A novel efficient strategy to generate liver sinusoidal endothelial cells from human pluripotent stem cells.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells (ECs) that play an important role in liver development and regeneration. Additionally, it is involved in various pathological processes, including steatosis, inflammation, fibrosis and hepatocellular carcinoma. However, the rapid dedifferentiation of LSECs after culture greatly limits their use in vitro modeling for biomedical applications. In this study, we developed a highly efficient protocol to induce LSEC-like cells from human induced pluripotent stem cells (hiPSCs) in only 8 days. Using single-cell transcriptomic analysis, we identified several novel LSEC-specific markers, such as EPAS1, LIFR, and NID1, as well as several previously revealed markers, such as CLEC4M, CLEC1B, CRHBP and FCN3. These LSEC markers are specifically expressed in our LSEC-like cells. Furthermore, hiPSC-derived cells expressed LSEC-specific proteins and exhibited LSEC-related functions, such as the uptake of acetylated low density lipoprotein (ac-LDL) and immune complex endocytosis. Overall, this study confirmed that our novel protocol allowed hiPSCs to rapidly acquire an LSEC-like phenotype and function in vitro. The ability to generate LSECs efficiently and rapidly may help to more precisely mimic liver development and disease progression in a liver-specific multicellular microenvironment, offering new insights into the development of novel therapeutic strategies.

Palladium-anchored calix[4]arene-derived porous organic polymer towards efficient hydrolytic cleavage of carbon disulfide.

The release of carbon disulfide can have adverse effects on our environment and human health. The stability of carbon disulfide and the slow kinetics of hydrolysis can make it challenging to achieve efficient and practical cleavage of the CS bonds. Herein, a calix[4]arene-based porous organic polymer (CPOP-1) is innovatively synthesized through an optimized polycondensation reaction using C-Methylcalix[4]resorcinarene and hexafluoro-hexaazatriphenylene as monomers. Subsequently, palladium-induced calix[4]arene-based porous organic polymer was also synthesized via strong Pd-N coordination bonds to construct the metal-induced porous catalyst (CPOP-2). The polymeric catalyst active center [Pd2+(N^N)(NO3-)2] demonstrated outstanding catalytic hydrolysis performance (11.14 µmol g-1 h-1) in 10.5 h which is significantly enhanced by ca.13.2 times as compared to reported mononuclear Bpy-Pd(NO3)2, and 7.07 times than model trinuclear complex catalyst HATN-Pd-1, respectively. The control experiments revealed that POP catalysts showcased robust stability, prolonged effectiveness, and feasible recyclability during the hydrolytic cleavage of carbon disulfide at room temperature in aqueous solutions. Furthermore, the coordination environment of [Pd2+(N^N)] was validated through XPS, EXAFS, and isotope labeling measurements, and the hydrolysis cleavage products were confirmed e. g. CO2, sulfide, and protons. More importantly, a reaction mechanism was formulated coupled with theoretical calculations, and simulations. The proposed mechanism involves sequential OH- nucleophilic attacks on the carbon atoms of insert-coordinated CS2 and COS, leading to the cleavage of double CS bonds and the formation of CO bonds. The concurrent dissociation of the C-S bond and liberation of CO2 result in an intermediate structure characterized by [(N^N)Pd2+](SH-)2. This intermediate motif serves as the source of the thermodynamic driving force for the reaction.

An analytic theory for the degree of Arctic Amplification.

Arctic Amplification (AA), the amplified surface warming in the Arctic relative to the globe, is a salient feature of climate change. While the basic physical picture of AA has been depicted, how its degree is determined has not been clearly understood. Here, by deciphering atmospheric heat transport (AHT), we build a two-box energy-balance model of AA and derive that the degree of AA is a simple nonlinear function of the Arctic and global feedbacks, the meridional heterogeneity in radiative forcing, and the partial sensitivities of AHT to global mean and meridional gradient of warming. The formula captures the varying AA in climate models and attributes the spread to models' feedback parameters and AHT physics. The formula clearly illustrates how essential physics mutually determine the degree of AA and limits its range within 1.5-3.5. Our results articulate AHT as both forcing and feedback to AA, highlight its fundamental role in forming a baseline AA that exists even with uniform feedbacks, and underscore its partial sensitivities instead of its total change as key parameters of AA. The lapse-rate feedback has been widely recognized as a major contributor to AA but its effect is fully offset by the water-vapor feedback.

Atmosphere teleconnections from abatement of China aerosol emissions exacerbate Northeast Pacific warm blob events.

During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.

Wide range of possible trajectories of North Atlantic climate in a warming world.

Decadal variability in the North Atlantic Ocean impacts regional and global climate, yet changes in internal decadal variability under anthropogenic radiative forcing remain largely unexplored. Here we use the Community Earth System Model 2 Large Ensemble under historical and the Shared Socioeconomic Pathway 3-7.0 future radiative forcing scenarios and show that the ensemble spread in northern North Atlantic sea surface temperature (SST) more than doubles during the mid-twenty-first century, highlighting an exceptionally wide range of possible climate states. Furthermore, there are strikingly distinct trajectories in these SSTs, arising from differences in the North Atlantic deep convection among ensemble members starting by 2030. We propose that these are stochastically triggered and subsequently amplified by positive feedbacks involving coupled ocean-atmosphere-sea ice interactions. Freshwater forcing associated with global warming seems necessary for activating these feedbacks, accentuating the impact of external forcing on internal variability. Further investigation on seven additional large ensembles affirms the robustness of our findings. By monitoring these mechanisms in real time and extending dynamical model predictions after positive feedbacks activate, we may achieve skillful long-lead North Atlantic decadal predictions that are effective for multiple decades.

Dynamic pathway linking Pakistan flooding to East Asian heatwaves.

In July to August 2022, Pakistan suffered historic flooding while record-breaking heatwaves swept southern China, causing severe socioeconomic impacts. Similar extreme events have frequently coincided between two regions during the past 44 years, but the underlying mechanisms remain unclear. Using observations and a suite of model experiments, here, we show that the upper-tropospheric divergent wind induced by convective heating over Pakistan excites a barotropic anomalous anticyclone over eastern China, which further leads to persistent heatwaves. Atmospheric model ensemble simulation indicates that this dynamic pathway linking Pakistan flooding and East Asian heatwaves is intrinsic to the climate system, largely independent of global sea surface temperature forcing. This dynamic connection is most active during July to August when convective variability is large over Pakistan and the associated divergent flow excites barotropic Rossby waves that propagate eastward along the upper troposphere westerly waveguide. This robust waveguide and the time delay offer hopes for improved subseasonal prediction of extreme events in East Asia.

Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma.

The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31-84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SILhigh subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SILlow subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.

The 2023 extreme coastal El Niño: Atmospheric and air-sea coupling mechanisms.

In the boreal spring of 2023, an extreme coastal El Niño struck the coastal regions of Peru and Ecuador, causing devastating rainfalls, flooding, and record dengue outbreaks. Observations and ocean model experiments reveal that northerly alongshore winds and westerly wind anomalies in the eastern equatorial Pacific, initially associated with a record-strong Madden-Julian Oscillation and cyclonic disturbance off Peru in March, drove the coastal warming through suppressed coastal upwelling and downwelling Kelvin waves. Atmospheric model simulations indicate that the coastal warming in turn favors the observed wind anomalies over the far eastern tropical Pacific by triggering atmospheric deep convection. This implies a positive feedback between the coastal warming and the winds, which further amplifies the coastal warming. In May, the seasonal background cooling precludes deep convection and the coastal Bjerknes feedback, leading to the weakening of the coastal El Niño. This coastal El Niño is rare but predictable at 1 month lead, which is useful to protect lives and properties.

Contribution of anthropogenic aerosols to persistent La Niña-like conditions in the early 21st century.

The discrepancy between the observed lack of surface warming in the eastern equatorial Pacific and climate model projections of an El Niño-like warming pattern confronts the climate research community. While anthropogenic aerosols have been suggested as a cause, the prolonged cooling trend over the equatorial Pacific appears in conflict with Northern Hemisphere aerosol emission reduction since the 1980s. Here, using CESM, we show that the superposition of fast and slow responses to aerosol emission change-an increase followed by a decrease-can sustain the La Niña-like condition for a longer time than expected. The rapid adjustment of Hadley Cell to aerosol reduction triggers joint feedback between low clouds, wind, evaporation, and sea surface temperature in the Southeast Pacific, leading to a wedge-shaped cooling that extends to the central equatorial Pacific. Meanwhile, the northern subtropical cell gradually intensifies, resulting in equatorial subsurface cooling that lasts for decades.

SLC38A5 promotes glutamine metabolism and inhibits cisplatin chemosensitivity in breast cancer.

BACKGROUND: Solute carrier family 38 member 5 (SLC38A5), as an amino acid transporter, play a vital role in cellular biological processes. In this study, we analyzed the function of SLC38A5 and its potential mechanism in breast cancer (BC) progression. METHODS: The expression of SLC38A5 in cancer and adjacent-normal tissues was analyzed by qRT-PCR and Western blot, and its correlation with patient prognosis was analyzed. The immunohistochemical staining of cancer tissues and adjacent-normal tissues was performed on SLC38A5-positive specimens. BC mice were successfully applied to examine the role of SLC38A5 on tumor proliferation using the CCK-8 assay. In BC cells and mouse tumor tissues, SLC38A5 and PCNA expression were determined by Western blotting. RESULTS: The study found that SLC38A5 was highly expressed in BC patients and associated with a poor survival. SLC38A5 silencing inhibited BC cell viability and glutamine uptake. In addition, SLC38A5 overexpression promoted BC cell viability via the glutamine metabolism. SLC38A5 inhibited cisplatin chemosensitivity in BC cells. Importantly, SLC38A5 silencing inhibited tumor growth in vivo. CONCLUSION: Our findings suggest that SLC38A5 enhances BC cell viability by glutamine metabolism, inhibits the chemical sensitivity of cisplatin in BC cells, and promotes tumor growth, emphasizing the clinical relevance of SLC38A5 in BC management as a novel potential therapeutic target.

Reversed asymmetric warming of sub-diurnal temperature over land during recent decades.

In the latter half of the twentieth century, a significant climate phenomenon "diurnal asymmetric warming" emerged, wherein global land surface temperatures increased more rapidly during the night than during the day. However, recent episodes of global brightening and regional droughts and heatwaves have brought notable alterations to this asymmetric warming trend. Here, we re-evaluate sub-diurnal temperature patterns, revealing a substantial increase in the warming rates of daily maximum temperatures (Tmax), while daily minimum temperatures have remained relatively stable. This shift has resulted in a reversal of the diurnal warming trend, expanding the diurnal temperature range over recent decades. The intensified Tmax warming is attributed to a widespread reduction in cloud cover, which has led to increased solar irradiance at the surface. Our findings underscore the urgent need for enhanced scrutiny of recent temperature trends and their implications for the wider earth system.

Anti-tau antibodies targeting a conformation-dependent epitope selectively bind seeds.

Neurodegenerative tauopathies are caused by the transition of tau protein from a monomer to a toxic aggregate. They include Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease (PiD). We have previously proposed that tau monomer exists in two conformational ensembles: an inert form (Mi), which does not self-assemble, and seed-competent form (Ms), which self-assembles and templates ordered assembly growth. We proposed that cis/trans isomerization of tau at P301, the site of dominant disease-associated S/L missense mutations, might underlie the transition of wild-type tau to a seed-competent state. Consequently, we created monoclonal antibodies using non-natural antigens consisting of fluorinated proline (P∗) at the analogous P270 in repeat 1 (R1), biased toward the trans-configuration at either the R1/R2 (TENLKHQP∗GGGKVQIINKK) or the R1/R3 (TENLKHQP∗GGGKVQIVYK) interfaces. Two antibodies, MD2.2 and MD3.1, efficiently immunoprecipitated soluble seeds from AD and PSP but not CBD or PiD brain samples. The antibodies efficiently stained brain samples of AD, PSP, and PiD, but not CBD. They did not immunoprecipitate or immunostain tau from the control brain. Creation of potent anti-seed antibodies based on the trans-proline epitope implicates local unfolding around P301 in pathogenesis. MD2.2 and MD3.1 may also be useful for therapy and diagnosis.

Soybean WRINKLED1 protein GmWRI1a promotes flowering under long-day conditions via regulating expressions of flowering-related genes.

Flowering time is an important agronomic character that influences the adaptability and yield of soybean [Glycine max (L.) Merrill]. WRINKLED 1 (WRI1) plays an important regulatory role in plant growth and development. In this study, we found that the expression of GmWIR1a could be induced by long days. Compared with the wild type, transgenic soybean overexpressing GmWRI1a showed earlier flowering and maturity under long days but no significant changes under short days. Overexpression of GmWRI1a led to up-regulated expression of genes involved in the regulation of flowering time. The GmWRI1a protein was able to directly bind to the promoter regions of GmAP1, GmFUL1a, GmFUL2 and up-regulated their expression. GmCOL3 was identified by yeast one-hybrid library screening using the GmWRI1a promoter as bait. GmCOL3 was revealed to be a nucleus-localized protein that represses the transcription of GmWRI1a. Expression of GmCOL3 was induced by short days. Taken together, the results show that overexpression of GmWRI1a promotes flowering under long days by promoting the transcriptional activity of flowering-related genes in soybean, and that GmCOL3 binds to the GmWRI1a promoter and directly down-regulates its transcription. This discovery reveals a new function for GmWRI1a, which regulates flowering and maturity in soybean.

Self-Assembly of an Anionic [Cu5I8]3- Supramolecular Cluster Driven by Ion-Pair Interaction and Catalytic Properties.

The rational design and controlling synthesis of an anionic cuprous iodide supramolecular cluster with high nuclearity through noncovalent interactions remains a significant challenge. Herein, a cationic organic ligand (L1)3+ was driven by anion-cation ion-pair electrostatic interaction to induce free cuprous iodide to aggregate into an anionic supramolecular cluster, [(Cu5I8)3-(L1)3+] (C1). Moreover, five copper(I) atoms bind with eight iodides through multiply bridged Cu-I bonds associated with intramolecular cuprophilic interactions in this butterfly-shaped cluster core. Supramolecular cluster C1 exhibited a solid-state emission at 380 nm and an emission at 405 nm in acetonitrile at room temperature, respectively. Interestingly, this unprecedented cuprous iodide cluster demonstrated a good catalytic performance for azide-alkyne cycloaddition reaction (CuAAC) and the catalytic yield can be up to 80% for eight different substrates at 80 °C. Furthermore, the density functional theory (DFT) calculation revealed that the thermodynamic-dependent cycloaddition reaction underwent a four-step pathway with an overall energy barrier of -43.6 kcal mol-1 on the basis of intermediates monitored by mass spectrum.

Pacific decadal oscillation causes fewer near-equatorial cyclones in the North Indian Ocean.

Tropical cyclones do not form easily near the equator but can intensify rapidly, leaving little time for preparation. We investigate the number of near-equatorial (originating between 5°N and 11°N) tropical cyclones over the north Indian Ocean during post-monsoon season (October to December) over the past 60 years. The study reveals a marked 43% decline in the number of such cyclones in recent decades (1981-2010) compared to earlier (1951-1980). Here, we show this decline in tropical cyclone frequency is primarily due to the weakened low-level vorticity modulated by the Pacific Decadal Oscillation (PDO) and increased vertical wind shear. In the presence of low-latitude basin-wide warming and a favorable phase of the PDO, both the intensity and frequency of such cyclones are expected to increase. Such dramatic and unique changes in tropical cyclonic activity due to the interplay between natural variability and climate change call for appropriate planning and mitigation strategies.

Prolonged thermocline warming by near-inertial internal waves in the wakes of tropical cyclones.

Turbulence-enhanced mixing of upper ocean heat allows interaction between the tropical atmosphere and cold water masses that impact climate at higher latitudes thereby regulating air-sea coupling and poleward heat transport. Tropical cyclones (TCs) can drastically enhance upper ocean mixing and generate powerful near-inertial internal waves (NIWs) that propagate down into the deep ocean. Globally, downward mixing of heat during TC passage causes warming in the seasonal thermocline and pumps 0.15 to 0.6 PW of heat into the unventilated ocean. The final distribution of excess heat contributed by TCs is needed to understand subsequent consequences for climate; however, it is not well constrained by current observations. Notably, whether or not excess heat supplied by TCs penetrates deep enough to be kept in the ocean beyond the winter season is a matter of debate. Here, we show that NIWs generated by TCs drive thermocline mixing weeks after TC passage and thus greatly deepen the extent of downward heat transfer induced by TCs. Microstructure measurements of the turbulent diffusivity ([Formula: see text]) and turbulent heat flux (J[Formula: see text]) in the Western Pacific before and after the passage of three TCs indicate that mean thermocline values of [Formula: see text] and J[Formula: see text] increased by factors of 2 to 7 and 2 to 4 (95% confidence level), respectively, after TC passage. Excess mixing is shown to be associated with the vertical shear of NIWs, demonstrating that studies of TC-climate interactions ought to represent NIWs and their mixing to accurately capture TC effects on background ocean stratification and climate.

Disentangling the mechanisms of equatorial Pacific climate change.

Most state-of-art models project a reduced equatorial Pacific east-west temperature gradient and a weakened Walker circulation under global warming. However, the causes of this robust projection remain elusive. Here, we devise a series of slab ocean model experiments to diagnostically decompose the global warming response into the contributions from the direct carbon dioxide (CO2) forcing, sea ice changes, and regional ocean heat uptake. The CO2 forcing dominates the Walker circulation slowdown through enhancing the tropical tropospheric stability. Antarctic sea ice changes and local ocean heat release are the dominant drivers for reduced zonal temperature gradient over the equatorial Pacific, while the Southern Ocean heat uptake opposes this change. Corroborating our model experiments, multimodel analysis shows that the models with greater Southern Ocean heat uptake exhibit less reduction in the temperature gradient and less weakening of the Walker circulation. Therefore, constraining the tropical Pacific projection requires a better insight into Southern Ocean processes.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

INTRODUCTION: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. METHODS: Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay). RESULTS: Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001). CONCLUSION: Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

Southern Ocean warming and its climatic impacts.

The Southern Ocean has warmed substantially, and up to early 21st century, Antarctic stratospheric ozone depletion and increasing atmospheric CO2 have conspired to intensify Southern Ocean warming. Despite a projected ozone recovery, fluxes to the Southern Ocean of radiative heat and freshwater from enhanced precipitation and melting sea ice, ice shelves, and ice sheets are expected to increase, as is a Southern Ocean westerly poleward intensification. The warming has far-reaching climatic implications for melt of Antarctic ice shelf and ice sheet, sea level rise, and remote circulations such as the intertropical convergence zone and tropical ocean-atmosphere circulations, which affect extreme weathers, agriculture, and ecosystems. The surface warm and freshwater anomalies are advected northward by the mean circulation and deposited into the ocean interior with a zonal-mean maximum at ∼45°S. The increased momentum and buoyancy fluxes enhance the Southern Ocean circulation and water mass transformation, further increasing the heat uptake. Complex processes that operate but poorly understood include interactive ice shelves and ice sheets, oceanic eddies, tropical-polar interactions, and impact of the Southern Ocean response on the climate change forcing itself; in particular, limited observations and low resolution of climate models hinder rapid progress. Thus, projection of Southern Ocean warming will likely remain uncertain, but recent community effort has laid a solid foundation for substantial progress.

Case report of severe coronary artery tortuosity with coexisting connective tissue disease.

Coronary artery tortuosity (CAT) is frequently detected during coronary angiography or coronary electron-beam computed tomography angiography by cardiovascular interventionalists. In this article, we described the case of a 69-year-old female patient with recurrent chest discomfort for 1 month and recurrence 1 week ago, accompanied by emaciation, gastrointestinal discomfort, and low skin temperature at the extremities. After a series of tests, the patient was finally diagnosed with severe CAT and coexisting connective tissue disease. Accordingly, she was treated with conventional medications, and diet and lifestyle modifications. The symptoms of the patient resolved gradually after 1 year of follow-up. Although there is no unanimous conclusion on the pathogenesis and clinical characteristics of CAT, this disease may provide a clue to the diagnosis of connective tissue disease, and warrants exploration through further research.