HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression.

Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1-deficient mice are resistant to metastasis and further protected by combined immune-checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF-ß1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK-target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.

From laboratory to pilot-scale: Assessing dissolved organic matter, biological stability and per- and polyfluoroalkyl substances removal on managed aquifer recharge performance.

Managed aquifer recharge (MAR) is a promising technique for enhancing groundwater resources and addressing water scarcity. Particularly, this research highlights the novelty and urgent need for MAR facilities in the Chungcheongnam-do region of South Korea as a solution to augment groundwater resources and combat water scarcity. This research encompasses a comprehensive assessment, ranging from laboratory-scale column experiments to pilot-scale tests, focusing on dissolved organic matter (DOM) characterization, natural organic matter (NOM) removal, and water quality improvement, including biological stability. In the laboratory, DOM characteristics of source water and recharged groundwater were analyzed using advanced dissolved organic characteristic tools, and their potential impacts on water quality, as well as per- and polyfluoroalkyl substances (PFASs) were assessed. DOM, total cell counts, and several PFASs with molecular weights >450 Da (particularly long-chain PFASs showing >99.9 % reduction) were effectively reduced in a laboratory-scale experiment. A laboratory-scale column study revealed that most selected PFASs were not effectively removed. Moving to the pilot-scale, a series of experiments were conducted to assess NOM removal during soil passage. Similar to the results of the laboratory-scale experiment, MAR demonstrated significant potential for reducing NOM concentrations, thus improving water quality. Regarding biological stability, assimilable organic carbon in production well (i.e., final produced water by MAR process) was lower than both two sources of surface water (e.g., SW1 and SW2). This suggests that water derived from PW (i.e., production well) exhibited biological stability, undergoing effective biodegradation by aerobic bacteria during soil passage. The findings from this study highlight the critical importance of implementing MAR techniques in regions facing water scarcity, emphasizing its potential to significantly enhance future water security initiatives.

SUnSeT: spectral unmixing of hyperspectral images for phenotyping soybean seed traits.

KEY MESSAGE: Hyperspectral features enable accurate classification of soybean seeds using linear discriminant analysis and GWAS for novel seed trait genes. Evaluating crop seed traits such as size, shape, and color is crucial for assessing seed quality and improving agricultural productivity. The introduction of the SUnSet toolbox, which employs hyperspectral sensor-derived image analysis, addresses this necessity. In a validation test involving 420 seed accessions from the Korean Soybean Core Collections, the pixel purity index algorithm identified seed- specific hyperspectral endmembers to facilitate segmentation. Various metrics extracted from ventral and lateral side images facilitated the categorization of seeds into three size groups and four shape groups. Additionally, quantitative RGB triplets representing seven seed coat colors, averaged reflectance spectra, and pigment indices were acquired. Machine learning models, trained on a dataset comprising 420 accession seeds and 199 predictors encompassing seed size, shape, and reflectance spectra, achieved accuracy rates of 95.8% for linear discriminant analysis model. Furthermore, a genome-wide association study utilizing hyperspectral features uncovered associations between seed traits and genes governing seed pigmentation and shapes. This comprehensive approach underscores the effectiveness of SUnSet in advancing precision agriculture through meticulous seed trait analysis.

Enhancing ToF-SIMS OLED Data Analysis with Neural Networks and Mathematical Spectral Mixing.

This study presents a method employing artificial neural networks (ANN) for automated interpretation and depth profiling of organic multilayers using a limited set of time-of-flight secondary ion mass spectrometry (ToF-SIMS) spectra. To overcome the challenges of acquiring massive data sets for OLEDs, training data was generated by combining existing ToF-SIMS data sets with mathematically generated spectra. The classification model achieved an impressive 99.9% accuracy in identifying the mixed layers of the OLED dyes. The study demonstrates the synergy of ToF-SIMS and ANN analysis for effective classification and depth profiling of the OLED layers, providing valuable insights for the development and optimization of organic electronic devices.

Spatial transcriptome analysis of amelanotic acral melanoma reveals distant molecular determinants compared to pigmented acral melanoma.

BACKGROUND: Amelanotic acral melanoma (AAM) is a rare type of acral melanoma associated with poor prognosis. OBJECTIVES: We aimed to investigate the transcriptomic differences between AAM and pigmented acral melanoma (PAM). METHODS: The differences in spatially resolved transcriptome profiles of 9 AAM patients with 29 regions of interest (ROIs) and 11 PAM patients with 46 ROIs were investigated using S100b and CD3 morphology markers. RESULTS: In S100b-positive tumor cell areas, we detected 11 upregulated differentially expressed genes (DEGs), including chaperone/ubiquitin-associated DEGs, and 82 downregulated DEGs, including human leukocyte antigen, in AAMs compared with PAMs. Protein-protein interaction network and pathway analyses revealed significant enrichment of dysregulated translational and nonsense-mediated decay pathways but significant decreases in antigen processing and presentation, interferon signaling, and melanin biosynthesis pathways in S100b-positive ROIs of AAMs compared with those of PAMs. In tumor-associated immune cell areas, the numbers of CD8 T cells (p = 0.044) and M1 macrophages (p = 0.014) were significantly decreased, whereas those of monocytes (p = 0.045) and endothelial cells (p = 0.04) were increased in AAMs compared with those in PAMs. CONCLUSIONS: In conclusion, these findings could widen our understanding of the biological differences between AAMs and PAMs that might result in a different clinical course.

Facial Dermatoses Associated With Mask-Wearing in the COVID-19 Era: A Nationwide, Cross-Sectional, Multicenter, Questionnaire-based Study.

BACKGROUND: Daily usage of facial masks during coronavirus disease 2019 pandemic influenced on facial dermatoses. OBJECTIVE: This study investigated the impact of mask-wearing habits on facial dermatoses. METHODS: A nationwide, observational, questionnaire-based survey was conducted from July through August 2021, involving 20 hospitals in Korea. RESULTS: Among 1,958 facial dermatoses, 75.9% of patients experienced aggravation or development of new-onset facial dermatoses after wearing masks. In aggravated or newly developed acne patients (543 out of 743), associated factors were healthcare provider, female gender, and a long duration of mask-wearing. Irritating symptoms, xerosis, and hyperpigmentation were more frequently observed in this group. Aggravated or newly developed rosacea patients (515 out of 660) were likely to be female, young, and have a long duration of mask-wearing per day. Seborrheic dermatitis patients who experienced aggravation or de novo development (132 out of 184) were younger, and they more frequently involved the chin and jaw in addition to the nasolabial folds and both cheeks. Contact dermatitis patients (132 out of 147) with aggravation or de novo development tended to be female, involve both cheeks, and complain of pruritus. Aggravated or newly developed atopic dermatitis patients (165 out of 224) were more likely to be female, and had a higher baseline investigator global assessment score before mask-wearing. CONCLUSION: Clinical features and factors related to aggravation were different according to the types of facial dermatoses.

Baseline Serum neutrophil-to-lymphocyte ratio in acral melanoma compared with nonacral melanoma and its prognostic significance.

BACKGROUND: Acral lentiginous melanoma (ALM), a cutaneous melanoma subtype, exhibits a poorer prognosis than nonacral cutaneous melanoma (NACM). The neutrophil-to-lymphocyte ratio (NLR) is emerging as a prognostic indicator across diverse cancers. OBJECTIVE: We explored the baseline NLR disparities between ALM and NACM, and the NLR's prognostic significance in patients with ALM. METHODS: We reviewed records of patients with ALM and NACM diagnosed between 1997 and 2022, analyzing medical data. RESULTS: Among 327 and 159 patients with ALM and NACM, respectively, baseline NLR varied based on distinct clinicopathologic factors between ALM and NACM. In stage 3 to 4 melanomas, the median NLR for ALM (2.18; IQR, 1.70-3.08) significantly surpassed NACM (1.74; IQR, 1.33-2.53) (P = .029). In patients with ALM, high NLR (hazard ratio, 1.64; 95% CI, 1.02-2.66; P = .043) was independently correlated with poor progression-free survival when adjusting for ulceration, Breslow thickness of ≥2 mm, and nodal invasion. LIMITATIONS: Single-center, retrospective design. CONCLUSION: Advanced-stage ALM exhibited a significantly higher baseline NLR compared with that of NACM. Evaluating baseline NLR could provide valuable prognostic insights for patients with ALM.

The microvillar protocadherin CDHR5 associates with EBP50 to promote brush border assembly.

Transporting epithelial cells of the gut and kidney interact with their luminal environment through a densely packed collection of apical microvilli known as a brush border (BB). Proper brush border assembly depends on the intermicrovillar adhesion complex (IMAC), a protocadherin-based adhesion complex found at the distal tips of microvilli that mediates adhesion between neighboring protrusions to promote their organized packing. Loss of the IMAC adhesion molecule Cadherin-related family member 5 (CDHR5) results in significant brush border defects, though the functional properties of this protocadherin have not been thoroughly explored. Here, we show that the cytoplasmic tail of CDHR5 contributes to its correct apical targeting and functional properties in an isoform-specific manner. Library screening identified the Ezrin-associated scaffolds EBP50 and E3KARP as cytoplasmic binding partners for CDHR5. Consistent with this, loss of EBP50 disrupted proper brush border assembly with cells exhibiting markedly reduced apical IMAC levels. Together, our results shed light on the apical targeting determinants of CDHR5 and further define the interactome of the IMAC involved in brush border assembly.

A randomized, double-blinded, vehicle-controlled clinical trial of topical cryosim-1, a synthetic TRPM8 agonist, in prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is an intensively pruritic skin disease that negatively influences quality of life. Cryosim-1 (Intrinsic IB Spot) is a synthetic, selective transient receptor potential melastatin 8 agonist. AIMS: To investigate the efficacy and safety of cryosim-1 in PN patients. PATIENTS/METHODS: A randomized, double-blinded, placebo-controlled clinical trial including 30 patients was conducted. The numerical rating scale (NRS) of pruritus was evaluated before and 2 h after cryosim-1 application at every visit. RESULTS: At week 8, the mean pruritus NRS before serum application (4.7 ± 0.4 treatment, 6.1 ± 0.5 placebo; p = 0.045) and 2 h after serum application (2.8 ± 0.4 treatment, 4.3 ± 0.5 placebo; p = 0.031) were significantly lower in the treatment group, and the mean NRS for sleep disorder was significantly lower in the treatment group (2.2 ± 0.5 treatment, 4.2 ± 0.8 placebo; p = 0.031). The mean satisfaction scales for pruritus improvement were significantly higher in the treatment group (7.2 ± 0.6) than in the placebo group (4.0 ± 0.9; p = 0.005). There was no difference in TEWL between the two groups, and no adverse reactions were reported. CONCLUSIONS: Cryosim-1 is a safe and effective topical treatment for PN patients.

Spatially Resolved Transcriptomes of CD30+-Transformed Mycosis Fungoides and Cutaneous Anaplastic Large-Cell Lymphoma.

Mycosis fungoides with large-cell transformation (MF-LCT) occurs in a minor proportion of aggressive lesions, which express CD30 similar to primary cutaneous anaplastic large-cell lymphoma (pcALCL). We investigated the differences in spatially resolved transcriptome profiles of MF-LCT and pcALCL using CD30 morphology markers and 28 and 24 regions of interest (ROIs) in MF-LCT and pcALCL, respectively. Differentially expressed genes, pathway analysis, and immune-cell deconvolution by selective analysis of CD30-positive tumor cells and CD30-negative extratumoral areas were undertaken. In CD30-positive ROIs of MF-LCT, 190 differentially expressed genes were upregulated (29 were directly or indirectly associated with extracellular matrix remodeling), whereas 255 differentially expressed genes were downregulated, compared with those of pcALCL. Except for cornified envelope formation and keratinization, all six pathways enriched in CD30-positive ROIs of MF-LCT were associated with extracellular matrix remodeling. In CD30-positive ROIs in MF-LCT compared with those in pcALCL, immune-cell deconvolution revealed significantly increased fibroblasts and M2 macrophages (P = 0.012 and P = 0.023, respectively) but decreased M1 macrophages (P = 0.031). In CD30-negative ROIs in MF-LCT compared with those in pcALCL, memory B (P = 0.021), plasma (P = 0.023), and CD8 memory T (P = 0.001) cells significantly decreased, whereas regulatory T cells (P = 0.024) increased. Predomination of extracellular matrix remodeling pathways and immunosuppressive microenvironment in MF-LCT indicates pathophysiological differences between MF-LCT and pcALCL.

A new genotype of decapod hepanhamaparvovirus 1 (DHPV) from cultured Penaeus vannamei in South Korea.

Decapod hepanhamaparvovirus 1 (DHPV), also known as hepatopancreatic parvovirus (HPV), has caused death in larvae or stunted growth in juveniles of cultured shrimp. To date, 4 genotypes (genotype I, II, III, and IV) have been reported from various shrimp species and various geographical regions. In the present study, we isolated 2 types of DHPV (GHPV-Goseong and DHPV-Geoje) from cultured Penaeus vannamei in Korea. Based on the capsid protein (VP) amino acid sequences, DHPV-Goseong was highly identical to previously reported DHPV genotype IV in Taiwan and Korea. Different from DHPV-Goseong, DHPV-Geoje showed approximately 63% similarity with DHPV genotype I, II, III and 84% similarity with DHPV genotype IV, suggesting an independent new genotype of DHPV (genotype V). Further research is needed to elucidate the origin and biological meanings of the present new genotype.

Modulation of warm temperature-sensitive growth using a phytochrome B dark reversion variant, phyB[G515E], in Arabidopsis and rice.

INTRODUCTION: Ambient temperature-induced hypocotyl elongation in Arabidopsis seedlings is sensed by the epidermis-localized phytochrome B (phyB) and transduced into auxin biosynthesis via a basic helix-loop-helix transcription factor, phytochrome-interacting factor 4 (PIF4). Once synthesized, auxin travels down from the cotyledons to the hypocotyl, triggering hypocotyl cell elongation. Thus, the phyB-PIF4 module involved in thermosensing and signal transduction is a potential genetic target for engineering warm temperature-insensitive plants. OBJECTIVES: This study aims to manipulate warm temperature-induced elongation of plants at the post-translational level using phyB variants with dark reversion, the expression of which is subjected to heat stress. METHODS: The thermosensitive growth response of Arabidopsis was manipulated by expressing the single amino acid substitution variant of phyB (phyB[G515E]), which exhibited a lower dark reversion rate than wild-type phyB. Other variants with slow (phyB[G564E]) or rapid (phyB[S584F]) dark reversion or light insensitivity (phyB[G767R]) were also included in this study for comparison. Warming-induced transient expression of phyB variants was achieved using heat shock-inducible promoters. Arabidopsis PHYB[G515E] and PHYB[G564E] were also constitutively expressed in rice in an attempt to manipulate the heat sensitivity of a monocotyledonous plant species. RESULTS: At an elevated temperature, Arabidopsis seedlings transiently expressing PHYB[G515E] under the control of a heat shock-inducible promoter exhibited shorter hypocotyls than those expressing PHYB and other PHYB variant genes. This warm temperature-insensitive growth was related to the lowered PIF4 and auxin responses. In addition, transgenic rice seedlings expressing Arabidopsis PHYB[G515E] and PHYB[G564E] showed warm temperature-insensitive shoot growth. CONCLUSION: Transient expression of phyB variants with altered dark reversion rates could serve as an effective optogenetic technique for manipulating PIF4-auxin-mediated thermomorphogenic responses in plants.

Drainage of Inferiorly Extended Peritonsillar Abscess Using an Endoscope and Radiofrequency Device: Technical note.

Peritonsillar abscess (PTA) is the most common deep neck infection of the head and neck, but pharyngeal edema extending behind or below the tonsil and spreading to the larynx is atypical. Accurate diagnosis and prompt treatment are required because airway obstruction, descending mediastinitis, or thrombophlebitis may result. We evaluated surgical outcomes of inferiorly extended PTA (IEPTA) using an endoscope and a radiofrequency device for intraoral drainage. We retrospectively reviewed the medical records of 56 patients with IEPTA who underwent incisional drainage between 2013 and 2021. Two experienced surgeons performed intraoral drainage using an endoscope and a radiofrequency device (endoscopic group [EG]) or without such devices (WEG). Thirty (male: 26, female: four; mean age: 51.3 years), and 26 (male: 21, female: five; mean age: 55.9 years) patients in the EG and WEG, respectively, were evaluated. The mean hospitalization durations were 6.7 and 14.5 days for the EG and WEG, respectively (p<0.01). There were significant between-group differences regarding the number of tracheostomies conducted to secure an airway or surgical field (EG: four (13.3%); WEG: 16 (61.5%); p<0.01. The hospitalization duration for patients undergoing tracheostomy was significantly shorter in the EG than in the WEG (9.3 vs. 18.5 days, respectively; p=0.01). No significant difference in the mean hospital stay was observed for patients who did not undergo tracheostomy ([EG: 6.3, WEG: 8.2] days; p=0.081). IEPTA drainage using an endoscope and a radiofrequency instrument can reduce duration of hospitalization and tracheostomy procedures compared with the conventional method. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03362-0.

Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy.

Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.

Do public subsidies trigger firms' overinvestment? Evidence from the Korean renewable energy technology industry.

We empirically investigate whether government subsidies result in firms' overinvestment using unbalanced panel data from 61 renewable energy technology firms in Korea between 1991 and 2018. Considering the diagnostic test results, we build a panel vector autoregression model and test how overinvestment is influenced by research and development and non-research and development government subsidies and the interactions between subsidies, leverage, and free cash flow. We find that these subsidies do not significantly induce overinvestment by firms. In addition, non-research and development subsidies affect overinvestment positively through leverage and affect it negatively through free cash flow interactions. We also find that leverage and free cash flow do not affect overinvestment in Korea's renewable energy technology sector directly; however, firms with positive free cash flow tend to overinvest. One factor that drives renewable energy technology firms in Korea to overinvest is external growth opportunities. We suggest various policy implications based on this study's results.

Clinicopathologic Characteristics of Trauma-Related Nail Apparatus Melanoma: A Comparative Study according to the Presence of Trauma prior to Melanoma Development.

BACKGROUND: Nail apparatus melanoma (NAM) is a subtype of cutaneous melanoma occurring at nail units and belongs to the acral lentiginous melanoma subgroup. Due to its unique anatomical structure to protect the acral site, mechanical trauma may have a clinicoprognostic impact on NAM. Therefore, we investigated the clinicoprognostic and histopathological characteristics of NAM according to the presence of trauma history prior to melanoma development. METHODS: Clinicopathological and follow-up data of patients with NAM according to trauma history were obtained. RESULTS: We included 87 patients with NAM, 21.8% of whom had a previous trauma history. Trauma-related NAMs were more likely to involve the toenail (p = 0.040), include a high proportion of amelanotic melanomas (p = 0.038) as well as nail bed tumor (p = 0.013), and have a longer time interval between the onset of nail change and confirmed diagnosis (p = 0.012). Moreover, survival analysis revealed that trauma-related NAMs more frequently showed progression in general (p = 0.034) and nodal metastasis (p = 0.047) and had worse prognosis in terms of progression-free survival (p = 0.004). CONCLUSION: In conclusion, NAMs with previous trauma have unique clinicoprognostic characteristics. The specific clinicopathological features of NAMs according to trauma indicate that trauma may play a role in melanoma development.

EEG-controlled tele-grasping for undefined objects.

This paper presents a teleoperation system of robot grasping for undefined objects based on a real-time EEG (Electroencephalography) measurement and shared autonomy. When grasping an undefined object in an unstructured environment, real-time human decision is necessary since fully autonomous grasping may not handle uncertain situations. The proposed system allows involvement of a wide range of human decisions throughout the entire grasping procedure, including 3D movement of the gripper, selecting proper grasping posture, and adjusting the amount of grip force. These multiple decision-making procedures of the human operator have been implemented with six flickering blocks for steady-state visually evoked potentials (SSVEP) by dividing the grasping task into predefined substeps. Each substep consists of approaching the object, selecting posture and grip force, grasping, transporting to the desired position, and releasing. The graphical user interface (GUI) displays the current substep and simple symbols beside each flickering block for quick understanding. The tele-grasping of various objects by using real-time human decisions of selecting among four possible postures and three levels of grip force has been demonstrated. This system can be adapted to other sequential EEG-controlled teleoperation tasks that require complex human decisions.

Adaptive Discount Factor for Deep Reinforcement Learning in Continuing Tasks with Uncertainty.

Reinforcement learning (RL) trains an agent by maximizing the sum of a discounted reward. Since the discount factor has a critical effect on the learning performance of the RL agent, it is important to choose the discount factor properly. When uncertainties are involved in the training, the learning performance with a constant discount factor can be limited. For the purpose of obtaining acceptable learning performance consistently, this paper proposes an adaptive rule for the discount factor based on the advantage function. Additionally, how to use the advantage function in both on-policy and off-policy algorithms is presented. To demonstrate the performance of the proposed adaptive rule, it is applied to PPO (Proximal Policy Optimization) for Tetris in order to validate the on-policy case, and to SAC (Soft Actor-Critic) for the motion planning of a robot manipulator to validate the off-policy case. In both cases, the proposed method results in a better or similar performance compared with cases using the best constant discount factors found by exhaustive search. Hence, the proposed adaptive discount factor automatically finds a discount factor that leads to comparable training performance, and that can be applied to representative deep reinforcement learning problems.