, and their functional connection in children with ADHD. METHODS: Electroencephalograms were recorded from typically developing (TD) children (n = 72) and children with ADHD (n = 96) while they performed a visual search task. RESULTS: Both the TD and ADHD groups showed significant midfrontal theta event-related synchronization (ERS) and posterior alpha lateralization. Compared with TD children, children with ADHD showed significantly lower theta ERS and higher target-induced alpha lateralization. TD children showed a positive trial-based correlation between theta ERS and alpha lateralization and a negative correlation between theta ERS and reaction time variability. However, all these correlations were absent in children with ADHD. CONCLUSIONS: Abnormal brain oscillations in children with ADHD indicate insufficient executive control function and the compensation of attention networks for attention deficits in visual selective attention. Cross-frequency disconnection reflects the common deficiency of executive control in the gating of target information. Our findings provide novel evidence for interpreting the features of brain oscillations during stimulus-driven selective attention in children with ADHD.

The effects of first-dose methylphenidate on the neural signatures of visual selective attention in children with attention-deficit/hyperactivity disorder.

Although methylphenidate (MPH) has been shown to significantly improve selective attention in children with attention-deficit/hyperactivity disorder (ADHD), the neural mechanism of this effect remains unclear. We investigated the effects of first-dose MPH on the neural signatures of visual selective attention in children with ADHD. We measured the impact of first-dose MPH on electrophysiological indexes from eighteen children with ADHD (8.9-15.2 years; 15 boys) while they performed a visual search task. MPH was administered in a double-blind placebo-controlled crossover design. MPH led to decreases in behavioral error rates and reaction times. For the electrophysiological indexes, MPH significantly increased the target-elicited N2pc amplitude and posterior P3 amplitude during the selective attention process. The trial-based correlation analysis revealed that the enhanced N2pc (more negative) and P3 (more positive) promoted the behavioral response speed for children with ADHD. The lower individual P3 amplitude was associated with higher severity of inattention symptoms. The severer inattention symptoms were related to weaker MPH effect on N2pc amplitude. These findings suggest that N2pc and P3 are closely related to the mechanism of MPH in the ADHD treatment.

Preparation of a Transient Thermal Expansion Rock Cracking Agent by Deposition Method and Its Nonisothermal Kinetics Study with Isoconversional Procedure and DAEM.

Cracking agents are indispensable and important products for national energy exploitation and large-scale infrastructure construction. Transient thermal expansion rock cracking agent is a new cracking agent product with excellent performance that has just appeared in recent years. However, it is still prepared by mechanical ball milling, which is considered not the best choice among traditional methods for preparing energetic materials. In this paper, a transient thermal expansion rock splitting agent was prepared by the chemical deposition method using carbon black and calcium peroxide as raw materials. The TG/DTG results show that the mass loss of the sample can be divided into four stages with the increase of temperature. It is worth noting that the mass loss of the TG curve of the sample during the entire thermal decomposition process is 93.385%, and the instantaneous weight loss is 78.07% (ß = 15 °C/min). Kinetic analysis of the thermal decomposition process of the samples was performed using an isotransformation program and a distributed activation energy model (DAEM). The activation energy E α of the thermal decomposition of the sample was iteratively calculated. The results show that the a-E a curve of the sample can be divided into two stages. The pyrolysis kinetics of the first stage was successfully analyzed by the DAEM method and its thermal conversion behavior was predicted. The thermal decomposition behavior of the second stage was analyzed by a traditional kinetic analysis method.

Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation.

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC50 and DC50 values, and ＞ 95 % maximum degradation (Dmax). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.

Functional characterization of Alzheimer's disease genetic variants in microglia.

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.