A highly conductive, robust, self-healable, and thermally responsive liquid metal-based hydrogel for reversible electrical switches.

This study introduces a thermally responsive smart hydrogel with enhanced electrical properties achieved through volume switching. This advancement was realized by incorporating multiscale liquid metal particles (LMPs) into the PNIPAM hydrogel during polymerization, using their inherent elasticity and conductivity when deswelled. Unlike traditional conductive additives, LMPs endow the PNIPAM hydrogel with a remarkably consistent volume switching ratio, significantly enhancing electrical switching. This is attributed to the minimal nucleation effect of LMPs during polymerization and their liquid-like behavior, like vacancies in the polymeric hydrogel under compression. The PNIPAM/LMP hydrogel exhibits the highest electrical switching, with an unprecedented switch of 6.1 orders of magnitude. Even after repeated swelling/deswelling cycles that merge some LMPs and increase the conductivity when swelled, the hydrogel consistently maintains an electrical switch exceeding 4.5 orders of magnitude, which is still the highest record to date. Comprehensive measurements reveal that the hydrogel possesses robust mechanical properties, a tissue-like compression modulus, biocompatibility, and self-healing capabilities. These features make the PNIPAM/LMP hydrogel an ideal candidate for long-term implantable bioelectronics, offering a solution to the mechanical mismatch with dynamic human tissues.

Shape memory polyurethanes crosslinked with castor oil-based multifunctional polyols.

As both the industry and academia become more focused on biomass-based smart materials, they are attracting a lot of attention. There has been a significant effort in the field of polyurethane (PU) synthesis to replace polyols used in synthesis with bio-derived polyols. Bio-derived polyols have limited application potential for bio-based PU due to their low functionality. Here, we reported castor oil (CO) based multifunctional polyols prepared by grafting thiols such as 1-mercaptoethanol or α-thioglycerol via a facile thiol-ene click reaction method (coded as COM and COT, respectively). Subsequently, bio-based shape memory polyurethanes (SMPU) crosslinked with prepared polyols were synthesized using a 2-step prepolymer method. By confirming the functionality of the synthesized polyols, it was determined that COT has an OH value of 380 mg KOH/g, which is approximately three times that of CO. The successful synthesis of SMPUs was confirmed through chemical structural analysis. It was also proved that the phase separation between the soft and hard segments was limited due to the increase in crosslinking density. As compared to SMPU crosslinked with CO, the mechanical strength of SMPU crosslinked with COT was improved by 80%, while the elongation was decreased by about 26%. As a result of shape memory behavior analysis, it was confirmed that the outstanding SMPU can be synthesized using CO-based multifunctional polyols.

Sex-Specific Comparison Between Triglyceride Glucose Index and Modified Triglyceride Glucose Indices to Predict New-Onset Hypertension in Middle-Aged and Older Adults.

Background Triglyceride and glucose (TyG) index and TyG-related indices combined with obesity-related markers are considered important markers of insulin resistance. We aimed to examine the association between the TyG index and modified TyG indices with new-onset hypertension and their predictive ability stratified by sex. Methods and Results We analyzed data from 5414 Korean Genome and Epidemiology Study participants aged 40 to 69 years. Multiple Cox proportional hazard regression analyses were conducted to estimate the hazard ratio (HR) and 95% CI for new-onset hypertension according to sex-specific tertile groups after confounder adjustments. To evaluate the predictive performance of these indices for new-onset hypertension, we calculated Harrell's C-index (95% CI). Over a 9.5-year follow-up period, 1014 men and 1012 women developed new-onset hypertension. Compared with the lowest tertile (T) group, the adjusted HR and 95% CI for new-onset hypertension in T3 for TyG, TyG-body mass index, TyG-waist circumference, and TyG-waist-to-height ratio were 1.16 (0.95-1.40), 1.11 (0.84-1.48), 1.77 (1.38-2.27), and 1.68 (1.33-2.13) in men and 1.37 (1.13-1.66), 1.55 (1.16-2.06), 1.43 (1.15-1.79), and 1.64 (1.30-2.07) in women, respectively. The C-indices of TyG-waist-to-height ratio for new-onset hypertension were significantly higher than those of TyG and TyG-body mass index in both men and women. Conclusions TyG and TyG-body mass index were significantly associated with new-onset hypertension only in women. TyG-waist circumference and TyG-waist-to-height ratio were significantly associated with new-onset hypertension in both men and women. A sex-specific approach is required when using TyG and modified TyG indices to identify individuals at risk of incident hypertension.

Amyloid Fibers Increase Free Radicals of Synthetic Melanin.

Functional amyloid fibers are crucial in melanogenesis, but their roles are incompletely understood. In particular, their relationship with intrinsic spin characters of melanin remains unexplored. Here, we show that adding an amyloid scaffold greatly augments the spin density in synthetic melanin. It also brings about concurrent alterations in water dispersibility, bandgaps, and radical scavenging properties of the synthetic melanin, which facilitates its applications in solar water remediation and protection of human keratinocytes from UV irradiation. This work provides implications in the unrevealed role of functional amyloid in melanogenesis and in the origin of the superiority of natural melanin toward its synthetic variants in terms of the spin-related properties.

Impact fracture mechanism and heat deflection temperature of PLA/PEICT blends reinforced by glass fiber.

To enhance the crack propagation and initiation properties and heat deflection temperature of poly(lactic acid) (PLA), PLA/poly(1,4-cyclohexanedimethylene isosorbide terephthalate) (PEICT) blend systems were prepared and glass fibers (GF) were incorporated as reinforcements. Due to high shear force during extrusion and injection molding the length of GF was reduced and was oriented towards the flow direction. Although the reinforcing effect of the GF deviated from the theoretical values calculated by the Halpin-Tsai equation, both tensile and flexural properties were greatly enhanced with increasing GF content. Dynamic mechanical and thermal testing showed improved storage modulus throughout the entire temperature range showing outstanding reinforcing ability. By incorporating GF into the PLA/PEICT blend, the crack propagation and initiation properties were enhanced compared to pristine PLA. Such an increase in crack propagation properties was the result of enhanced modulus with the added GF. Moreover, because of the increased modulus, the heat deflection temperatures of the GF reinforced blends were drastically increased showing a value of 91.4 °C at 20 wt% GF loading. The high performance reached by the biomass-based composites developed in this research shows great possibility of replacing these conventional petroleum-based polymer systems.

Association between poly-sensitisation and sensitisation to staphylococcal enterotoxin A and B affecting allergic severity in children.

PURPOSE: Accumulating evidence suggests that Staphylococcus aureus plays a significant role as a disease modifier in upper and lower airway diseases. We aimed to assess the association between staphylococcal enterotoxins (SEs) with allergic diseases and the degree of allergen sensitisation in children, which remains unclear. METHODS: We retrospectively reviewed the medical records of 455 patients aged 3-18 years between March 2018 and March 2022. Clinical history and demographic data were obtained. The baseline study included paranasal sinus X-ray scan, multiple allergen simultaneous test, and ImmunoCAP® for measuring serum total and specific immunoglobulin E (IgE) levels to allergens and staphylococcal enterotoxin A and B (SEA and SEB). RESULTS: The mean age was 9.77 ± 4.3 years. 133 patients (29.2%) were sensitised to one inhalant allergen, and 188 patients (41.3%) showed polysensitisation. Patients sensitised to SEs showed higher total and specific IgE levels and total eosinophil counts compared to non-SE-sensitised patients. Sensitisation to SEs is closely associated with polysensitisation to inhalant allergens and allergic multimorbidity. When the SE-IgE value was 0.35 or higher, the odds ratio for allergen polysensitisation was significantly higher than when the SE-IgE value was lower than 0.35. CONCLUSIONS: Association between polysensitisation and sensitisation to SEs in children shows the higher the specific IgE levels for SEs, the higher the likelihood of polysensitisation. Considering the relationship between polysensitisation, high IgE levels, and the severity of allergic morbidity, sensitisation to SEs is thought to be related to allergy severity.

SARS-CoV-2 restructures host chromatin architecture.

Some viruses restructure host chromatin, influencing gene expression, with implications for disease outcome. Whether this occurs for SARS-CoV-2, the virus causing COVID-19, is largely unknown. Here we characterized the 3D genome and epigenome of human cells after SARS-CoV-2 infection, finding widespread host chromatin restructuring that features widespread compartment A weakening, A-B mixing, reduced intra-TAD contacts and decreased H3K27ac euchromatin modification levels. Such changes were not found following common-cold-virus HCoV-OC43 infection. Intriguingly, the cohesin complex was notably depleted from intra-TAD regions, indicating that SARS-CoV-2 disrupts cohesin loop extrusion. These altered 3D genome/epigenome structures correlated with transcriptional suppression of interferon response genes by the virus, while increased H3K4me3 was found in the promoters of pro-inflammatory genes highly induced during severe COVID-19. These findings show that SARS-CoV-2 acutely rewires host chromatin, facilitating future studies of the long-term epigenomic impacts of its infection.

CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC patients typically exhibit unfavorable outcomes due to its rapid growth and metastatic potential. Here, we found overexpression of CCN3 in TNBC patients. We identified that CCN3 knockdown diminished cancer stem cell formation, metastasis, and tumor growth in vitro and in vivo. Mechanistically, ablation of CCN3 reduced activity of the EGFR/MAPK pathway. Transcriptome profiling revealed that CCN3 induces glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, which in turn activates the EGFR pathway. An interrogation of the TCGA dataset further supported the transcriptional regulation of GPNMB by CCN3. Finally, we showed that CCN3 activates Wnt signaling through a ligand-dependent or -independent mechanism, which increases microphthalmia-associated transcription factor (MITF) protein, a transcription factor inducing GPNMB expression. Together, our findings demonstrate the oncogenic role of CCN3 in TNBC, and we propose CCN3 as a putative therapeutic target for TNBC.

Learning curve comparable study of microscopic and endoscopic type 1 tympanoplasty.

OBJECTIVES: The comparative efficacy of microscopic tympanoplasty (MT) and endoscopic tympanoplasty (ET) has been widely studied to some extent through meta-analyses. However, most studies on learning curve comparisons between the two surgeries were performed by experienced ET surgeons. We compared the surgical outcomes of MT and ET and evaluated the difference of learning curve between ET and MT performed by a single unskilled, in both MT and ET, surgeon. DESIGN: A total of 91 patients underwent ET and MT at a tertiary hospital. We reviewed the patients' medical records and analyzed all findings, including otoscopic pictures, pure tone audiometry (PTA) before and after surgery, and operation records. All operations were performed by a single otologist who had an experience of a year of otology fellowship at a tertiary university hospital. We compared the demographic and clinical characteristics, including age, sex, admission duration, and audiological outcomes before and after surgery. We also assessed the difference in the decrease in operation time. RESULTS: Among 91 patients, 44 were in the ET group and 47 were in the MT group. The mean age was 51.15 years, and 37 (40.7%) were men. Eighty-two (90.1%) patients were administered local anesthesia. Graft failure was observed in 19 (20.9%) patients, and the mean postoperative follow-up duration was 66.42 days. There were no statistically significant differences in age, sex, affected side, graft failure rate, and operation time between the ET and MT groups. There was a significant improvement in air conduction hearing and air-bone gap after surgery in both groups. Bone conduction hearing did not change before and after the surgery in either group. However, the improvement in air condition and reduction in the air-bone gap did not differ between the two groups. Multivariate linear regression analysis showed that there were no significant variables that affected operation time among age, sex, operation method (ET or MT), anesthesia, graft material, and technique. The spline regression analysis showed the decrease in operative time in ET was significantly faster than MT in the period from 8th to 19th cases. CONCLUSIONS: The surgical outcomes of ET are comparable to those of MT in terms of operation time, graft uptake, and postoperative hearing results, even in surgeons who are not experienced with both MT and ET. The operation time of ET was longer than that of MT in the early phase, and the decrease in the operating time was significantly faster in ET than in MT. Both MT and ET reached a plateau in the operation time, and this plateau appeared to be similar in both surgeries.

Acute depletion of human core nucleoporin reveals direct roles in transcription control but dispensability for 3D genome organization.

The nuclear pore complex (NPC) comprises more than 30 nucleoporins (NUPs) and is a hallmark of eukaryotes. NUPs have been suggested to be important in regulating gene transcription and 3D genome organization. However, evidence in support of their direct roles remains limited. Here, by Cut&Run, we find that core NUPs display broad but also cell-type-specific association with active promoters and enhancers in human cells. Auxin-mediated rapid depletion of two NUPs demonstrates that NUP93, but not NUP35, directly and specifically controls gene transcription. NUP93 directly activates genes with high levels of RNA polymerase II loading and transcriptional elongation by facilitating full BRD4 recruitment to their active enhancers. dCas9-based tethering confirms a direct and causal role of NUP93 in gene transcriptional activation. Unexpectedly, in situ Hi-C and H3K27ac or H3K4me1 HiChIP results upon acute NUP93 depletion show negligible changesS2211-1247(22)01437-1 of 3D genome organization ranging from A/B compartments and topologically associating domains (TADs) to enhancer-promoter contacts.

Occurrence of a postoperative maxillary mucocele 20 years after orbital wall reconstruction.

Mucoceles of the paranasal sinus are epithelial-lined cystic structures filled with mucus and have multiple etiologies, including recurrent inflammation, trauma, or intrinsic disease. Particularly, a postoperative maxillary mucocele (POMM) is a delayed complication of radical surgery of the maxillary sinus, and most cases occur after Caldwell-Luc operations. Patients mainly complain of facial swelling, toothache, and tenderness. POMM has rarely been reported from other causes; however, there have been no reports on the occurrence of POMM following orbital wall reconstruction. Herein, we report a case of a patient with a POMM that developed 20 years after the aforementioned surgery. The patient complained of facial pain with visual disturbance, and underwent marsupialization using a combination of sublabial and endoscopic approaches, and the symptoms improved without recurrence.

Synthesis and characterization of biopolyurethane crosslinked with castor oil-based hyperbranched polyols as polymeric solid-solid phase change materials.

Novel crosslinking bio polyurethane based polymeric solid-solid phase change materials (SSPCM) were synthesized using castor oil (CO) based hyperbranched polyols as crosslinkers. CO-based hyperbranched polyols were synthesized by grafting 1-mercaptoethanol or α-thioglycerol via a thiol-ene click reaction method (coded as COM and COT, respectively). Subsequently, the three SSPCMs were synthesized by a two-step prepolymer method. Polyethylene glycol was used as the phase change material in the SSPCMs, while the CO-based hyperbranched polyols and two types of diisocyanate (hexamethylene diisocyanate (HDI) and 4,4'-diphenylmethane diisocyanate) served as the molecular frameworks. Fourier transform infrared spectroscopy indicated the successful synthesis of the SSPCMs. The solid-solid transition of the prepared SSPCMs was confirmed by X-ray diffraction analysis and polarized optical microscopy. The thermal transition properties of the SSPCMs were analyzed by differential scanning microscopy. The isocyanate and crosslinker types had a significant influence on the phase transition properties. The SSPCM samples prepared using HDI and COT exhibited the highest phase transition enthalpy of 126.5 J/g. The thermal cycling test and thermogravimetric analysis revealed that SSPCMs exhibit outstanding thermal durability. Thus, the novel SSPCMs based on hyperbranched polyols have great potential for application as thermal energy storage materials.

Nasopharyngeal Tuberculosis with Concomitant Middle Ear Tuberculosis: A Case Report and Literature Review.

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), can affect the lungs (pulmonary TB) as well as other sites (extrapulmonary TB). Nasopharyngeal tuberculosis (NPTB) is a rare type of extrapulmonary TB. Since NPTB has nonspecific clinical presentation with low index of suspicion, it is difficult for clinicians to make an early diagnosis and proper treatment. We recently encountered a 42-year-old woman with NPTB concomitant with middle ear TB, which strongly mimicked nasopharyngeal carcinoma. Since the diagnosis of NPTB was difficult to confirm based on endoscopic findings and imaging studies, this patient underwent nasopharyngeal biopsy, and finally, polymerase chain reaction (PCR) confirmed NPTB. This report describes our NPTB case as well as summarizes all cases of NPTB reported in South Korea. We highlight that active tissue biopsy with antibacterial smear and additional PCR or specific TB blood test should be considered for cases with high suspicion of NPTB.

NANOG prion-like assembly mediates DNA bridging to facilitate chromatin reorganization and activation of pluripotency.

Human NANOG expression resets stem cells to ground-state pluripotency. Here we identify the unique features of human NANOG that relate to its dose-sensitive function as a master transcription factor. NANOG is largely disordered, with a C-terminal prion-like domain that phase-transitions to gel-like condensates. Full-length NANOG readily forms higher-order oligomers at low nanomolar concentrations, orders of magnitude lower than typical amyloids. Using single-molecule Förster resonance energy transfer and fluorescence cross-correlation techniques, we show that NANOG oligomerization is essential for bridging DNA elements in vitro. Using chromatin immunoprecipitation sequencing and Hi-C 3.0 in cells, we validate that NANOG prion-like domain assembly is essential for specific DNA recognition and distant chromatin interactions. Our results provide a physical basis for the indispensable role of NANOG in shaping the pluripotent genome. NANOG's unique ability to form prion-like assemblies could provide a cooperative and concerted DNA bridging mechanism that is essential for chromatin reorganization and dose-sensitive activation of ground-state pluripotency.

Sarcopenia's Prognostic Impact on Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

BACKGROUND: Although sarcopenia has been reported to predict survival in cancer patients, its impact on patients who received immune checkpoint inhibitors (ICIs) has not been thoroughly investigated. This systematic review aimed to assess the long-term oncologic impact of sarcopenia on patients who received ICIs. METHODS: A systematic review of studies indexed in the PubMed, Embase, and Cochrane databases, up to April 1, 2021, was conducted. Studies that reported hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) based on sarcopenia in patients treated with ICIs were included. The inverse variance method was used with a random-effects model for data analysis. RESULTS: A total of 1284 patients from 14 studies were included. Among the patients who received ICIs, patients with sarcopenia had a significant increase in overall mortality compared to patients without sarcopenia in univariate analyses (HR = 1.66, 95% CI = 1.20-2.29, p = 0.002) and in adjusted HRs (HR = 1.55, 95% CI = 1.15-2.10, p = 0.004). The same results were obtained for PFS by both univariate analysis (HR = 1.75, 95% CI = 1.37-2.23, p < 0.001) and adjusted HRs (HR = 1.63, 95% CI 1.28-2.09, p < 0.001). CONCLUSIONS: Sarcopenia appears to be an effective biomarker for predicting long-term oncologic outcomes in patients receiving ICI therapy and hence plays an important role when making treatment decisions. However, the fundamental role of this association with survival should be further investigated in large cohorts and clinical trials.

Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation.

The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control.

SARS-CoV-2 Restructures the Host Chromatin Architecture.

SARS-CoV-2 has made >190-million infections worldwide, thus it is pivotal to understand the viral impacts on host cells. Many viruses can significantly alter host chromatin 1 , but such roles of SARS-CoV-2 are largely unknown. Here, we characterized the three-dimensional (3D) genome architecture and epigenome landscapes in human cells after SARS-CoV-2 infection, revealing remarkable restructuring of host chromatin architecture. High-resolution Hi-C 3.0 uncovered widespread A compartmental weakening and A-B mixing, together with a global reduction of intra-TAD chromatin contacts. The cohesin complex, a central organizer of the 3D genome, was significantly depleted from intra-TAD regions, supporting that SARS-CoV-2 disrupts cohesin loop extrusion. Calibrated ChIP-Seq verified chromatin restructuring by SARS-CoV-2 that is particularly manifested by a pervasive reduction of euchromatin modifications. Built on the rewired 3D genome/epigenome maps, a modified activity-by-contact model 2 highlights the transcriptional weakening of antiviral interferon response genes or virus sensors (e.g., DDX58 ) incurred by SARS-CoV-2. In contrast, pro-inflammatory genes (e.g. IL-6 ) high in severe infections were uniquely regulated by augmented H3K4me3 at their promoters. These findings illustrate how SARS-CoV-2 rewires host chromatin architecture to confer immunological gene deregulation, laying a foundation to characterize the long-term epigenomic impacts of this virus.

Usefulness of stress-related hormones as predictors and prognostic factors for idiopathic sudden sensorineural hearing loss.

BACKGROUND: The pathogenesis of Idiopathic sudden sensorineural hearing loss (ISSNHL) is ambiguous. Stress is commonly defined as a cause of the disease. Serum levels of stress-related hormone (cortisol, growth hormone, aldosterone, ADH, ACTH) may be elevated in patients with ISSNHL patients. OBJECTIVES: We aimed to determine whether psychological factors and stress hormones in patients are associated with the severity of hearing loss and therapeutic outcomes. We hypothesized that the stress hormone level in the disease sequence is a strong prognostic factor of ISSNHL. Additionally, we investigated whether the subjective degree of psychological stress is likely to contribute to the therapeutic prognosis of ISSNHL, as determined using questionnaires. METHODS: We conducted a prospective study of patients aged between 19 and 65 years admitted for the treatment of ISSNHL at our hospital. All patients underwent pure tone audiometry (PTA) on day 0, day 5 and 2 weeks after discharge. As an objective indicator of stress, we measured the level of HPA axis-related hormones. So, we measured serum cortisol, adrenocorticotropic hormone (ACTH), aldosterone and dehydroepiandrosterone sulfate (DHEAS) levels in the venous blood sample of patients on day 1 and day 5 after admission. In addition, for subjective stress measurements, depression and anxiety levels were assessed using self-reported questionnaires, Beck Depression Inventory (BDI), and Perceived Stress Scale (PSS) in the revised to Korean versions. RESULTS: Eighteen patients diagnosed with ISSNHL at the Department of Otorhino-laryngology were enrolled. Serum DHEAS level measured on day 1 showed a statistically significant correlation with the hearing threshold in the hearing test performed at the time of diagnosis (p = .037, correlation coefficients(r) = 0.541). Serum ACTH level was measured on day 1, and patients were classified into normal and elevated groups based on a threshold of 1.5 pg/mL; the normal group had better hearing thresholds in the first and second hearing test than the elevated group (p = .040, 0.015, respectively). In the stress-related questionnaires, the BDI score showed a statistically significant correlation with the last hearing test (p = .015, correlation coefficients(r) = 0.613). CONCLUSION: We demonstrated the possible role of stress-related hormones in the pathogenesis of ISSNHL and suggest that depressive stress response can be a strong predictor of treatment response in patients with ISSNHL. However, the impact of response to stress on the inner ear and endolymph homeostasis remains unknown. Since this is a cross-sectional study, we can only comment on the relationship between stress and ISSNHL, not a causal relationship. Further investigation is necessary to identify the mechanism of interaction between stress and hearing ability in the inner ear.

RNA m6A modification orchestrates a LINE-1-host interaction that facilitates retrotransposition and contributes to long gene vulnerability.

The molecular basis underlying the interaction between retrotransposable elements (RTEs) and the human genome remains poorly understood. Here, we profiled N6-methyladenosine (m6A) deposition on nascent RNAs in human cells by developing a new method MINT-Seq, which revealed that many classes of RTE RNAs, particularly intronic LINE-1s (L1s), are strongly methylated. These m6A-marked intronic L1s (MILs) are evolutionarily young, sense-oriented to hosting genes, and are bound by a dozen RNA binding proteins (RBPs) that are putative novel readers of m6A-modified RNAs, including a nuclear matrix protein SAFB. Notably, m6A positively controls the expression of both autonomous L1s and co-transcribed L1 relics, promoting L1 retrotransposition. We showed that MILs preferentially reside in long genes with critical roles in DNA damage repair and sometimes in L1 suppression per se, where they act as transcriptional "roadblocks" to impede the hosting gene expression, revealing a novel host-weakening strategy by the L1s. In counteraction, the host uses the SAFB reader complex to bind m6A-L1s to reduce their levels, and to safeguard hosting gene transcription. Remarkably, our analysis identified thousands of MILs in multiple human fetal tissues, enlisting them as a novel category of cell-type-specific regulatory elements that often compromise transcription of long genes and confer their vulnerability in neurodevelopmental disorders. We propose that this m6A-orchestrated L1-host interaction plays widespread roles in gene regulation, genome integrity, human development and diseases.

Enhancer release and retargeting activates disease-susceptibility genes.

The functional engagement between an enhancer and its target promoter ensures precise gene transcription1. Understanding the basis of promoter choice by enhancers has important implications for health and disease. Here we report that functional loss of a preferred promoter can release its partner enhancer to loop to and activate an alternative promoter (or alternative promoters) in the neighbourhood. We refer to this target-switching process as 'enhancer release and retargeting'. Genetic deletion, motif perturbation or mutation, and dCas9-mediated CTCF tethering reveal that promoter choice by an enhancer can be determined by the binding of CTCF at promoters, in a cohesin-dependent manner-consistent with a model of 'enhancer scanning' inside the contact domain. Promoter-associated CTCF shows a lower affinity than that at chromatin domain boundaries and often lacks a preferred motif orientation or a partnering CTCF at the cognate enhancer, suggesting properties distinct from boundary CTCF. Analyses of cancer mutations, data from the GTEx project and risk loci from genome-wide association studies, together with a focused CRISPR interference screen, reveal that enhancer release and retargeting represents an overlooked mechanism that underlies the activation of disease-susceptibility genes, as exemplified by a risk locus for Parkinson's disease (NUCKS1-RAB7L1) and three loci associated with cancer (CLPTM1L-TERT, ZCCHC7-PAX5 and PVT1-MYC).