The prodomain of Arabidopsis metacaspase 2 positively regulates immune signaling mediated by pattern-recognition receptors.

Metacaspases (MCs) are structural homologs of mammalian caspases found in plants, fungi, and protozoa. Type-I MCs carry an N-terminal prodomain, the function of which is unclear. Through genetic analysis of Arabidopsis mc2-1, a T-DNA insertion mutant of MC2, we demonstrated that the prodomain of metacaspase 2 (MC2) promotes immune signaling mediated by pattern-recognition receptors (PRRs). In mc2-1, immune responses are constitutively activated. The receptor-like kinases (RLKs) BAK1/BKK1 and SOBIR1 are required for the autoimmune phenotype of mc2-1, suggesting that immune signaling mediated by the receptor-like protein (RLP)-type PRRs is activated in mc2-1. A suppressor screen identified multiple mutations in the first exon of MC2, which suppress the autoimmunity in mc2-1. Further analysis revealed that the T-DNA insertion at the end of exon 1 of MC2 causes elevated expression of the MC2 prodomain, and overexpression of the MC2 prodomain in wild-type (WT) plants results in the activation of immune responses. The MC2 prodomain interacts with BIR1, which inhibits RLP-mediated immune signaling by interacting with BAK1, suggesting that the MC2 prodomain promotes plant defense responses by interfering with the function of BIR1. Our study uncovers an unexpected function of the prodomain of a MC in plant immunity.

Evaluation of Resistance Resources and Analysis of Resistance Mechanisms of Maize to Stalk Rot Caused by Fusarium graminearum.

Stalk rot is one of the most destructive and widely distributed diseases in maize plants worldwide. Research on the performance and resistance mechanisms of maize against stem rot is constantly improving. In this study, among 120 inbred maize lines infected by Fusarium graminearum using the injection method, 4 lines (3.33%) were highly resistant to stalk rot, 28 lines (23.33%) were resistant, 57 lines (47.50%) were susceptible, and 31 lines (25.84%) were highly susceptible. The inbred lines 18N10118 and 18N10370 were the most resistant and susceptible with disease indices of 7.5 and 75.6, respectively. Treatment of resistant and susceptible maize inbred seedlings with F. graminearum showed that root hair growth of the susceptible inbred lines was significantly inhibited, and a large number of hyphae attached and adsorbed multiple conidia near the root system. However, the resistant inbred lines were delayed and inconspicuous, with only a few hyphae and spores appearing near the root system. Compared with susceptible inbred lines, resistant maize inbred line seedlings treated with F. graminearum exhibited elevated activities of catalase, phenylalanine ammonia-lyase, polyphenol oxidase, and superoxide dismutase. We identified 153 genes related to disease resistance by transcriptome analysis. The mitogen-activated protein kinase signaling and peroxisome pathways mainly regulated the resistance mechanism of maize inbred lines to F. graminearum infection. These two pathways might play an important role in the disease resistance mechanism, and the function of genes in the two pathways must be further studied, which might provide a theoretical basis for further understanding the molecular resistance mechanism of stalk rot and resistance gene mining.

Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.

We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.

Risk factor analysis for diabetic foot ulcer-related amputation including Controlling Nutritional Status score and neutrophil-to-lymphocyte ratio.

Diabetic foot ulcer often leads to amputation, and both nutritional status and immune function have been associated with this process. We aimed to investigate the risk factors of diabetic ulcer-related amputation including the Controlling Nutritional Status score and neutrophil-to-lymphocyte ratio biomarker. We evaluated data from hospital in patients with diabetic foot ulcer, performing univariate and multivariate analyses to screen for high-risk factors and Kaplan-Meier analysis to correlate high-risk factors with amputation-free survival. Overall, 389 patients underwent 247 amputations over the follow-up period. After correction to relevant variables, we identified five independent risk factors for diabetic ulcer-related amputation: ulcer severity, ulcer site, peripheral arterial disease, neutrophil-to-lymphocyte ratio and nutritional status. Amputation-free survival was lower for the moderate-to-severe versus mild cases, for the plantar forefoot versus hindfoot location, for the concomitant peripheral artery disease versus without and in the high versus low neutrophil-to-lymphocyte ratio (all p < 0.01). The results showed that ulcer severity (p < 0.01), ulcer site (p < 0.01), peripheral artery disease (p < 0.01), neutrophil-to-lymphocyte ratio (p < 0.01) and Controlling Nutritional Status score (p < 0.05) were independent risk factors for amputation in diabetic foot ulcer patients and have predictive values for diabetic foot ulcer progression to amputation.

Cross-platform privacy-preserving CT image COVID-19 diagnosis based on source-free domain adaptation.

In the wake of the Coronavirus disease (COVID-19) pandemic, chest computed tomography (CT) has become an invaluable component in the rapid and accurate detection of COVID-19. CT scans traditionally require manual inspections from medical professionals, which is expensive and tedious. With advancements in machine learning, deep neural networks have been applied to classify CT scans for efficient diagnosis. However, three challenges hinder this application of deep learning: (1) Domain shift across CT platforms and human subjects impedes the performance of neural networks in different hospitals. (2) Unsupervised Domain Adaptation (UDA), the traditional method to overcome domain shift, typically requires access to both source and target data. This is not realistic in COVID-19 diagnosis due to the sensitivity of medical data. The privacy of patients must be protected. (3) Data imbalance may exist between easy/hard samples and between data classes which can overwhelm the training of deep networks, causing degenerate models. To overcome these challenges, we propose a Cross-Platform Privacy-Preserving COVID-19 diagnosis network (CP 3 Net) that integrates domain adaptation, self-supervised learning, imbalanced label learning, and rotation classifier training into one synergistic framework. We also create a new CT benchmark by combining real-world datasets from multiple medical platforms to facilitate the cross-domain evaluation of our method. Through extensive experiments, we demonstrate that CP 3 Net outperforms many popular UDA methods and achieves state-of-the-art results in diagnosing COVID-19 using CT scans.

A dual-function transcription factor, SlJAF13, promotes anthocyanin biosynthesis in tomato.

Unlike modern tomato (Solanum lycopersicum) cultivars, cv. LA1996 harbors the dominant Aft allele, which is associated with anthocyanin synthesis in tomato fruit peel. However, the control of Aft anthocyanin biosynthesis remains unclear. Here, we used ethyl methanesulfonate-induced and CRISPR/Cas9-mediated mutation of LA1996 to show, respectively, that two class IIIf basic helix-loop-helix (bHLH) transcription factors, SlJAF13 and SlAN1, are involved in the control of anthocyanin synthesis. These transcription factors are key components of the MYB-bHLH-WD40 (MBW) complex, which positively regulates anthocyanin synthesis. Molecular and genetic analyses showed that SlJAF13 functions as an upstream activation factor of SlAN1 by binding directly to the G-Box motif of its promoter region. On the other hand, SlJAZ2, a JA signaling repressor, interferes with formation of the MBW complex to suppress anthocyanin synthesis by directly binding these two bHLH components. Unexpectedly, the transcript level of SlJAZ2 was in turn repressed in a SlJAF13-dependent manner. Mechanistically, SlJAF13 interacts with SlMYC2, inhibiting SlMYC2 activation of SlJAZ2 transcription, thus constituting a negative feedback loop governing anthocyanin accumulation. Taken together, our findings support a sophisticated regulatory network, in which SlJAF13 acts as an upstream dual-function regulator that fine tunes anthocyanin biosynthesis in tomato.

Characterization of inflammatory profiles and endothelial dysfunction in diabetic limb arterial occlusion.

Our study aims to detect the changes of adiponectin (APN), endothelin 1 (ET)-1, nitric oxide (NO), cystatin C (cysC) in diabetic limb arterial occlusion (DLAO) patients and unravel their associations with endothelial function. Total 240 type 2 diabetes mellitus (T2DM) patients were divided into a DM group (n = 80, ankle brachial index (ABI) ≥ 0.9) and a DLAO group (n = 160, ABI < 0.9). ABI, flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD), serum APN, ET-1, NO, and cysC were compared. There were significant increases in cysC and ET-1, and significant decreases in APN, NO, FMD and NMD of DLAO patients compared to T2DM patients. Serum APN and NO were positively correlated with ABI, while serum cysC and ET-1 were negatively correlated with ABI. cysC, ET-1 and diastolic blood pressure (DBP) were independent predictors of the severity of DLAO. Serum APN was positively correlated with FMD, NMD and NO, but was negatively correlated with ET-1 and cysC. FMD and NMD were positively correlated with APN and NO, and negatively correlated with ET-1 and cysC. Our study deciphers opposite roles of APN, NO, cysC and ET-1 in the development of DLAO and maintaining endothelial function.

Device-Free Multi-Location Human Activity Recognition Using Deep Complex Network.

Wi-Fi-based human activity recognition has attracted broad attention for its advantages, which include being device-free, privacy-protected, unaffected by light, etc. Owing to the development of artificial intelligence techniques, existing methods have made great improvements in sensing accuracy. However, the performance of multi-location recognition is still a challenging issue. According to the principle of wireless sensing, wireless signals that characterize activity are also seriously affected by location variations. Existing solutions depend on adequate data samples at different locations, which are labor-intensive. To solve the above concerns, we present an amplitude- and phase-enhanced deep complex network (AP-DCN)-based multi-location human activity recognition method, which can fully utilize the amplitude and phase information simultaneously so as to mine more abundant information from limited data samples. Furthermore, considering the unbalanced sample number at different locations, we propose a perception method based on the deep complex network-transfer learning (DCN-TL) structure, which effectively realizes knowledge sharing among various locations. To fully evaluate the performance of the proposed method, comprehensive experiments have been carried out with a dataset collected in an office environment with 24 locations and five activities. The experimental results illustrate that the approaches can achieve 96.85% and 94.02% recognition accuracy, respectively.

Can fractal dimension analysis be used in quantitating collagen structure?

It is well known that collagen tissue, especially the collagen structure, plays an important role in wound healing. However, most research on collagen has been qualitative and morphological, based on sections, and cannot be used for real-time monitoring and clinical prediction. There are no standardized methods of quantitative analysis based on the whole skin sample in three dimensions (3-D). In order to explore a 3-D quantitative analysis, we developed a method that was derived from that of material science and physics, combined with our previous technique, X-ray scattering (SAXS). We hypothesized that the dermis might be analysed by fractal dimensions. To test this hypothesis, we performed the analysis in different pathological conditions, such as scar tissue, different time points after wounding, skin in different degrees of burns and skin in diabetes. The results showed that fractal dimension analysis could detect differences in different locations of the scar tissue, at different time points after wounding, and at a different extent of the severity of skin in diabetes. The research demonstrated that fractal dimension analysis can describe the 3-D structure of the collagen tissue of the skin, which will be beneficial for studying wound healing and finding new clinical treatments.

BrLETM2 Protein Modulates Anthocyanin Accumulation by Promoting ROS Production in Turnip (Brassica rapa subsp. rapa).

In 'Tsuda' turnip, the swollen root peel accumulates anthocyanin pigments in a light-dependent manner, but the mechanism is unclear. Here, mutant g120w which accumulated extremely low levels of anthocyanin after light exposure was identified. Segregation analysis showed that the anthocyanin-deficient phenotype was controlled by a single recessive gene. By using bulked-segregant analysis sequencing and CAPS marker-based genetic mapping analyses, a 21.6-kb region on chromosome A07 was mapped, in which a calcium-binding EF hand family protein named BrLETM2 was identified as the causal gene. RNA sequencing analysis showed that differentially expressed genes (DEGs) between wild type and g120w in light-exposed swollen root peels were enriched in anthocyanin biosynthetic process and reactive oxygen species (ROS) biosynthetic process GO term. Furthermore, nitroblue tetrazolium (NBT) staining showed that the ROS level decreased in g120w mutant. Anthocyanins induced by UV-A were abolished by the pre-treatment of seedlings with DPI (an inhibitor of nicotinamide adenine nucleoside phosphorylase (NADPH) oxidase) and decreased in g120w mutant. These results indicate that BrLETM2 modulates ROS signaling to promote anthocyanin accumulation in turnip under UV-A and provides new insight into the mechanism of how ROS and light regulate anthocyanin production.

Investigating the co-firing characteristics of bamboo wastes and coal through cone calorimetry and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy.

To evaluate the combustion characteristics of raw or torrefied bamboo wastes and coal blends, the co-firing process determined by cone and pollutant emission was investigated by thermogravimetric analysis coupled with Fourier transform infrared spectroscopy. The results showed that torrefaction improved the fuel properties of bamboo wastes. Torrefied bamboo had a lower volatile fuel ratio, H/C and O/C ratios, pollutant emission and a higher heating value. They further affected the co-firing process of raw or torrefied bamboo and coal. All blends had a lower ignition temperature and a more stable flame than coal. Torrefied bamboo and coal blends had a lower percentage of quality loss, a higher heat release rate (HRR), total heat release (THR) and total smoke release (TSR). With an increase in the proportion of torrefied bamboo in the blends, the HRR, THR, TSR and percentage of quality loss increased. The main pollutant emissions included CO2, CO, SO2 and NOx. All blends of torrefied bamboo and coal had a lower pollutant emission. The optimum blend suggested was 20% torrefied bamboo/80% coal.

TMP778, a selective inhibitor of RORγt, suppresses experimental autoimmune uveitis development, but affects both Th17 and Th1 cell populations.

Experimental autoimmune uveitis (EAU), an animal model for severe intraocular inflammatory eye diseases, is mediated by both Th1 and Th17 cells. Here, we examined the capacity of TMP778, a selective inhibitor of RORγt, to inhibit the development of EAU, as well as the related immune responses. EAU was induced in B10.A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP). Treatment with TMP778 significantly inhibited the development of EAU, determined by histological examination. In addition, the treatment suppressed the cellular immune response to IRBP, determined by reduced production of IL-17 and IFN-γ, as well as lower percentages of lymphocytes expressing these cytokines, as compared to vehicle-treated controls. The inhibition of IFN-γ expression by TMP778 is unexpected in view of this compound being a selective inhibitor of RORγt. The observation was further confirmed by the finding of reduced expression of the T-bet (Tbx21) gene, the transcription factor for IFN-γ, by cells of TMP778-treated mice. Thus, these data demonstrate the capacity of TMP778 to inhibit pathogenic autoimmunity in the eye and shed new light on its mode of action in vivo.

Exploring nanoscale structure change of dermal tissues suffering injury by small angle X-ray scattering and transmission electron microscopy.

Scar formation and wound non-healing often occur during wound repair after skin injury, which are still unresolved. Clinic indicated that the structure played an important role in the wound repair. Our previous research showed that the wound over-healed (scar formation) when the integrity and continuity of dermal tissues was destroyed by injury. Other evidences showed that wound healing was impaired in diabetes because the underlying alternation in their skin tissues occurred caused by advanced glycation end products (AGES) aggregation. In order to explore the changes of the structure of skin at nanoscale, the small angle X-ray scattering (SAXS), compared with transmission electron microscopy (TEM), was applied to observe the skin in different pathological status. The results showed that there were some regular patterns in the structure of dermal tissue. The patterns were changed by different pathological status, which would result in wound healing disorder. These will be beneficial for clarifying the pathological mechanisms of wound healing.

Nitrogen Self-Doped Activated Carbons Derived from Bamboo Shoots as Adsorbent for Methylene Blue Adsorption.

Bamboo shoots, a promising renewable biomass, mainly consist of carbohydrates and other nitrogen-related compounds, such as proteins, amino acids and nucleotides. In this work, nitrogen self-doped activated carbons derived from bamboo shoots were prepared via a simultaneous carbonization and activation process. The adsorption properties of the prepared samples were evaluated by removing methylene blue from waste water. The factors that affect the adsorption process were examined, including initial concentration, contact time and pH of methylene blue solution. The resulting that BSNC-800-4 performed better in methylene blue removal from waste water, due to its high specific surface area (2270.9 m2 g-1), proper pore size (2.19 nm) and relatively high nitrogen content (1.06%). Its equilibrium data were well fitted to Langmuir isotherm model with a maximum monolayer adsorption capacity of 458 mg g-1 and a removal efficiency of 91.7% at methylene blue concentration of 500 mg L-1. The pseudo-second-order kinetic model could be used to accurately estimate the carbon material's (BSNC-800-4) adsorption process. The adsorption mechanism between methylene blue solution and BSNC-800-4 was controlled by film diffusion. This study provides an alternative way to develop nitrogen self-doped activated carbons to better meet the needs of the adsorption applications.

Identification of Light-Independent Anthocyanin Biosynthesis Mutants Induced by Ethyl Methane Sulfonate in Turnip "Tsuda" (Brassica rapa).

The epidermis of swollen storage roots in purple cultivars of turnip "Tsuda" (Brassica rapa) accumulates anthocyanin in a light-dependent manner, especially in response to UV-A light, of which the mechanism is unclear. In this study, we mutagenized 15,000 seeds by 0.5% (v/v) ethyl methane sulfonate (EMS) and obtained 14 mutants with abnormal anthocyanin production in their epidermis of swollen storage roots. These mutants were classified into two groups: the red mutants with constitutive anthocyanin accumulation in their epidermis of storage roots even in underground parts in darkness and the white mutants without anthocyanin accumulation in the epidermis of storage roots in aboveground parts exposed to sunlight. Test cross analysis demonstrated that w9, w68, w204, r15, r21, r30 and r57 contained different mutations responsible for their phenotypic variations. Further genetic analysis of four target mutants (w9, w68, w204 and r15) indicated that each of them was controlled by a different recessive gene. Intriguingly, the expression profiles of anthocyanin biosynthesis genes, including structural and regulatory genes, coincided with their anthocyanin levels in the epidermis of storage roots in the four target mutants. We proposed that potential genes responsible for the mutations should be upstream factors of the anthocyanin biosynthesis pathway in turnips, which provided resources to further investigate the mechanisms of light-induced anthocyanin accumulation.

Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo.

IL-17-producing CD4(+)Th17 cells, CD8(+)Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23-induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8(+) Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23-induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

In vivo regulation of gene expression and T helper type 17 differentiation by RORγt inverse agonists.

The orphan nuclear receptor, retinoic acid receptor-related orphan nuclear receptor γt (RORγt), is required for the development and pathogenic function of interleukin-17A-secreting CD4(+) T helper type 17 (Th17) cells. Whereas small molecule RORγt antagonists impair Th17 cell development and attenuate autoimmune inflammation in vivo, the broader effects of these inhibitors on RORγt-dependent gene expression in vivo has yet to be characterized. We show that the RORγt inverse agonist TMP778 acts potently and selectively to block mouse Th17 cell differentiation in vitro and to impair Th17 cell development in vivo upon immunization with the myelin antigen MOG35-55 plus complete Freund's adjuvant. Importantly, we show that TMP778 acts in vivo to repress the expression of more than 150 genes, most of which fall outside the canonical Th17 transcriptional signature and are linked to a variety of inflammatory pathologies in humans. Interestingly, more than 30 genes are related with SMAD3, a transcription factor involved in the Th17 cell differentiation. These results reveal novel disease-associated genes regulated by RORγt during inflammation in vivo, and provide an early read on potential disease indications and safety concerns associated with pharmacological targeting of RORγt.

Effects of modified Danggui Sini Decoction as adjuvant therapy for angina pectoris in coronary heart disease: a systematic review and meta-analysis based on randomised controlled trials.

Introduction: This systematic review evaluates the efficacy of the Chinese herbal formula modified Danggui Sini Decoction as an adjunctive treatment for angina pectoris in patients with coronary heart disease. Methods: We conducted a comprehensive search for randomized controlled trials that investigated the effects of modified Danggui Sini Decoction in combination with conventional Western medication on angina pectoris in coronary artery disease, published up to July 2023 across eight databases, including China Knowledge International Literature screening and data extraction were performed by two researchers following predefined inclusion and exclusion criteria. The quality of included studies was assessed using the Cochrane Handbook version 5.1, and meta-analysis was executed via RevMan 5.4 software. Results: Thirteen studies encompassing 1,232 participants were incorporated. The meta-analysis revealed that combining modified Danggui Sini Decoction with conventional Western medication significantly enhanced overall clinical efficacy, reduced the duration of angina attacks, decreased the Chinese medicine syndrome score, improved inflammatory markers and cardiac function, lowered serum NT-proBNP levels, and elevated the Seattle Angina Questionnaire scores compared to the control group. Conclusion: Modified Danggui Sini Decoction, when used alongside conventional Western medications, shows promise in treating coronary artery disease patients with angina pectoris and may serve as a beneficial adjunctive therapy in clinical settings. Nonetheless, due to the limited quantity and quality of the included studies, further high-caliber research is essential to substantiate these findings. Systematic Review Registration: https://inplasy.com/? s=202390078, identifier INPLASY 202390078.

Toward ubiquitous sensing: Researchers turn WiFi signals into human activity patterns.

Jianfei Yang, a principal investigator and postdoc at Nanyang Technological University (NTU), and his student Xinyan Chen have developed a comprehensive benchmark and library for WiFi sensing. Their Patterns paper highlights the advantages of deep learning for WiFi sensing and provides constructive suggestions on model selection, learning scheme, and training strategy for developers and data scientists in this field. They talk about their view of data science, their experience with interdisciplinary WiFi sensing research, and the future of WiFi sensing applications.

Advancing Imbalanced Domain Adaptation: Cluster-Level Discrepancy Minimization With a Comprehensive Benchmark.

Unsupervised domain adaptation methods have been proposed to tackle the problem of covariate shift by minimizing the distribution discrepancy between the feature embeddings of source domain and target domain. However, the standard evaluation protocols assume that the conditional label distributions of the two domains are invariant, which is usually not consistent with the real-world scenarios such as long-tailed distribution of visual categories. In this article, the imbalanced domain adaptation (IDA) is formulated for a more realistic scenario where both label shift and covariate shift occur between the two domains. Theoretically, when label shift exists, aligning the marginal distributions may result in negative transfer. Therefore, a novel cluster-level discrepancy minimization (CDM) is developed. CDM proposes cross-domain similarity learning to learn tight and discriminative clusters, which are utilized for both feature-level and distribution-level discrepancy minimization, palliating the negative effect of label shift during domain transfer. Theoretical justifications further demonstrate that CDM minimizes the target risk in a progressive manner. To corroborate the effectiveness of CDM, we propose two evaluation protocols according to the real-world situation and benchmark existing domain adaptation approaches. Extensive experiments demonstrate that negative transfer does occur due to label shift, while our approach achieves significant improvement on imbalanced datasets, including Office-31, Image-CLEF, and Office-Home.