Structural insights into a spindle-shaped archaeal virus with a sevenfold symmetrical tail.

Archaeal viruses with a spindle-shaped virion are abundant and widespread in extremely diverse environments. However, efforts to obtain the high-resolution structure of a spindle-shaped virus have been unsuccessful. Here, we present the structure of SSV19, a spindle-shaped virus infecting the hyperthermophilic archaeon Sulfolobus sp. E11-6. Our near-atomic structure reveals an unusual sevenfold symmetrical virus tail consisting of the tailspike, nozzle, and adaptor proteins. The spindle-shaped capsid shell is formed by seven left-handed helical strands, constructed of the hydrophobic major capsid protein, emanating from the highly glycosylated tail assembly. Sliding between adjacent strands is responsible for the variation of a virion in size. Ultrathin sections of the SSV19-infected cells show that SSV19 virions adsorb to the host cell membrane through the tail after penetrating the S-layer. The tailspike harbors a putative endo-mannanase domain, which shares structural similarity to a Bacteroides thetaiotaomicro endo-mannanase. Molecules of glycerol dibiphytanyl glycerol tetraether lipid were observed in hydrophobic clefts between the tail and the capsid shell. The nozzle protein resembles the stem and clip domains of the portals of herpesviruses and bacteriophages, implying an evolutionary relationship among the archaeal, bacterial, and eukaryotic viruses.

Structural Reversibility of Nanoscaled Sn Anodes.

Alloying-type anode materials provide high capacity for lithium-ion batteries; however, they suffer pulverization problems resulting from the volume change during cycling. Realizing the cycling reversibility of these anodes is therefore critical for sustaining their electrochemical performance. Here, we investigate the structural reversibility of Sn NPs during cycling at atomic-level resolution utilizing in situ high-resolution TEM. We observed a surprisingly near-perfect structural reversibility after a complete cycle. A three-step phase transition happens during lithiation, accompanied by the generation of a significant number of defects, grain boundaries, and up to 202% volume expansion. In subsequent delithiation, the volume, morphology, and crystallinity of the Sn NPs were restored to their initial state. Theoretical calculations show that compressive stress drives the removal of vacancies generated within the NPs during delithiation, therefore maintaining their intact morphology. This work demonstrates that removing vacancies during cycling can efficiently improve the structural reversibility of high-capacity anode materials.

Platelet-Rich Plasma in Young and Elderly Humans Exhibits a Different Proteomic Profile.

As people age, their ability to resist injury and repair damage decreases significantly. Platelet-rich plasma (PRP) has demonstrated diverse therapeutic effects on tissue repair. However, the inconsistency of patient outcomes poses a challenge to the practical application of PRP in clinical practice. Furthermore, a comprehensive understanding of the specific impact of aging on PRP requires a systematic investigation. We derived PRP from 6 young volunteers and 6 elderly volunteers, respectively. Subsequently, 95% of high-abundance proteins were removed, followed by mass spectrometry analysis. Data are available via ProteomeXchange with the identifier PXD050061. We detected a total of 739 proteins and selected 311 proteins that showed significant differences, including 76 upregulated proteins in the young group and 235 upregulated proteins in the elderly group. Functional annotation and enrichment analysis unveiled upregulation of proteins associated with cell apoptosis, angiogenesis, and complement and coagulation cascades in the elderly. Conversely, IGF1 was found to be upregulated in the young group, potentially serving as the central source of enhanced cell proliferation ability. Our investigation not only provides insights into standardizing PRP preparation but also offers novel strategies for augmenting the functionality of aging cells or tissues.

High-Efficiency Circularly Polarized Light-Emitting Diodes Based on Chiral Metal Nanoclusters.

Circularly polarized light-emitting diodes (CP-LEDs) are critical for next-generation optical technologies, ranging from holography to quantum information processing. Currently deployed chiral luminescent materials, with their intricate synthesis and processing and limited efficiency, are the main bottleneck for CP-LEDs. Chiral metal nanoclusters (MNCs) are potential CP-LED materials, given their ease of synthesis and processability as well as diverse structures and excited states. However, their films are usually plagued by inferior electronic quality and aggregation-caused photoluminescence quenching, necessitating their incorporation into host materials; without such a scheme, MNC-based LEDs exhibit external quantum efficiencies (EQEs) < 10%. Herein, we achieve an efficiency leap for both CP-LEDs and cluster-based LEDs by using novel chiral MNCs with aggregation-induced emission enhancement. CP-LEDs using enantiopure MNC films attain EQEs of up to 23.5%. Furthermore, by incorporating host materials, the devices yield record EQEs of up to 36.5% for both CP-LEDs and cluster-based LEDs, along with electroluminescence dissymmetry factors (|gEL|) of around 1.0 × 10-3. These findings open a new avenue for advancing chiral light sources for next-generation optoelectronics.

Cardiac-specific deletion of heat shock protein 60 induces mitochondrial stress and disrupts heart development in mice.

Congenital heart diseases are the most common birth defects around the world. Emerging evidence suggests that mitochondrial homeostasis is required for normal heart development. In mitochondria, a series of molecular chaperones including heat shock protein 60 (HSP60) are engaged in assisting the import and folding of mitochondrial proteins. However, it remains largely obscure whether and how these mitochondrial chaperones regulate cardiac development. Here, we generated a cardiac-specific Hspd1 deletion mouse model by αMHC-Cre and investigated the role of HSP60 in cardiac development. We observed that deletion of HSP60 in embryonic cardiomyocytes resulted in abnormal heart development and embryonic lethality, characterized by reduced cardiac cell proliferation and thinner ventricular walls, highlighting an essential role of cardiac HSP60 in embryonic heart development and survival. Our results also demonstrated that HSP60 deficiency caused significant downregulation of mitochondrial ETC subunits and induced mitochondrial stress. Analysis of gene expression revealed that P21 that negatively regulates cell proliferation is significantly upregulated in HSP60 knockout hearts. Moreover, HSP60 deficiency induced activation of eIF2α-ATF4 pathway, further indicating the underlying mitochondrial stress in cardiomyocytes after HSP60 deletion. Taken together, our study demonstrated that regular function of mitochondrial chaperones is pivotal for maintaining normal mitochondrial homeostasis and embryonic heart development.

Identification and genetic characterization of a recently identified enterovirus C116 in China.

Enterovirus C116 (EV-C116) is a new member of the enterovirus C group which is closely associated with several infectious diseases. Although sporadic studies have detected EV-C116 in clinical samples worldwide, there is currently limited information available. In this study, two EV-C-positive fecal specimens were detected in apparently healthy children, which harbored low abundance, through meta-transcriptome sequencing. Based on the prototypes of several EV-Cs, two lineages were observed. Lineage 1 included many types that could not cause EV-like cytopathic effect in cell culture. Three genogroups of EV-C116 were divided in the maximum likelihood tree, and the two strains in this study (XZ2 and XZ113) formed two different lineages, suggesting that EV-C116 still diffuses worldwide. Obvious inter-type recombination events were observed in the XZ2 strain, with CVA22 identified as a minor donor. However, another strain (XZ113) underwent different recombination situations, highlighting the importance of recombination in the formation of EV-Cs biodiversity. The EV-C116 strains could propagate in rhabdomyosarcoma cell cultures at low titer; however, EV-like cytopathic effects were not observed. HEp-2, L20B, VERO, and 293T cell lines did not provide an appropriate environment for EV-C116 growth. These results challenge the traditional recognition of the uncultured nature of EV-C116 strains and explain the difficulty of clinical detection.

ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Structural changes in bacteriophage T7 upon receptor-induced genome ejection.

Many tailed bacteriophages assemble ejection proteins and a portal-tail complex at a unique vertex of the capsid. The ejection proteins form a transenvelope channel extending the portal-tail channel for the delivery of genomic DNA in cell infection. Here, we report the structure of the mature bacteriophage T7, including the ejection proteins, as well as the structures of the full and empty T7 particles in complex with their cell receptor lipopolysaccharide. Our near-atomic-resolution reconstruction shows that the ejection proteins in the mature T7 assemble into a core, which comprises a fourfold gene product 16 (gp16) ring, an eightfold gp15 ring, and a putative eightfold gp14 ring. The gp15 and gp16 are mainly composed of helix bundles, and gp16 harbors a lytic transglycosylase domain for degrading the bacterial peptidoglycan layer. When interacting with the lipopolysaccharide, the T7 tail nozzle opens. Six copies of gp14 anchor to the tail nozzle, extending the nozzle across the lipopolysaccharide lipid bilayer. The structures of gp15 and gp16 in the mature T7 suggest that they should undergo remarkable conformational changes to form the transenvelope channel. Hydrophobic α-helices were observed in gp16 but not in gp15, suggesting that gp15 forms the channel in the hydrophilic periplasm and gp16 forms the channel in the cytoplasmic membrane.

[Design and Testing of a Pressure Measurement and Adjustment Device for Fracture Ends].

Objective: To design and test a device which is capable of accurately measuring and dynamically adjusting the axial pressure at the fracture end in real-time. Methods: Upon completion of the design, the pressure measurement and adjustment device was implemented in a canine tibial fracture external fixation model. A pressure sensor was mounted at the fracture end, and the displayed values of the pressure sensor were used as the standard for comparison. The relationship between the displayed values of the measurement and adjustment device and the pressure sensor under identical conditions was examined. Results: The device was utilized in external fixation models of tibial fractures in five beagles. A linear correlation was observed between the displayed values of the device and the pressure sensor at the fracture end. The measurement values from the device could be transformed into fracture end pressure through the application of coefficients, thereby facilitating accurate measurement and dynamic adjustment of the fracture end pressure. Conclusion: The pressure measurement and adjustment device at the fracture end is easy to operate, enabling precise measurement and dynamic regulation of the pressure at the fracture end. It is well-suited for animal experiments aimed at investigating the impact of axial compression on fracture healing, demonstrating promising potential for experimental applications.

Smart Reversible Transformations between Chiral Superstructures of Copper Clusters for Optical and Chiroptical Switching.

Superstructures made from nanoscale clusters with new collective properties are promising in high-tech applications; however, chiral superstructures remain elusive, and the limited intercluster coupling effect at room temperature hampers the tailoring of collective properties. Here, we show that from chiral monomeric copper clusters to two enantiomeric pairs of supercrystals with distinct phases, the absorption band edge red-shifts by over 1.3 eV, with photoluminescence and circularly polarized phosphorescence from visible (572 nm) to near-infrared (NIR, 858 nm). These supercrystals with high NIR quantum yields of up to 45% at room temperature are prototyped for night-vision imaging. In response to solvent and temperature stimuli, chiral supercrystal-to-supercrystal transformations occurred, concomitant with high-contrast optical/chiroptical switching. In situ single-crystal X-ray diffraction (SCXRD), steady-state and time-resolved optical spectroscopy, and response experiments combined with theoretical calculations demonstrate that distance-sensitive intercluster orbital interactions contribute to the exceptional collective optical responses. Such chiral supercrystals built from subnanoscale metal clusters with novel collective chiroptical responses would be useful in the fields of information storage and NIR optical devices.

Chiral Hydride Cu18 Clusters Transform to Superatomic Cu15Ag4 Clusters: Circularly Polarized Luminescence Lighting.

The manipulation of metal cluster enantiomers and their reconstruction remain challenging. Here, for the first time, we report an enantiomeric pair of hydride copper clusters [Cu18H(R/S-PEA)12](BF4)5 (R/S-Cu18H) made using designed chiral ligands. By manipulation of R/S-Cu18H with Ag+ ions, H- ions are released, leading to the reconstruction of 15 Cu atoms. Moreover, 4 Ag atoms replaced Cu atoms at the specific sites, resulting in the formation of homochiral [Cu15Ag4(R/S-PEA)12](BF4)5 (R/S-Cu15Ag4) with an isomorphic metal skeleton. This process was accompanied by a reduction reaction generating two free valence elections in the chiral alloying counterparts, which displayed orange emission. The solid-state R/S-Cu15Ag4 exhibited a photoluminescence quantum yield of 7.02% and excellent circularly polarized luminescence. The chiral transformations were resolved by single-crystal X-ray diffraction. The development of chiral copper hydride precursor-based metal clusters with chiroptical activities holds tremendous promise for advancing the field of optoelectronics and enabling new applications in lighting, displays, and beyond.

Resuscitation-Promoting Factor Accelerates Enrichment of Highly Active Tetrachloroethene/Polychlorinated Biphenyl-Dechlorinating Cultures.

The anaerobic bioremediation of polychlorinated biphenyls (PCBs) is largely impeded by difficulties in massively enriching PCB dechlorinators in short periods of time. Tetrachloroethene (PCE) is often utilized as an alternative electron acceptor to preenrich PCB-dechlorinating bacteria. In this study, resuscitation promoting factor (Rpf) was used as an additive to enhance the enrichment of the microbial communities involved in PCE/PCBs dechlorination. The results indicated that Rpf accelerates PCE dechlorination 3.8 to 5.4 times faster than control cultures. In Aroclor 1260-fed cultures, the amendment of Rpf enables significantly more rapid and extensive dechlorination of PCBs. The residual high-chlorinated PCB congeners (≥5 Cl atoms) accounted for 36.7% and 59.8% in the Rpf-amended cultures and in the corresponding controls, respectively. This improvement was mainly attributed to the enhanced activity of the removal of meta-chlorines (47.7 mol % versus 14.7 mol %), which did not appear to affect dechlorination pathways. The dechlorinators, including Dehalococcoides in Chloroflexi and Desulfitobacterium in Firmicutes, were greatly enriched via Rpf amendment. The abundance of nondechlorinating populations, including Methanosarcina, Desulfovibrio, and Bacteroides, was also greatly enhanced via Rpf amendment. These results suggest that Rpf serves as an effective additive for the rapid enrichment of active dechlorinating cultures so as to provide a new approach by which to massively cultivate bioinoculants for accelerated in situ anaerobic bioremediation. IMPORTANCE The resuscitation promoting factor (Rpf) of Micrococcus luteus has been reported to resuscitate and stimulate the growth of functional microorganisms that are involved in the aerobic degradation of polychlorinated biphenyls (PCBs). However, few studies have been conducted to investigate the role of Rpf on anaerobic microbial populations. In this study, the enhancement of Rpf on the anaerobic microbial dechlorination of PCE/PCBs was discovered. Additionally, the Rpf-responsive populations underlying the enhanced dechlorination were uncovered. This report reveals the rapid enrichment of active dechlorinating cultures via Rpf amendment, and this sheds light on massively enriching PCB dechlorinators in short periods of time. The enhanced in situ anaerobic bioremediation of PCBs could be expected by supplementing Rpf.

Grape polysaccharides: compositional changes in grapes and wines, possible effects on wine organoleptic properties, and practical control during winemaking.

Polysaccharides present in grapes interact with wine sensory-active compounds (polyphenols and volatile compounds) via different mechanisms and can affect wine organoleptic qualities such as astringency, color and aroma. Studies on the role that grape polysaccharides play in wines are reviewed in this paper. First, the composition of grape polysaccharides and their changes during grape ripening, winemaking and aging are introduced. Second, different interaction mechanisms of grape polysaccharides and wine sensory-active compounds (flavanols, anthocyanins and volatiles) are introduced, and the possible effects on wine astringency, color and aroma caused by these interactions are illustrated. Finally, the control of the grape polysaccharide content in practice is discussed, including classical winemaking methods (applying different maceration enzymes, temperature control, co-fermentation, blending), modern vinification technologies (pulsed electric field, ultrasound treatment), and the development of new grape polysaccharide products.

Identification of lysine isobutyrylation as a new histone modification mark.

Short-chain acylations of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity in vitro, especially p300 and HAT1. Transfection and western blot experiments showed that p300 regulated histone isobutyrylation levels in the cell. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Together, our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.

Inositol 1,4,5-trisphosphate receptors are essential for fetal-maternal connection and embryo viability.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ release channels located on the ER membrane, which in mammals consist of 3 different subtypes (IP3R1, IP3R2, and IP3R3) encoded by 3 genes, Itpr1, Itpr2, and Itpr3, respectively. Studies utilizing genetic knockout mouse models have demonstrated that IP3Rs are essential for embryonic survival in a redundant manner. Deletion of both IP3R1 and IP3R2 has been shown to cause cardiovascular defects and embryonic lethality. However, it remains unknown which cell types account for the cardiovascular defects in IP3R1 and IP3R2 double knockout (DKO) mice. In this study, we generated conditional IP3R1 and IP3R2 knockout mouse models with both genes deleted in specific cardiovascular cell lineages. Our results revealed that deletion of IP3R1 and IP3R2 in cardiomyocytes by TnT-Cre, in endothelial / hematopoietic cells by Tie2-Cre and Flk1-Cre, or in early precursors of the cardiovascular lineages by Mesp1-Cre, resulted in no phenotypes. This demonstrated that deletion of both IP3R genes in cardiovascular cell lineages cannot account for the cardiovascular defects and embryonic lethality observed in DKO mice. We then revisited and performed more detailed phenotypic analysis in DKO embryos, and found that DKO embryos developed cardiovascular defects including reduced size of aortas, enlarged cardiac chambers, as well as growth retardation at embryonic day (E) 9.5, but in varied degrees of severity. Interestingly, we also observed allantoic-placental defects including reduced sizes of umbilical vessels and reduced depth of placental labyrinth in DKO embryos, which could occur independently from other phenotypes in DKO embryos even without obvious growth retardation. Furthermore, deletion of both IP3R1 and IP3R2 by the epiblast-specific Meox2-Cre, which targets all the fetal tissues and extraembryonic mesoderm but not extraembryonic trophoblast cells, also resulted in embryonic lethality and similar allantoic-placental defects. Taken together, our results demonstrated that IP3R1 and IP3R2 play an essential and redundant role in maintaining the integrity of fetal-maternal connection and embryonic viability.

PLFace: Progressive learning for face recognition with mask bias.

The outbreak of the COVID-19 coronavirus epidemic has promoted the development of masked face recognition (MFR). Nevertheless, the performance of regular face recognition is severely compromised when the MFR accuracy is blindly pursued. More facts indicate that MFR should be regarded as a mask bias of face recognition rather than an independent task. To mitigate mask bias, we propose a novel Progressive Learning Loss (PLFace) that achieves a progressive training strategy for deep face recognition to learn balanced performance for masked/mask-free faces recognition based on margin losses. Particularly, our PLFace adaptively adjusts the relative importance of masked and mask-free samples during different training stages. In the early stage of training, PLFace mainly learns the feature representations of mask-free samples. At this time, the regular sample embeddings shrink to the prototype. In the later stage of training, PLFace converges on mask-free samples and further focuses on masked samples until the masked sample embeddings are also gathered in the center of the class. The entire training process emphasizes the paradigm that normal samples shrink first and masked samples gather afterward. Extensive experimental results on popular regular and masked face benchmarks demonstrate the superiority of our PLFace over state-of-the-art competitors.

Projective Synchronization of Delayed Uncertain Coupled Memristive Neural Networks and Their Application.

In this article, the authors analyzed the nonlinear effects of projective synchronization between coupled memristive neural networks (MNNs) and their applications. Since the complete signal transmission is difficult under parameter mismatch and different projective factors, the delays, which are time-varying, and uncertainties have been taken to realize the projective synchronization of MNNs with multi-links under the nonlinear control method. Through the extended comparison principle and a new approach to dealing with the mismatched parameters, sufficient criteria have been determined under different types of projective factors and the framework of the Lyapunov-Krasovskii functional (LKF) for projective convergence of the coupled MNNs. Instead of the classical treatment for secure communication, the concept of error of synchronization between the drive and response systems has been applied to solve the signal encryption/decryption problem. Finally, the simulations in numerical form have been demonstrated graphically to confirm the adaptability of the theoretical results.

A network-based deep learning methodology for stratification of tumor mutations.

MOTIVATION: Tumor stratification has a wide range of biomedical and clinical applications, including diagnosis, prognosis and personalized treatment. However, cancer is always driven by the combination of mutated genes, which are highly heterogeneous across patients. Accurately subdividing the tumors into subtypes is challenging. RESULTS: We developed a network-embedding based stratification (NES) methodology to identify clinically relevant patient subtypes from large-scale patients' somatic mutation profiles. The central hypothesis of NES is that two tumors would be classified into the same subtypes if their somatic mutated genes located in the similar network regions of the human interactome. We encoded the genes on the human protein-protein interactome with a network embedding approach and constructed the patients' vectors by integrating the somatic mutation profiles of 7344 tumor exomes across 15 cancer types. We firstly adopted the lightGBM classification algorithm to train the patients' vectors. The AUC value is around 0.89 in the prediction of the patient's cancer type and around 0.78 in the prediction of the tumor stage within a specific cancer type. The high classification accuracy suggests that network embedding-based patients' features are reliable for dividing the patients. We conclude that we can cluster patients with a specific cancer type into several subtypes by using an unsupervised clustering algorithm to learn the patients' vectors. Among the 15 cancer types, the new patient clusters (subtypes) identified by the NES are significantly correlated with patient survival across 12 cancer types. In summary, this study offers a powerful network-based deep learning methodology for personalized cancer medicine. AVAILABILITY AND IMPLEMENTATION: Source code and data can be downloaded from https://github.com/ChengF-Lab/NES. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Solid Base Assisted Dual-Promoted Heterogeneous Conversion of PVC to Metal-Free Porous Carbon Catalyst.

Polyvinyl chloride (PVC) is widely used in daily life, but its waste has become a serious environmental problem. A solid base assisted low-temperature solvothermal dehalogenation was developed in this work to sustainably and efficiently transform PVC into high-value dimethylamine hydrochloride (DMACl) chemical and N,O co-doped carbon monolith with hierarchically porous structure. The synergistic promotion of solid-base catalyst and solvent decomposition with the removal of HCl can shift forward the chemical equilibrium to promote the dechlorination of PVC and increase the carbon yield. Meanwhile, the solid-base catalyst can also act as a pore-forming additive to fabricate the carbon monolith with hierarchical pores. Induced by the high specific surface area, hierarchical pores and N,O co-doped structure, the generated carbon monolith exhibits superior electrocatalytic performance towards H2 evolution. These discoveries shed light on the design of synergistically coupled solvent and solid catalyst to promote the heterogeneous conversion of waste chlorinated plastics into high-value chemicals for a sustainable future.

Expression of immune checkpoint molecules programmed death protein 1, programmed death-ligand 1 and inducible T-cell co-stimulator in mycosis fungoides and Sézary syndrome: association with disease stage and clinical outcome.

BACKGROUND: The relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T-cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL. OBJECTIVES: The aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T-cell co-stimulator (ICOS) and programmed death-ligand 1 (PD-L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival. METHODS: This consecutive case series enrolled 47 patients: 57% had stage IA-IIA disease and 43% had stage IIB-IVA2 disease (including seven with SS). RESULTS: PD1, PD-L1 and ICOS expression was seen in all biopsies. Notably, PD-L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD-L1 was associated with advanced-stage disease (P = 0·007 for both) and with the appearance of large-cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD-L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD-L1 and ICOS) was associated with advanced-stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014). CONCLUSIONS: These findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD-L1 in advanced disease.