Regulation of drought tolerance in Arabidopsis involves the PLATZ4-mediated transcriptional repression of plasma membrane aquaporin PIP2;8.

Plant A/T-rich protein and zinc-binding protein (PLATZ) transcription factors play important roles in plant growth, development and abiotic stress responses. However, how PLATZ influences plant drought tolerance remains poorly understood. The present study showed that PLATZ4 increased drought tolerance in Arabidopsis thaliana by causing stomatal closure. Transcriptional profiling analysis revealed that PLATZ4 affected the expression of a set of genes involved in water and ion transport, antioxidant metabolism, small peptides and abscisic acid (ABA) signaling. Among these genes, the direct binding of PLATZ4 to the A/T-rich sequences in the plasma membrane intrinsic protein 2;8 (PIP2;8) promoter was identified. PIP2;8 consistently reduced drought tolerance in Arabidopsis through inhibiting stomatal closure. PIP2;8 was localized in the plasma membrane, exhibited water channel activity in Xenopus laevis oocytes and acted epistatically to PLATZ4 in regulating the drought stress response in Arabidopsis. PLATZ4 increased ABA sensitivity through upregulating the expression of ABSCISIC ACID INSENSITIVE 3 (ABI3), ABI4 and ABI5. The transcripts of PLATZ4 were induced to high levels in vegetative seedlings under drought and ABA treatments within 6 and 3 h, respectively. Collectively, these findings reveal that PLATZ4 positively influences plant drought tolerance through regulating the expression of PIP2;8 and genes involved in ABA signaling.

A long non-coding RNA functions as a competitive endogenous RNA to modulate TaNAC018 by acting as a decoy for tae-miR6206.

Increasing evidence indicates a strong correlation between the deposition of cuticular waxes and drought tolerance. However, the precise regulatory mechanism remains elusive. Here, we conducted a comprehensive transcriptome analysis of two wheat (Triticum aestivum) near-isogenic lines, the glaucous line G-JM38 rich in cuticular waxes and the non-glaucous line NG-JM31. We identified 85,143 protein-coding mRNAs, 4,485 lncRNAs, and 1,130 miRNAs. Using the lncRNA-miRNA-mRNA network and endogenous target mimic (eTM) prediction, we discovered that lncRNA35557 acted as an eTM for the miRNA tae-miR6206, effectively preventing tae-miR6206 from cleaving the NAC transcription factor gene TaNAC018. This lncRNA-miRNA interaction led to higher transcript abundance for TaNAC018 and enhanced drought-stress tolerance. Additionally, treatment with mannitol and abscisic acid (ABA) each influenced the levels of tae-miR6206, lncRNA35557, and TaNAC018 transcript. The ectopic expression of TaNAC018 in Arabidopsis also improved tolerance toward mannitol and ABA treatment, whereas knocking down TaNAC018 transcript levels via virus-induced gene silencing in wheat rendered seedlings more sensitive to mannitol stress. Our results indicate that lncRNA35557 functions as a competing endogenous RNA to modulate TaNAC018 expression by acting as a decoy target for tae-miR6206 in glaucous wheat, suggesting that non-coding RNA has important roles in the regulatory mechanisms responsible for wheat stress tolerance.

Ni and Co Active Site Transition and Competition in Fluorine-Doped NiCo(OH)2 LDH Electrocatalysts for Oxygen Evolution Reaction.

The oxygen evolution reaction (OER) performance of NiCo LDH electrocatalysts can be improved through fluorine doping. The roles of Ni and Co active sites in such catalysts remain ambiguous and controversial. In addressing the issue, this study draws upon the molecular orbital theory and proposes the active center competitive mechanism between Ni and Co. The doped F-atoms can directly impact the valence state of metal atoms or exert an indirect influence through the dehydrogenation, thereby modulating the active center. As the F-atoms are progressively aggregate, the eg orbitals of Ni and Co transition from e2 g to e1 g , and subsequently to e0 g . The corresponding valence state elevates from +2 to +3, and then to +4, signifying an initial increase followed by a subsequent decrease in the electrocatalytic performance. Furthermore, a series of F-NiCo LDH catalysts are synthesized to verify the eg orbital occupancy analysis, and the catalytic OER overpotentials are 303, 243, 240, and 246 mV at the current density of 10 mA cm-2 , respectively, which coincides well with the theoretical prediction. This investigation not only provides novel mechanistic insights into the transition and competition of Ni and Co in F-NiCo LDH catalysts but also establishes a foundation for the design of high-performance catalysts.

An efficient genetic transformation system mediated by Rhizobium rhizogenes in fruit trees based on the transgenic hairy root to shoot conversion.

Genetic transformation is a critical tool for gene editing and genetic improvement of plants. Although many model plants and crops can be genetically manipulated, genetic transformation systems for fruit trees are either lacking or perform poorly. We used Rhizobium rhizogenes to transfer the target gene into the hairy roots of Malus domestica and Actinidia chinensis. Transgenic roots were generated within 3 weeks, with a transgenic efficiency of 78.8%. Root to shoot conversion of transgenic hairy roots was achieved within 11 weeks, with a regeneration efficiency of 3.3%. Finally, the regulatory genes involved in stem cell activity were used to improve shoot regeneration efficiency. MdWOX5 exhibited the most significant effects, as it led to an improved regeneration efficiency of 20.6% and a reduced regeneration time of 9 weeks. Phenotypes of the overexpression of RUBY system mediated red roots and overexpression of MdRGF5 mediated longer root hairs were observed within 3 weeks, suggesting that the method can be used to quickly screen genes that influence root phenotype scores through root performance, such as root colour, root hair, and lateral root. Obtaining whole plants of the RUBY system and MdRGF5 overexpression lines highlights the convenience of this technology for studying gene functions in whole plants. Overall, we developed an optimized method to improve the transformation efficiency and stability of transformants in fruit trees.

Salt responsive alternative splicing of a RING finger E3 ligase modulates the salt stress tolerance by fine-tuning the balance of COP9 signalosome subunit 5A.

Increasing evidence points to the tight relationship between alternative splicing (AS) and the salt stress response in plants. However, the mechanisms linking these two phenomena remain unclear. In this study, we have found that Salt-Responsive Alternatively Spliced gene 1 (SRAS1), encoding a RING-Type E3 ligase, generates two splicing variants: SRAS1.1 and SRAS1.2, which exhibit opposing responses to salt stress. The salt stress-responsive AS event resulted in greater accumulation of SRAS1.1 and a lower level of SRAS1.2. Comprehensive phenotype analysis showed that overexpression of SRAS1.1 made the plants more tolerant to salt stress, whereas overexpression of SRAS1.2 made them more sensitive. In addition, we successfully identified the COP9 signalosome 5A (CSN5A) as the target of SRAS1. CSN5A is an essential player in the regulation of plant development and stress. The full-length SRAS1.1 promoted degradation of CSN5A by the 26S proteasome. By contrast, SRAS1.2 protected CSN5A by competing with SRAS1.1 on the same binding site. Thus, the salt stress-triggered AS controls the ratio of SRAS1.1/SRAS1.2 and switches on and off the degradation of CSN5A to balance the plant development and salt tolerance. Together, these results provide insights that salt-responsive AS acts as post-transcriptional regulation in mediating the function of E3 ligase.

Mutations in troABCD against Copper Overload in a copA Mutant of Streptococcus suis.

Streptococcus suis is a major swine pathogen that is increasingly recognized as a porcine zoonotic pathogen that threatens the health of both pigs and humans. Metal homeostasis plays a critical role during the process of bacterial infection. In this study, RNA sequencing was used to identify potential candidate genes involved in the maintenance of intracellular copper homeostasis. CopA was identified as the primary copper exporter in S. suis. The copA deletion mutant strain was found to be more sensitive to copper and accumulated more intracellular copper than the wild-type (WT) parent strain. In addition, adding manganese increased the ability of S. suis to resist copper, and the manganese transporter, TroABCD, was involved in tolerance to copper. The copA deletion mutant strain accumulated less copper when supplemented with manganese. Furthermore, when cultured with copper, the double deletion mutant (ΔcopAΔtroA) exhibited improved growth compared to the copA deletion mutant strain. In addition, the double deletion mutant (ΔcopAΔtroA) accumulated less copper than the copA deletion mutant strain. These data were consistent with a model wherein defective TroABCD resulted in decreased cellular copper accumulation and protected the strain against copper poisoning. IMPORTANCE Metal homeostasis plays a critical role during the process of bacterial infection. We identified three important potential candidate genes involved in maintenance of intracellular copper homeostasis. CopA was demonstrated to be the main copper exporter in Streptococcus suis, and manganese increased the tolerance of S. suis to copper. The double deletion mutant (ΔcopAΔtroA) improved growth ability over the copA deletion mutant strain in the presence of high concentrations of copper and accumulated less copper. These findings are consistent with a model wherein defective TroABCD resulted in decreased cellular accumulation of copper and protected the strain against copper poisoning.

Intronic microRNA-directed regulation of mitochondrial reactive oxygen species enhances plant stress tolerance in Arabidopsis.

MicroRNAs (miRNAs) play crucial roles in regulating plant development and stress responses. However, the functions and mechanism of intronic miRNAs in plants are poorly understood. This study reports a stress-responsive RNA splicing mechanism for intronic miR400 production, whereby miR400 modulates reactive oxygen species (ROS) accumulation and improves plant tolerance by downregulating its target expression. To monitor the intron splicing events, we used an intronic miR400 splicing-dependent luciferase transgenic line. Luciferase activity was observed to decrease after high cadmium concentration treatment due to the retention of the miR400-containing intron, which inhibited the production of mature miR400. Furthermore, we demonstrated that under Cd treatments, Pentatricopeptide Repeat Protein 1 (PPR1), the target of miR400, acts as a positive regulator by inducing ROS accumulation. Ppr1 mutation affected the Complex III activity in the electron transport chain and RNA editing of the mitochondrial gene ccmB. This study illustrates intron splicing as a key step in intronic miR400 production and highlights the function of intronic miRNAs as a 'signal transducer' in enhancing plant stress tolerance.

The Spatial Distribution and Potential Risk Assessment of POPs in Farmland around a Typical E-Waste Dismantling Site.

Pollution from electronic-waste (E-waste) dismantling is of great concern. This study investigated the concentrations of polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and polybrominated diphenyl ethers (PBDEs) in 253 cropland soil samples around an abandoned E-waste dismantling site in Taizhou city, Zhejiang province in China, using an analytical method which simultaneously extracted, purified and determined the identity and quantity of the three types of persistent organic pollutants. Meanwhile, their spatial distributions, pollution characteristics, and risk assessments were further analyzed. Total PCBs in the test soils ranged from below method detection limits (ND) to 2985.25 µg kg-1 on a dry weight basis (d.w.), and the spatial distribution indicated a "hot spot" of PCBs pollution in the study area. The PAHs were detected in all samples with total concentrations ranging from 4.99 to 2723.06 µg kg-1 d.w. The distribution of PBDEs showed the pollution characteristics of "family-run workshops", with a total content range of ND ~ 899.34 µg kg-1 d.w., of which BDE209 was typically the dominant congener, accounting for 74.05% of the total PBDEs content in the test soils, with the highest content reaching 857.72 µg kg-1 d.w. Results showed that the ecological and lifetime carcinogenic risks of PCBs and PAHs were low in the study area, but the health risk caused by oral ingestion and dermal contact accounted for the highest proportion of the total exposure risks, while inhalation could be ignored. PBDEs in soils of the study area were a potential chronic non-carcinogenic risk, particularly for children. Therefore, in order to protect human health and environment, it is necessary to regulate the management of E-waste dismantling sites and pollution control.

BREVIPEDICELLUS Positively Regulates Salt-Stress Tolerance in Arabidopsis thaliana.

Salt stress is one of the major environmental threats to plant growth and development. However, the mechanisms of plants responding to salt stress are not fully understood. Through genetic screening, we identified and characterized a salt-sensitive mutant, ses5 (sensitive to salt 5), in Arabidopsis thaliana. Positional cloning revealed that the decreased salt-tolerance of ses5 was caused by a mutation in the transcription factor BP (BREVIPEDICELLUS). BP regulates various developmental processes in plants. However, the biological function of BP in abiotic stress-signaling and tolerance are still not clear. Compared with wild-type plants, the bp mutant exhibited a much shorter primary-root and lower survival rate under salt treatment, while the BP overexpressors were more tolerant. Further analysis showed that BP could directly bind to the promoter of XTH7 (xyloglucan endotransglucosylase/hydrolase 7) and activate its expression. Resembling the bp mutant, the disruption of XTH7 gave rise to salt sensitivity. These results uncovered novel roles of BP in positively modulating salt-stress tolerance, and illustrated a putative working mechanism.

Tyrosylprotein sulfotransferase suppresses ABA signaling via sulfation of SnRK2.2/2.3/2.6.

Phytohormone abscisic acid (ABA) plays vital roles in stress tolerance, while long-term overactivation of ABA signaling suppresses plant growth and development. However, the braking mechanism of ABA responses is not clear. Protein tyrosine sulfation catalyzed by tyrosylprotein sulfotransferase (TPST) is a critical post-translational modification. Through genetic screening, we identified a tpst mutant in Arabidopsis that was hypersensitive to ABA. In-depth analysis revealed that TPST could interact with and sulfate SnRK2.2/2.3/2.6, which accelerated their degradation and weakened the ABA signaling. Taken together, these findings uncovered a novel mechanism of desensitizing ABA responses via protein sulfation.

Effects of bovine milk and buffalo milk on lipid metabolism in mice.

Buffalo milk contains more polyunsaturated fatty acids than bovine milk. However, it is not clear about the effects of buffalo milk and bovine milk on lipid metabolism. In this study, a mouse model was used to explore the effects of buffalo milk and bovine milk on lipid metabolism in mice. The experiment was divided into three groups: a control group on a normal diet; a bovine milk group infused with bovine milk; a buffalo milk group infused with buffalo milk. We fed three groups of mice (n = 6) for 6 weeks. These results showed that bovine milk and buffalo milk had no effect on body weight gain. Bovine milk increased the content of ApoA1, ApoB and glucose in serum, compared with the control group, but buffalo milk has no profound change in serum ApoB. Remarkably, buffalo milk decreased the content of total cholesterol (TC) and triglyceride (TG) in the liver lipid profile, and also downregulated the expression of the carnitine palmitoyltransferase 2 (Cpt2) gene involved in the fatty acid oxidation in the liver. This study also found that bovine milk and buffalo milk did not cause the expression of pro-inflammatory factors in serum and colon tissues. This experiment proved that buffalo milk has beneficial effects on the regulation of lipid metabolism, and also does not affect the normal growth and pro-inflammatory response of the colon in mice. It provides a theoretical basis for future in-depth research on the special functions of buffalo milk and the development of buffalo milk functional foods.

[Efficacy of Urapidil in treating lower urinary tract symptoms in patients with benign prostatic hyperplasia: A systematic review and meta-analysis].

OBJECTIVE: To investigate the potential application of α-1 blocker (urapidil) in the treatment of lower urinary tract symptoms (LUTS) in male patients with benign prostatic hypertrophy (BPH), we conducted a comprehensive meta-analysis. METHODS: Our study involved identifying and collecting randomized controlled trials (RCT) and clinical observational studies from databases including PubMed、MEDLINE、Web of science、CNKI and Wanfang database. We performed meta-analysis using RevMan 5.2.0 software for both fixed effects model and random effects model. RESULTS: Our analysis included 3 short-term (within 1 month) observational studies and 1 RCT involving 142 patients. We found that urapidil significantly improved the International Prostate Symptom Score (IPSS, MD=－5.57, 95%CI: －7.98～－3.16，P<0.00001), nocturia（MD=－0.7, 95%CI: －1.16～－0.24，P=0.003）, residual urine rate（MD=－6.97；95%CI: －12.57～－1.37，P=0.01）, average flow rate（MD=2.04；95%CI: 0.52～3.56，P=0.008）, and maximum flow rate （MD=4.29；95%CI: 0.58～8.01，P=0.02）of patients. However, there was no significant difference in the residual urine volume（MD=－35.93；95%CI: －78.62～6.76，P=0.10）between pre-treatment and post-treatment groups. CONCLUSION: Urapidil is an effective medication for relieving LUTS in BPH patients. However, due to the limited quantity and quality of current RCT studies, high-quality and large-scale RCT studies are still needed to further confirm this conclusion.

A feature-based convolutional neural network for reconstruction of interventional MRI.

Real-time interventional MRI (I-MRI) could help to visualize the position of the interventional feature, thus improving patient outcomes in MR-guided neurosurgery. In particular, in deep brain stimulation, real-time visualization of the intervention procedure using I-MRI could improve the accuracy of the electrode placement. However, the requirements of a high undersampling rate and fast reconstruction speed for real-time imaging pose a great challenge for reconstruction of the interventional images. Based on recent advances in deep learning (DL), we proposed a feature-based convolutional neural network (FbCNN) for reconstructing interventional images from golden-angle radially sampled data. The method was composed of two stages: (a) reconstruction of the interventional feature and (b) feature refinement and postprocessing. With only five radially sampled spokes, the interventional feature was reconstructed with a cascade CNN. The final interventional image was constructed with a refined feature and a fully sampled reference image. With a comparison of traditional reconstruction techniques and recent DL-based methods, it was shown that only FbCNN could reconstruct the interventional feature and the final interventional image. With a reconstruction time of ~ 500 ms per frame and an acceleration factor of ~ 80, it was demonstrated that FbCNN had the potential for application in real-time I-MRI.

Maize HEAT UP-REGULATED GENE 1 plays vital roles in heat stress tolerance.

Increasing temperature is one of the major threats to maize growth and yield globally. Under heat stress conditions, intracellular protein homeostasis is seriously disturbed, leading to accumulation of abnormally folded proteins, especially in the endoplasmic reticulum (ER). Molecular chaperones are vital players in the renaturation process and in preventing protein aggregation. However, heat stress tolerance-associated chaperones are not well documented in maize. Here, we characterized the biological roles of HEAT UP-REGULATED GENE 1 (ZmHUG1) in maize. ZmHUG1 encodes a heat-inducible holdase-type molecular chaperone localized in the ER. Knockout mutant of ZmHUG1 exhibited remarkably enhanced sensitivity to heat stress. Accordingly, the zmhug1 mutant showed severe ER stress under high temperature. MAIZE PRENYLATED RAB ACCEPTOR 1.C1 (ZmPRA1.C1) was identified as a client of ZmHUG1, and heat-induced aggregation of ZmPRA1.C1 was accelerated in the zmhug1 mutant. Furthermore, the expression of ZmHUG1 was rapidly transactivated by ER stress sensor BASIC LEUCINE ZIPPER DOMAIN 60 (bZIP60) when heat stress occurred. This study reveals a ZmHUG1-based thermo-protective mechanism in maize.

The VraSR two-component signal transduction system contributes to the damage of blood-brain barrier during Streptococcus suis meningitis.

Streptococcus suis (S. suis) is an important zoonotic pathogen that can cause high morbidity and mortality in both humans and swine. As the most important life-threatening infection of the central nervous system (CNS), meningitis is an important syndrome of S. suis infection. The vancomycin resistance associated sensor/regulator (VraSR) is a critical two-component signal transduction system that affects the ability of S. suis to resist the host innate immune system and promotes its ability to adhere to brain microvascular endothelial cells (BMECs). Prior work also found mice infected with ΔvraSR had no obvious neurological symptoms, unlike mice infected with wild-type SC19. Whether and how VraSR participates in the development of S. suis meningitis remains unknown. Here, we found ΔvraSR-infected mice did not show obvious meningitis, compared with wild-type SC19-infected mice. Moreover, the proinflammatory cytokines and chemokines in serum and brains of ΔvraSR-infected mice, including IL-6, TNF-α, MCP-1 and IFN-γ, were significantly lower than wild-type infected group. Besides, blood-brain barrier (BBB) permeability also confirmed that the mutant had lower ability to disrupt BBB. Furthermore, in vivo and in vitro experiments showed that SC19 could increase BBB permeability by downregulating tight junction (TJ) proteins such as ZO-1, ß-Catenin, Occludin, and Clauidn-5, compared with mutant ΔvraSR. These findings provide new insight into the influence of S. suis VraSR on BBB disruption during the pathogenic process of streptococcal meningitis, thereby offering potential targets for future preventative and therapeutic strategies against this disease.

Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations.

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

Deep Learning in Medical Hyperspectral Images: A Review.

With the continuous progress of development, deep learning has made good progress in the analysis and recognition of images, which has also triggered some researchers to explore the area of combining deep learning with hyperspectral medical images and achieve some progress. This paper introduces the principles and techniques of hyperspectral imaging systems, summarizes the common medical hyperspectral imaging systems, and summarizes the progress of some emerging spectral imaging systems through analyzing the literature. In particular, this article introduces the more frequently used medical hyperspectral images and the pre-processing techniques of the spectra, and in other sections, it discusses the main developments of medical hyperspectral combined with deep learning for disease diagnosis. On the basis of the previous review, tne limited factors in the study on the application of deep learning to hyperspectral medical images are outlined, promising research directions are summarized, and the future research prospects are provided for subsequent scholars.

Constructing Atomic Heterometallic Sites in Ultrathin Nickel-Incorporated Cobalt Phosphide Nanosheets via a Boron-Assisted Strategy for Highly Efficient Water Splitting.

Identification of active sites for highly efficient catalysts at the atomic scale for water splitting is still a great challenge. Herein, we fabricate ultrathin nickel-incorporated cobalt phosphide porous nanosheets (Ni-CoP) featuring an atomic heterometallic site (NiCo16-xP6) via a boron-assisted method. The presence of boron induces a release-and-oxidation mechanism, resulting in the gradual exfoliation of hydroxide nanosheets. After a subsequent phosphorization process, the resultant Ni-CoP nanosheets are implanted with unsaturated atomic heterometallic NiCo16-xP6 sites (with Co vacancies) for alkaline hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). The optimized Ni-CoP exhibits a low overpotential of 88 and 290 mV at 10 mA cm-2 for alkaline HER and OER, respectively. This can be attributed to reduced free energy barriers, owing to the direct influence of center Ni atoms to the adjacent Co/P atoms in NiCo16-xP6 sites. These provide fundamental insights on the correlation between atomic structures and catalytic activity.

DEMETHYLATION REGULATOR 1 regulates DNA demethylation of the nuclear and mitochondrial genomes.

Active DNA demethylation effectively modulates gene expression during plant development and in response to stress. However, little is known about the upstream regulatory factors that regulate DNA demethylation. We determined that the demethylation regulator 1 (demr1) mutant exhibits a distinct DNA methylation profile at selected loci queried by methylation-sensitive polymerase chain reaction and globally based on whole-genome bisulfite sequencing. Notably, the transcript levels of the DNA demethylase gene REPRESSOR OF SILENCING 1 (ROS1) were lower in the demr1 mutant. We established that DEMR1 directly binds to the ROS1 promoter in vivo and in vitro, and the methylation level in the DNA methylation monitoring sequence of ROS1 promoter decreased by 60% in the demr1 mutant. About 40% of the hyper-differentially methylated regions (DMRs) in the demr1 mutant were shared with the ros1-4 mutant. Genetic analysis indicated that DEMR1 acts upstream of ROS1 to positively regulate abscisic acid (ABA) signaling during seed germination and seedling establishment stages. Surprisingly, the loss of DEMR1 function also caused a rise in methylation levels of the mitochondrial genome, impaired mitochondrial structure and an early flowering phenotype. Together, our results show that DEMR1 is a novel regulator of DNA demethylation of both the nuclear and mitochondrial genomes in response to ABA and plant development in Arabidopsis.

An enhanced machine learning tool for cis-eQTL mapping with regularization and confounder adjustments.

Many expression quantitative trait loci (eQTL) studies have been conducted to investigate the biological effects of variants in gene regulation. However, these eQTL studies may suffer from low or moderate statistical power and overly conservative false-discovery rate. In practice, most algorithms for eQTL identification do not model the joint effects of multiple genetic variants with weak or moderate influence. Here we present a novel machine-learning algorithm, lasso least-squares kernel machine (LSKM-LASSO) that model the association between multiple genetic variants and phenotypic traits simultaneously with the existence of nongenetic and genetic confounding. With a more general and flexible framework for the estimation of genetic confounding, LSKM-LASSO is able to provide a more accurate evaluation of the joint effects of multiple genetic variants. Our simulations demonstrate that our approach outperforms three state-of-the-art alternatives in terms of eQTL identification and phenotype prediction. We then apply our method to genotype and gene expression data of 11 tissues obtained from the Genotype-Tissue Expression project. Our algorithm was able to identify more genes with eQTL than other algorithms. By incorporating a regularization term and combining it with least-squares kernel machine, LSKM-LASSO provides a powerful tool for eQTL mapping and phenotype prediction.