Kaposi's sarcoma-associated herpesvirus (KSHV) LANA prevents KSHV episomes from degradation.

Protein knockdown with an inducible degradation system is a powerful tool for studying proteins of interest in living cells. Here, we adopted the auxin-inducible degron (AID) approach to detail Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) function in latency maintenance and inducible viral lytic gene expression. We fused the mini-auxin-inducible degron (mAID) tag at the LANA N-terminus with KSHV bacterial artificial chromosome 16 recombination, and iSLK cells were stably infected with the recombinant KSHV encoding mAID-LANA. Incubation with 5-phenyl-indole-3-acetic acid, a derivative of natural auxin, rapidly degraded LANA within 1.5 h. In contrast to our hypothesis, depletion of LANA alone did not trigger lytic reactivation but rather decreased inducible lytic gene expression when we stimulated reactivation with a combination of ORF50 protein expression and sodium butyrate. Decreased overall lytic gene induction seemed to be associated with a rapid loss of KSHV genomes in the absence of LANA. The rapid loss of viral genomic DNA was blocked by a lysosomal inhibitor, chloroquine. Furthermore, siRNA-mediated knockdown of cellular innate immune proteins, cyclic AMP-GMP synthase (cGAS) and simulator of interferon genes (STING), and other autophagy-related genes rescued the degradation of viral genomic DNA upon LANA depletion. Reduction of the viral genome was not observed in 293FT cells that lack the expression of cGAS. These results suggest that LANA actively prevents viral genomic DNA from sensing by cGAS-STING signaling axis, adding novel insights into the role of LANA in latent genome maintenance.IMPORTANCESensing of pathogens' components is a fundamental cellular immune response. Pathogens have therefore evolved strategies to evade such cellular immune responses. KSHV LANA is a multifunctional protein and plays an essential role in maintaining the latent infection by tethering viral genomic DNA to the host chromosome. We adopted the inducible protein knockdown approach and found that depletion of LANA induced rapid degradation of viral genomic DNA, which is mediated by innate immune DNA sensors and autophagy pathway. These observations suggest that LANA may play a role in hiding KSHV episome from innate immune DNA sensors. Our study thus provides new insights into the role of LANA in latency maintenance.

Simultaneous Visualization of Microscopic Conductivity and Deformation in Conductive Elastomers.

Conductive elastomers are promising for a wide range of applications in many fields due to their unique mechanical and electrical properties, and an understanding of the conductive mechanisms of such materials under deformation is crucial. However, revealing the microscopic conduction mechanism of conductive elastomers is a challenge. In this study, we developed a method that combines in situ deformation nanomechanical atomic force microscopy (AFM) and conductive AFM to successfully and simultaneously characterize the microscopic deformation and microscopic electrical conductivity of nanofiller composite conductive elastomers. With this approach, we visualized the conductive network structure of carbon black and carbon nanotube composite conductive elastomers at the nanoscale, tracked their microscopic response under different compressive strains, and revealed the correlation between microscopic and macroscopic electrical properties. This technique is important for understanding the conductive mechanism of conductive elastomers and improving the design of conductive elastomers.

Insights into Mechanical Dynamics of Nanoscale Interfaces in Epoxy Composites Using Nanorheology Atomic Force Microscopy.

Interfacial polymer layers with nanoscale size play critical roles in dissipating the strain energy around cracks and defects in structural nanocomposites, thereby enhancing the material's fracture toughness. However, understanding how the intrinsic mechanical dynamics of the interfacial layer determine the toughening and reinforcement mechanisms in various polymer nanocomposites remains a major challenge. Here, by means of a recently developed nanorheology atomic force microscopy method, also known as nanoscale dynamic mechanical analysis (nDMA), we report direct mapping of dynamic mechanical responses at the interface of a model epoxy nanocomposite under the transition from a glassy to a rubbery state. We demonstrate a significant deviation in the dynamic moduli of the interface from matrix behavior. Interestingly, the sign of the deviation is observed to be reversed when the polymer changes from a glassy to a rubbery state, which provides an excellent explanation for the difference in the modulus reinforcement between glassy and rubbery epoxy nanocomposites. More importantly, nDMA loss tangent images unambiguously show an enhanced viscoelastic response at the interface compared to the bulk matrix in the glassy state. This observation can therefore provide important insights into the nanoscale toughening mechanism that occurs in epoxy nanocomposites due to viscoelastic energy dissipation at the interface.

Inhibition of high-fat diet-induced inflammatory responses in adipose tissue by SF1-expressing neurons of the ventromedial hypothalamus.

Inflammation and thermogenesis in white adipose tissue (WAT) at different sites influence the overall effects of obesity on metabolic health. In mice fed a high-fat diet (HFD), inflammatory responses are less pronounced in inguinal WAT (ingWAT) than in epididymal WAT (epiWAT). Here we show that ablation and activation of steroidogenic factor 1 (SF1)-expressing neurons in the ventromedial hypothalamus (VMH) oppositely affect the expression of inflammation-related genes and the formation of crown-like structures by infiltrating macrophages in ingWAT, but not in epiWAT, of HFD-fed mice, with these effects being mediated by sympathetic nerves innervating ingWAT. In contrast, SF1 neurons of the VMH preferentially regulated the expression of thermogenesis-related genes in interscapular brown adipose tissue (BAT) of HFD-fed mice. These results suggest that SF1 neurons of the VMH differentially regulate inflammatory responses and thermogenesis among various adipose tissue depots and restrain inflammation associated with diet-induced obesity specifically in ingWAT.

The Effect of the Axle End Structure and Number of Through-Space Bonds on the Properties of Rotaxane Crosslinked Polymers.

A rotaxane crosslinker (RC) is known to toughen the resulting rotaxane crosslinked polymer (RCP) via a stress dispersion effect that is attributed to the movable nature of the crosslinking structure. To evaluate this toughening mechanism in detail, a series of structure-definite RCs equipped with different axle end structures or different numbers of wheel components were synthesized, and subjected to free radical polymerization with a vinyl monomer to obtain RCPs. Analyses of the obtained RCPs revealed that the size of the axle end structure should be well-balanced to produce a strong toughening effect, and a [3]rotaxane crosslinker works more effectively than [2]rotaxane to toughen RCPs. The mobility of the crosslinking points, in terms of rotational and flipping movements, was more crucial to toughening the RCP than that of translational movement along the axle. The first observation of the above crucial findings proved the utility of the systematic molecular design used in this study.

Nonspherical Epoxy Resin Polymer Particles Synthesized via Solvent-Free Polyaddition Reactions.

Cubic liquid marbles (LMs) were fabricated by using various epoxy monomers as internal liquids and millimeter-sized polymer plates as stabilizers. Successively, cubic polymer particles were synthesized via solvent-free polyaddition reactions by exposing the cubic LMs to NH3 vapor used as a curing agent. The effect of the solubility parameters (SPs) for the epoxy monomers on the formation of the cubic polymer particles was investigated. As a result, we succeeded in fabricating cubic polymer particles reflecting the shapes of the original LMs by using epoxy monomers with SP values of 23.70-21.66 (MPa)1/2. Furthermore, the shapes of the LMs could be controlled on demand (e.g., pentahedral and rectangular) by control of the number of polymer plates per LM and/or coalescence of the LMs, resulting in fabrication of polymer particles with shapes reflecting those of the LMs.

Simultaneous Force and Fluorescence Spectroscopy on Single Chains of Polyfluorene: Effect of Intra-Chain Aggregate Coupling.

Conjugated polymer chains in compact conformations or in films exhibit spectral features that can be attributed to interactions between individual conjugated segments of the chain, including formation of aggregates or excimers. Here, we use atomic force microscopy (AFM) on single chains of the conjugated polymer polyfluorene (PFO) to control the intersegment interactions by mechanically unfolding the chain. Simultaneously with the force spectroscopy we monitor fluorescence from the single PFO chains using a fluorescence microscope. We found that mechanical stretching of the chain causes disappearance of the green emission band. This observation provides evidence that the green emission originates from an intrachain aggregated state on the self-folded chain, which is decoupled by the stretching. In addition, the stretching upon laser irradiation leads to the appearance of additional features in the force spectra, small force peaks in the initial stages of the unfolding. These features are attributed to a combination of excitonic and van der Waals coupling of a ground-state intrachain aggregate.

Overcoming the entropy of polymer chains by making a plane with terminal groups: a thermoplastic PDMS with a long-range 1D structural order.

Due to its unique physical and chemical properties, polydimethylsiloxane (PDMS) is widely used in many applications, in which covalent cross-linking is commonly used to cure the fluidic polymer. The formation of a non-covalent network achieved through the incorporation of terminal groups that exhibit strong intermolecular interactions has also been reported to improve the mechanical properties of PDMS. Through the design of a terminal group capable of two-dimensional (2D) assembly, rather than the generally used multiple hydrogen bonding motifs, we have recently demonstrated an approach for inducing long-range structural ordering of PDMS, resulting in a dramatic change in the polymer from a fluid to a viscous solid. Here we present an even more surprising terminal-group effect: simply replacing a hydrogen with a methoxy group leads to extraordinary enhancement of the mechanical properties, giving rise to a thermoplastic PDMS material without covalent cross-linking. This finding would update the general notion that less polar and smaller terminal groups barely affect polymer properties. Based on a detailed study of the thermal, structural, morphological and rheological properties of the terminal-functionalized PDMS, we revealed that 2D assembly of the terminal groups results in networks of PDMS chains, which are arranged as domains with long-range one-dimensional (1D) periodic order, thereby increasing the storage modulus of the PDMS to exceed its loss modulus. Upon heating, the 1D periodic order is lost at around 120 °C, while the 2D assembly is maintained up to ∼160 °C. The 2D and 1D structures are recovered in sequence upon cooling. Due to the thermally reversible, stepwise structural disruption/formation as well as the lack of covalent cross-linking, the terminal-functionalized PDMS shows thermoplastic behavior and self-healing properties. The terminal group presented herein, which can form a 'plane', might also drive other polymers to assemble into a periodically ordered network structure, thereby allowing for significant modulation of their mechanical properties.

Newborn screening for spinal muscular atrophy in Osaka -challenges in a Japanese pilot study.

OBJECTIVE: This study aimed to establish an optional newborn screening program for spinal muscular atrophy (SMA-NBS) in Osaka. METHODS: A multiplex TaqMan real-time quantitative polymerase chain reaction assay was used to screen for SMA. Dried blood spot samples obtained for the optional NBS program for severe combined immunodeficiency, which covers about 50% of the newborns in Osaka, were used. To obtain informed consent, participating obstetricians provided information about the optional NBS program to all parents by giving leaflets to prospective parents and uploading the information onto the internet. We prepared a workflow so that babies that were diagnosed with SMA through the NBS could be treated immediately. RESULTS: From 1 February 2021 to 30 September 2021, 22,951 newborns were screened for SMA. All of them tested negative for survival motor neuron (SMN)1 deletion, and there were no false-positives. Based on these results, an SMA-NBS program was established in Osaka and included in the optional NBS programs run in Osaka from 1 October 2021. A positive baby was found by screening, diagnosed with SMA (the baby possessed 3 copies of the SMN2 gene and was pre-symptomatic), and treated immediately. CONCLUSION: The workflow of the Osaka SMA-NBS program was confirmed to be useful for babies with SMA.

In Situ Nanostress Visualization Method to Reveal the Micromechanical Mechanism of Nanocomposites by Atomic Force Microscopy.

An in situ atomic force microscopy (AFM) nanomechanical technique was used to directly visualize the micromechanical behaviors of polymer nanocomposites during compressive strain. We obtained a stress distribution image of carbon black (CB)-filled rubber at the nanoscale for the first time, and we traced the microscopic deformation behaviors of CB particles. Through this experiment, we directly revealed the microscopic reinforcement mechanisms of rubber composites. We found that CB-filled rubbers exhibited heterogeneous local microscopic deformations, which were related to the dispersion of CB particles in rubber matrices. The local stress distributions of the rubber composites showed heterogeneity, and the stresses were concentrated in the regions near the CB particles during compression. The area of stress concentration gradually expanded with increasing strain and eventually formed a stress network structure. This stress network bore most of the macroscopic stress and was considered the key reinforcement mechanism of CB-filled rubber. The stress transfer process in the rubber matrix was visualized in real space for the first time. Based on the image data from the AFM experiments, we used finite-element method (FEM) simulations to reproduce the microscopic deformation process of CB-filled rubber. The stress distribution images simulated by FEM showed heterogeneity consistent with AFM. In this study, an in situ visualization of material deformation confirmed the predictions of microscopic deformation behavior from previous theories and models; it also provided new insights into the microscopic reinforcement mechanisms of CB-filled rubber composites based on microscopic stress distribution images.

Unraveling Nanoscale Elastic and Adhesive Properties at the Nanoparticle/Epoxy Interface Using Bimodal Atomic Force Microscopy.

The addition of a small fraction of solid nanoparticles to thermosetting polymers can substantially improve their fracture toughness, while maintaining various intrinsic thermomechanical properties. The underlying mechanism is largely related to the debonding process and subsequent formation of nanovoids at a nanoscale nanoparticle/epoxy interface, which is thought to be associated with a change in the structural and mechanical properties of the formed epoxy network at the interface compared with the matrix region. However, a direct characterization of the local physical properties at this nanoscale interface remains significantly challenging. Here, we employ a recently developed bimodal atomic force microscopy technique for the direct mapping of nanoscale elastic and adhesive responses of an amine-cured epoxy resin filled with ∼50 nm diameter silica nanoparticles. The obtained elastic modulus and dissipated energy maps with high spatial resolution evidence the existence of a ∼20-nm-thick interfacial epoxy layer surrounding the nanoparticles, which exhibits a reduced modulus and weaker adhesive response in comparison with the matrix properties. While the presence of such a soft and weak-adhesive interfacial layer is found not to affect the architecture of structural heterogeneities in the epoxy matrix, it conceivably supports the toughening mechanism related to the debonding and plastic nanovoid growth at the silica/epoxy interface. The incorporation of this soft interfacial layer into the Halpin-Tsai model also provides a good explanation for the effect of the silica fraction on the tensile modulus of cured epoxy nanocomposites.

Neural insights into sweet taste transduction and hunger-induced taste modification in mice.

Feeding is one of the most fundamental activities in the survival and reproduction of animals. During feeding, the gustatory system functions as a gatekeeper to evaluate food quality. Accumulated evidence in the field of taste research has shown that 5 basic tastes (sweet, umami, sour, bitter, and salty) are sensed by the corresponding taste receptors expressed in taste receptor cells on the tongue. In contrast, brain mechanisms that transduce or modify taste information have been less studied. In this review, I introduce our recent findings on the sweet taste transduction in the brainstem of mice and explain the hypothalamic neuronal network regulating hunger-induced taste modification. Finally, future perspectives are discussed.

Usefulness of 18F-FDG PET/computed tomography in differentiating between subacute and chronic aortic dissection: initial investigation.

OBJECTIVES: In the selection of thoracic endovascular repair for aortic dissection (AD), it is important to distinguish between the subacute and chronic phases, but there is no reliable way to distinguish between them in patients with unknown onset of AD. The purpose of this study was to assess the diagnostic performance of 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG)-PET/computed tomography (PET/CT) for discriminating subacute AD from chronic AD. METHODS: Thirteen patients with AD who were medically treated and followed up for 6 months were studied. 18F-FDG PET/CT images were obtained for each patient in the subacute phase (the first scan) and at 6 months (the second scan) after the onset. Target-to-background ratio (TBR) was measured as the maximum standardized uptake value (SUV) in the dissected aortic wall divided by blood pool SUV. RESULTS: TBR was significantly higher in the first scan (mean ± SD, 1.97 ± 0.32) than in the second scan (1.69 ± 0.29, P = 0.007). The area under the receiver operating characteristic curve of TBR for discriminating subacute AD from chronic AD was 0.76. With a threshold of 1.74, the TBR showed the sensitivity, specificity, and positive and negative predictive value of 85%, 69%, 73%, and 82%, respectively, for the discrimination of subacute AD from chronic AD. CONCLUSION: Metabolic assessment of dissected aortic wall by 18F-FDG PET/CT is useful in differentiating between subacute and chronic AD and can provide important information in determining the appropriate indication for treatment for patients with AD of unknown onset.

KSHV episome tethering sites on host chromosomes and regulation of latency-lytic switch by CHD4.

Kaposi sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the cell nucleus, but where KSHV episomal genomes are tethered and the mechanisms underlying KSHV lytic reactivation are unclear. Here, we study the nuclear microenvironment of KSHV episomes and show that the KSHV latency-lytic replication switch is regulated via viral long non-coding (lnc)RNA-CHD4 (chromodomain helicase DNA binding protein 4) interaction. KSHV episomes localize with CHD4 and ADNP proteins, components of the cellular ChAHP complex. The CHD4 and ADNP proteins occupy the 5'-region of the highly inducible lncRNAs and terminal repeats of the KSHV genome together with latency-associated nuclear antigen (LANA). Viral lncRNA binding competes with CHD4 DNA binding, and KSHV reactivation sequesters CHD4 from the KSHV genome, which is also accompanied by detachment of KSHV episomes from host chromosome docking sites. We propose a model in which robust KSHV lncRNA expression determines the latency-lytic decision by regulating LANA/CHD4 binding to KSHV episomes.

Treatment Strategies for Improving the Surgical Outcomes of Ruptured Abdominal Aortic Aneurysm: Single-Center Experience in Japan.

Objective: We aimed to examine the surgical outcomes of ruptured abdominal aortic aneurysm cases at our hospital and considered strategies for improvement. Material and Methods: We examined the preoperative characteristics of hospital mortality, postoperative complications, and long-term outcomes of 91 surgical cases of ruptured abdominal aortic aneurysm performed between January 2009 and December 2020 at our hospital. Results: Of the 91 cases, 24 died at the hospital (mortality, 26.3%). Mortality was mostly due to hemorrhage/disseminated intravascular coagulation and intestinal necrosis. Ten patients required preoperative aortic clamp by thoracotomy or insertion of intra-aortic balloon occlusion, and eight of them died. Ten patients required open abdominal management due to abdominal compartment syndrome, and five of them died. There was no significant difference between the two groups in terms of the long-term results of the open repair and abdominal endovascular aneurysm repair (EVAR). Conclusion: To improve the surgical outcomes of ruptured abdominal aortic aneurysms, it is necessary to start surgery immediately. Therefore, the choice of surgical method (open surgery or EVAR) should be based on the resources and discretion of the hospital. To prevent postoperative intestinal necrosis, risk factors for acute compartment syndrome should be considered, and open abdominal management should be introduced.

Insulating Polymer Blend Organic Thin-Film Transistors Based on Bilayer-Type Alkylated Benzothieno[3,2-b]naphtho[2,3-b]thiophene.

Herein, we developed a practical method to produce high-performance organic thin-film transistors (OTFTs) based on highly layered crystalline organic semiconductors (OSCs) that form bilayer-type layered herringbone (b-LHB) packing and exhibit high intrinsic mobility. We applied the insulating polymer blend technique using a typical b-LHB OSC of 2-octyl-benzothieno[3,2-b]naphtho[2,3-b]thiophene (2-C8-BTNT) and fabricated polycrystalline thin-film transistors (TFTs) via short-duration spin coating and subsequent annealing. The use of blends and the choice of polymer additive strongly affected the performance of the polycrystalline TFTs, and poly(methyl methacrylate) (PMMA) blend TFTs exhibited a high mobility exceeding 4 cm2/(V s) and small device-to-device variations. Using extended techniques in atomic force microscopy (AFM), we investigated the thin-film morphologies by bimodal AFM and the carrier transport properties by Kelvin probe force microscopy (KPFM). We demonstrated that the PMMA blend system enables the formation of a well-ordered polycrystalline thin film induced by vertical phase separation between the OSC and PMMA over a large area, resulting in uniform TFT performance. These findings pave the way for obtaining high-performance TFTs using simple processes, representing a substantial advancement toward the realization of printed electronics.

Utility of Psoas Muscle Area in Selecting Older Patients Feasible for Thoracic Endovascular Aortic Repair.

BACKGROUND: The impact of psoas muscle area on overall survival is unknown for older patients undergoing elective thoracic endovascular aortic repair. METHODS: We retrospectively reviewed 105 patients aged 75 years or more who underwent elective thoracic endovascular aortic repair for descending thoracic aortic aneurysm between January 2010 and December 2019. Psoas muscle area was measured at the L3 level with preoperative computed tomography and adjusted by height squared to derive psoas muscle mass index. The patients were stratified into two groups, sarcopenia and nonsarcopenia. sarcopenia was defined as a psoas muscle mass index less than 5.40 cm2/m2 for men and less than 3.56 cm2/m2 for women. The overall survival was compared with the age- and sex-matched general population using the one-sample log rank test. The propensity score adjusted Cox proportional hazards model was applied to determine the hazard ratio for all-cause mortality. RESULTS: Twenty-three patients died during the follow-up period (median, 3 years). Thirty-eight patients (36%) were classified as sarcopenia. The 5-year overall survival rate was 46% (95% confidence interval, 29% to 73%) for sarcopenia and 84% (95% confidence interval, 74% to 94%) for nonsarcopenia. The overall survival was significantly lower in the sarcopenia group than in its matched general population (P = .004), whereas no statistically significant difference in overall survival was found between the nonsarcopenia group and its matched general population (P = .417). Sarcopenia was an independent risk factor for all-cause mortality (adjusted hazard ratio 2.64; 95% confidence interval, 1.02 to 6.82; P = .045). CONCLUSIONS: Psoas muscle mass index may be a good predictor of mortality among older patients undergoing elective thoracic endovascular aortic repair for descending thoracic aortic aneurysm.

Therapeutic window for obtaining favorable remodeling after thoracic endovascular aortic repair of type B aortic dissection.

OBJECTIVE: The purpose of the present study was to determine the most appropriate timing for thoracic endovascular aortic repair (TEVAR) of type B aortic dissection (TBAD) in terms of remodeling of the aorta. METHODS: A total of 41 patients who had undergone TEVAR for the treatment of aortic dissection were included in the present study. The patients were divided into two groups: those who had undergone TEVAR in the acute or subacute phase (group A) and those who had undergone TEVAR in the chronic phase (group B). The indications for TEVAR as the treatment of TBAD were the presence of aortic rupture or malperfusion of the aortic branches, a maximum aortic diameter of ≥40 mm on the initial diagnostic computed tomography scan, and/or expansion of the aorta of ≥5 mm within 3 months for acute and subacute TBAD. The indication was a maximum aortic diameter of ≥50 mm or expansion of the aorta of ≥5 mm within 1 year for chronic TBAD. The diameters of the aorta, true lumen, and false lumen were measured at the level of the most dilated part of the descending aorta (level M) and at the diaphragm (level D) on the computed tomography scan obtained before TEVAR and at the 2-year follow-up examination. RESULTS: The median interval between TEVAR and the onset of TBAD was 0.2 month (interquartile range, 0.03-0.7 month) in group A (n = 21) and 32 months (interquartile range, 4.7-35.2 months) in group B (n = 20). Except for the aortic diameter at level D in group B, favorable remodeling was obtained at both levels in both groups. The diameter change ratio of the aorta at level D was significantly greater in group A than in group B (P = .02). Receiver operating characteristic curve analysis of the interval for a significant decrease in the aortic diameter at level D yielded 4.2 months as the optimal threshold for performing TEVAR (area under the curve, 0.859; 95% confidence interval, 0.7-1.0). CONCLUSIONS: TEVAR for TBAD will result in favorable outcomes, irrespective of the timing of the procedure. However, it might be more effective to perform TEVAR within 4.2 months of the onset of TBAD, provided that the TEVAR procedure can be performed safely.

Direct Visualization of Interfacial Regions between Fillers and Matrix in Rubber Composites Observed by Atomic Force Microscopy-Based Nanomechanics Assisted by Electron Tomography.

In order to explain or predict the macroscopic mechanical properties of polymer composites with complex nanostructures, atomic force microscopy (AFM)-based nanomechanics is one of the most appropriate tools because the local mechanical properties can be obtained by it. However, automatic force curve analysis based on contact mechanics would mislead us to the wrong conclusion. The purpose of this study is to elucidate this point by applying AFM nanomechanics on a carbon black (CB)-reinforced isoprene rubber (IR). The CB aggregates underneath the rubber surface prevent us from quantitatively evaluating the ratio of CB and interfacial polymer region (IPR), which is an important parameter to determine the macroscopic mechanical properties. In order to overcome this problem, transmission electron microtomography was incorporated to investigate the 3D structure in the same field of view as AFM nanomechanics. As a result, it was found that there are buried structures that do not appear in the AFM topographic image. In addition, we were able to reveal the existence of a force curve with an inflection point, which is characteristic of such "false" IPRs. To put it another way, we evidenced the existence of true IPRs for the first time by combining these state-of-the-art techniques.

KSHV transactivator-derived small peptide traps coactivators to attenuate MYC and inhibits leukemia and lymphoma cell growth.

In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.