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  • Clinical Applications and Therapeutic Mechanisms of Yiaikang Capsules,

    Clinical Applications and Therapeutic Mechanisms of Yiaikang Capsules,

    Introduction

    Human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS), which induces the progressive depletion of CD4+ T cells in humans.1 Infection with HIV can result in life-threatening opportunistic infections and may progress to AIDS. Since the start of the HIV epidemic, approximately 88.4 million people have been infected and 42.3 million people have died from AIDS-related illnesses.2 The Joint United Nations Programme on HIV/AIDS estimates that, in 2023, there were 39.9 million people living with HIV (PLWH), 1.3 million new infections, and 630,000 deaths from AIDS-related illnesses globally.2 Antiretroviral therapy (ART) is an effective therapeutic approach for preventing and treating HIV, thereby promoting a healthy lifespan.3 However, many individuals struggle with adherence to ART because of side effects, pill fatigue or aversion, and stigma.4 Therefore, it is necessary to find new drugs or treatments, such as traditional Chinese medicine (TCM).

    TCM formulations have been used to treat AIDS in China since 2004. A national trial was conducted in the 19 major provinces to investigate the effects of TCM on AIDS, in addition to a series of research studies funded by the National Natural Science Foundation of China.5 Consequently, multiple TCM preparations have been developed to treat AIDS, many of which have demonstrated effectiveness.6 The Shuyu pill is a classic Chinese herbal formula for the treatment of Xu Lao for more 1800 years. Yiaikang(YAK) capsules, a modified form of Shuyu pills for the treatment of AIDS, which has antiviral and immune activities and improves the level of clinical application of symptoms and signs (eg, weakness, shortness of breath, spontaneous sweating, and diarrhea) in China.7 The main active components of YAK capsules, which are derived from the TCM prescription known as “Shuyu-Wan”, have been identified.8 Although YAK contains a total of 22 Chinese herbs, we summarize here the six key herbs and 11 bioactive ingredients that are used to treat AIDS, with a focus on their main target pathways, mechanisms, and therapeutic effects (Table 1). Among the active ingredients, Astragaloside IV combined Ginsenoside Rg1 have synergitic inhibition on autophagy injury.9

    Table 1 Active Ingredients, Targets/Pathways, Mechanisms, and Therapeutic Effects of the Six Major Chinese Herbs of Yiaikang (YAK) Capsules Against Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS)

    Mechanisms of YAK in HIV Treatment

    According to recent research,21–27 the functions and mechanisms of YAK include the following: blocking virus binding to its receptor, increasing the CD4+ T-cell count, regulating cytokine and chemokine responses, regulating the balance of T helper (Th)17 cells and regulatory T cells (Tregs), increasing the cytotoxic function of natural killer (NK) cells and maintaining the integrity of the intestinal mucosal barrier (Figure 1). According to previous studies, long-term application of Yiaikang is both safety and efficacy.28 YAK combined with LPV/r can alleviate liver injury caused by LPV/r and combined with FTC+PMPA+RAL has no significant effect on the routine blood parameters in the treatment of SIVmac239 infected rhesus monkey AIDS model.29 Studies shown that YAK combined with LPV/r in the treatment of SIVmac239 infected rhesus can maintain the stability of blood biochemical levels, reduce thrombocytopenia caused by ART, alleviate the side effects caused by LPV/r, and increase the efficacy of ART.30

    Figure 1 Therapeutic actions of Yiaikang (YAK) capsules. (A) YAK inhibits the viral Tat and Rev proteins as well as host intercellular adhesion molecule 1 (ICAM-1), assisting with the replication of HIV. YAK also increases CD4+ T-cell counts, possibly by restoring the expression of C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4), as well as T-cell activation levels. YAK significantly inhibits interleukin (IL)-13, increases the IL-2 and interferon (IFN)-γ cytokine response, and enhances host antiviral defense. (B) YAK significantly promotes the proliferation of natural killer (NK) cells and increases secretion of IFN-γ, enhancing immune function. (C) YAK regulates the imbalance in T helper 17 (Th17) cell/ regulatory T cell (Treg) imbalance by increasing RORγt expression and reducing FoxP3 expression, enhancing host antiviral defense. (D) YAK maintains the integrity of the intestinal mucosal barrier through inhibition of the expression of tight junction proteins ZO-1, Claudin-1, and Claudin-5, and chemokines. Created in BioRender. Xue, D. (2025) https://BioRender.com/l95e206.

    Inhibition of Viral Replication

    The HIV-1 envelope consists of two noncovalently associated fragments: gp120 and gp41. During infection, gp120 binds to the CD4 receptor on the surface of the host cell, interacting through its V3 ring with a coreceptor (eg, C-C chemokine receptor type 5 [CCR5] or C-X-C chemokine receptor type 4 [CXCR4]). This induces a conformational change that activates gp41, leading to the insertion of its viral fusion peptide to promote fusion of the viral and host cell membranes.31 The main target cells of HIV invasion and replication are CD4+ T lymphocytes,32 which are destroyed, thereby damaging the immune system.33

    The HIV genome contains two regulatory genes (trans-activator of transcription [tat] and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). HIV-1 gene expression and replication largely depend on the Tat and Rev regulatory proteins.34 Viral mRNA transcription is driven by the long terminal repeat, regulated by Tat and several host factors. Rev is transported to the infected host cell nucleus via its nuclear localization signal, where it binds to the Rev response element on viral RNA, accelerating viral mRNA transport outside of the nucleus.35 Li et al36 found that tat/rev expression and HIV-1 load in venous blood decreased significantly in the group that administration with YAK for 6 months compared with that in the control group, which suggesting that YAK may inhibit replication of HIV-1 by reducing the expression of Tat/Rev (mRNA level).

    The levels of intercellular adhesion molecule 1 (ICAM-1), a glycoprotein that participates in immune responses, are abnormally increased on the surface of various cells following HIV infection, even under ART. ICAM-1 expression exhibits rapid upregulation in response to stimulation by cytokines, including interferon (IFN)-γ.37 High levels of cell-surface ICAM-1 promote HIV production and virus spread,38 and are positively correlated with HIV disease progression. ICAM-1 binds to the integrin lymphocyte function-associated antigen (LFA)-1, thereby stimulating HIV-infected dendritic cells and T cells and promoting viral spread.39 Inhibition of ICAM-1/LFA-1 reduces HIV replication and transmission in vitro, suggesting the potential of ICAM-1 as a therapeutic target in HIV infection. Yue et al40 observed an elevation in CD4+ T cells in YAK+ART group, with significantly decreased expression of ICAM-1/LFA-1 in CD4+ T cells following 6 months of YAK administration compared with ART controls. These results suggest that YAK directly affects the immune response in PLWH by decreasing the expression of ICAM-1 and LFA-1.

    Improvement of Immune Response

    CD4+ T-cell depletion is key to disease progression in PLWH. HIV-1 infection occurs when the virus binds to chemokine receptors and CD4 molecules on the surface of T cells. As the first recognition sites for HIV on the host cell surface, chemokine receptors CCR5 and CXCR4 are crucial in HIV infection.41,42 Targeting these receptors is an attractive strategy for blocking HIV entry into host cells.43

    The active ingredients and other components of YAK regulate T cells through multiple targets and pathways, increasing the number of CD4+ T cells (Figure 1A). Liu et al44 found that anticoagulant whole blood collected from PLWH at 6 months of YAK treatment exhibited restoration of CCR5 and CXCR4 expression, an increased number of CD4+ T cells, and a decreased HIV-1 load compared with that from healthy controls. Such findings suggest that YAK may restore coreceptor and T-cell activation levels to reverse the virus-induced immune damage in PLWH.

    Regulation of Cytokine and Chemokine Responses

    HIV infection of the human body activates T cells, which rapidly proliferate and secrete high levels of two inflammatory markers: interleukin (IL)-6 and sCD14.45 IL-6 and sCD14 predict disease progression and are associated with increased risks of HIV/AIDS and death.46 Th1 cells produce IL-2, triggering IFN-γ expression to activate NK cells and leading to apoptosis of HIV-1-infected T cells, which may be critical for controlling HIV-1.47,48 Cytokine IL-13 has received considerable attention as the regulator of CD4+ Th2 immunity,49 with inhibition of IL-13 expression increasing the activity of CD8+ T cells and protecting against viral infection.50

    Li et al51 collected the venous blood of PLWH to screen for HIV-1 load and cytokines at 6 months and 12 months of YAK treatment. They found improvements in the levels of IL-2, IL-13, and IFN-γ, number of CD4+ T cells, and anti-HIV activity at 12 months, suggesting that YAK may improving the immune status of PLWH by increasing cytokines and inhibiting HIV-1 (Figure 1A).

    Increased Proliferation of NK Cells

    HIV infection changes the distribution and functions of the NK cell subpopulation, even after ART.52 NK cells are important in HIV-1 infection, inhibiting viral entry into CD4+ T cells and preventing HIV-1 transmission.53 IFN-γ (also known as immune IFN) is produced by T cells and is involved in immune regulation, activating NK cells and increasing their cytotoxic capabilities.54 Targeting NK cells to restore their residual functionality can bolster their antiviral effects.

    YAK was shown to significantly increase the proliferation and cytotoxic function of the human NK cell line NK-92MI55 (Figure 1B). Qian et al55 cultured NK-92MI cells in blank control and YAK-containing serum (4%, 8%, 15%, 25%) in vitro. Compared with the control, NKG2A expression was downregulated and IFN-γ secretion was upregulated at 6 hours of culture (P < 0.05). Thus, YAK significantly increased the proliferation and cytotoxicity of NK-92MI by inhibiting NKG2A receptors and increasing secretion of IFN-γ.

    Regulation of Th17/Treg Balance

    An altered Th17/Treg ratio, indicative of rapid depletion of Th17 cells and increased frequency of Tregs, is a hallmark of HIV infection and a marker of disease progression. This imbalance contributes to immune dysfunction and microbial translocation, which leads to chronic immune activation/inflammation and disease progression.56 Th17 cells and Tregs are important gatekeepers of mucosal interfaces, with transcriptional profiles that are controlled by the lineage transcription factors RORγt/RORC2 and FOXP3, respectively.57 HIV-1 infection can modify the mRNA expression of these transcription factors, which may decrease the immune response of Tregs and Th17 cells.58

    YAK regulates Th17/Treg imbalance by increasing the level of Th17 cells and decreasing the level of Tregs (Figure 1C). Huang59 found that, compared with healthy control, 6 months of YAK treatment led to increases in the proportion of Th17 cells and the expression of RORγt mRNA, alongside reduced levels of Tregs and mRNA expression of Foxp3, in peripheral blood mononuclear cells. Therefore, YAK appears to increase CD4+ T cell counts by regulating the Th17/Treg ratio.

    Maintenance of the Intestinal Mucosal Barrier

    HIV-1 infection disrupts gut-associated lymphatic tissue, leading to loss of intestinal integrity, translocation of pathological microorganisms across the compromised gastrointestinal barrier, and systemic immune activation, even after ART.60 CD4+ memory T cells in the gut carry higher levels of HIV DNA compared with blood.61 Virus-induced changes in microbial translocation and damage to the intestinal barrier contribute to inflammation and immune activation, induces apoptosis of CD4+T cells, and aggravates immune failure.62 The homing of lymphocytes from the bloodstream to the intestine is a prerequisite for establishing the immune barrier of the intestinal mucosa. This occurs through binding of the homing receptors on the surface of lymphocytes to specific ligands in the intestinal mucosal tissue.63 Maintaining the integrity of intestinal mucosa and the balance of intestinal flora is crucial in the pathogenesis of HIV infection.

    YAK reduces the permeability of the intestinal mucosal barrier, maintaining its integrity, through inhibition of the expression of tight junction (TJ) proteins (Figure 1D). Li et al64 found that two ingredients of astragalus polysaccharide and ginseng stem saponin in YAK, significantly upregulated expression of the chemokines CCL25 and CCL28, chemokine receptors CCR9 and CCR10, CD80, CD86, major histocompatibility complex II (MHC-II), Toll-like receptor 4 (TLR4), and nuclear factor (NF)-ĸB p65 in intestinal mucosal tissue. These changes promoted the homing of intestinal lymphocytes and stimulated the activation of other immune cells (T and B cells), thereby enhancing intestinal mucosal immunity.

    To simulate the intestinal mucosal injury induced by HIV-1, Sang et al65 stimulated monolayers of Caco-2 human epithelial cells with IFN-γ. They then examined changes in membrane electrical impedance, fluorescein sodium transmittance, and mRNA expression of genes encoding TJ proteins at different time points following treatment with YAK or blank control group. YAK reduced the permeability of the simulated intestinal mucosal barrier and maintained its integrity, which was found to be related to inhibition of the expression of proteins ZO-1, Claudin-1, and Claudin-5.

    Traditional Chinese medicine has unique advantages in regulating the abundance of flora and restoring immune reconstitution. YAK can regulates the intestinal flora, improves intestinal homeostasis, promotes immune reconstitution, and enhances immune function. YAK combined with ART has a certain clinical effect on PLWH, which can improve the proportion of protective factors of intestinal mucosa bacteria (such as Streptococcus, Macromonas, Wesneria, Streptococcus lactis).66 YAK decreased the abundance of Lachnoclostridium, Muribaculaceae, Lactobacillaceae, Alphaproteobacteria, Aeromonadales and Prevotella and increase the abundance of Fusobacteriota and Lachnospiraceae and enhance body immunity in HIV/AIDS patients with poor immune reconstitution.67

    Regulation of Abnormal Lipid Metabolism of HIV

    HIV-1 infection, chronic inflammation, and ART therapy are all related to changes in lipid metabolism, posing risk factors for cardiovascular and cerebrovascular diseases among PLWH.68,69

    Shen et al70 used the 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and fluorogenic quantitative PCR to examine the effects of a range of concentrations of YAK-containing serum and ritonavir at different time points on the proliferation of human hepatoma Hep G2 cells and the expression of genes related to lipid metabolism, respectively. Compared with the blank control, the ritonavir + YAK treatment group inhibited cell viability at 24 and 48 hours, while the YAK group upregulated the expression of CYP7A1 and downregulated that of HMG-CoA reductase and peroxisome proliferator-activated receptor (PPAR)α at 48 hours. The role of YAK in lipid lowering may involve inhibition of endogenous cholesterol, promotion of fatty acid transport, and removal of lipids from. Baicalin, a compound present in YAK, has metabolic effects exerted through increasing the activation of brown and white adipose tissue via the AMPK/PGC1α pathway.71,72

    Clinical Applications of YAK in AIDS

    Impacts on Clinical Manifestations, Quality of Life (QoL), Survival Rate, Anemia, and Lung Infections

    YAK can be used to improve the clinical symptoms of HIV/AIDS. Clinical trials showed that patients receiving YAK had significantly improved clinical manifestations of AIDS compared with combination therapy of YAK and ART has been shown to benefit AIDS patients. China National Knowledge Infrastructure, Wanfang, Chinese Biomedicine Literature Database, PubMed, Embase and Medline were searched for studies on the effect of YAK on HIV/AIDS published up to February 2025. Data was presented in the Table 2.

    Table 2 Studies Showing the Benefits of Yiaikang (YAK) Capsules in Combination with Antiretroviral Therapy for the Treatment of Acquired Immunodeficiency Syndrome (AIDS)

    The prevalence of anemia and lung infections among PLWH is high,82,83 but can be prevented using YAK. In a cross-sectional analysis of 8632 PLWH, patients receiving YAK therapy had a lower prevalence of anemia than those who did not.82 In addition, a randomized placebo-controlled trial performed in Henan Province, China, found that 4.9% of PLWH in the treatment group experienced a lung infection, compared with 6.0% of PLWH in the control group.84

    Survival rate is an indicator of the effectiveness of AIDS management. Jin et al reported a retrospective cohort study that compared the survival rate of HIV infection in patients with and without YAK treatment. A total of 3229 HIV-infected patients were followed for 21,876 person-years, showing 8-year cumulative survival rates of 78.5% in the YAK group (n = 1442) and 74.0% in the non-YAK group (n = 1787). The follow-up studies also showed that YAK increased the survival rate and increased lifetime in HIV-infected patients.85,86

    QoL refers to awareness and satisfaction with social status and living conditions. PLWH often face both physical and psychological stress, and thus require greater attention to their QoL. In a cross-sectional study of 275 PLWH, mean QoL scores (excluding spirituality/personal beliefs) were significantly higher in the YAK + ART group than in the ART group (P < 0.05).87

    Adjuvant Drugs for Common AIDS-Related Conditions

    As an adjuvant medicine, YAK can improve the efficacy of the primary treatment for many of the symptoms and illnesses common in PLWH. It has been widely used to treat abnormal lipid metabolism, diarrhea, anxiety/depression, ulcers, cough, and HIV/hepatitis C with hepatic fibrosis (Table 3).

    Table 3 Illnesses and Symptoms Treated with Yiaikang (YAK) Capsule Therapy in Patients with Human Immunodeficiency Virus (HIV) Infection

    Improvement in Clinical Symptoms of Abnormal Lipid Metabolism

    Yu et al95 performed a clinical trial with 40 PLWH who took YAK + ART. After 6 months of YAK treatment, patients experience alleviation of clinical symptoms (asthma, spontaneous sweating, chest tightness, fatigue, and palpitation), achieved through regulation of phosphatidylcholine, phosphatidylethanolamine, cholesterol ester, and sphingomyelin, along with improvements in lipid metabolism and decreased vascular endothelial injury.

    Conclusions

    The therapeutic effects and mechanisms of action of YAK in the treatment of patients with AIDS have become a focus of TCM research.96 By outlining these mechanisms and progress in clinical research on YAK in HIV/AIDS, this review has highlighted novel therapeutic targets and effective complementary approaches to ART. The key actions of YAK include the following: blocking virus–receptor binding, elevating CD4+ T-cell counts, regulating cytokine/chemokine responses, regulating Th17/Treg balance, enhancing NK cytotoxicity, and maintaining the integrity of the intestinal mucosal barrier. These effects are mediated through a number of pathological pathways involving NF-ĸB, PPAR, PD-1, transforming growth factor (TGF)-β/Smad, T-cell receptors (TCRs), and TLRs. Clinical studies have demonstrated the therapeutic efficacy of YAK in terms of improvements in clinical symptoms and QoL, longer survival times, and reduced mortality in patients with AIDS. As an herbal medicine, YAK is complementary to ART. However, there is limited clinical trial data on the effects of YAK in AIDS. Firstly, its pharmacology and therapeutic mechanism have not been extensively explored, necessitating further research to optimize its clinical application. Secondly, due to limited number and quality of clinical studies included in the analysis, further research is needed. Lately, we support large-scale clinical trials to evaluate the protective efficacy of YAK in AIDS, as well as single-cell and spatial multi-omics studies of its mechanisms of action. YAK shows great promise as a complementary treatment to ART and warrants further exploration.

    Funding

    This work was supported by the Zhengzhou Medical and Health Science and Technology Innovation Guidance Program (2024YLZDJH134), Henan Province Pilot Project of Treating AIDS with Traditional Chinese Medicine(No. 2004ZYA109), Henan Province Key Research and Development and Promotion Project (252102310488) and Traditional Chinese Medicine Research Project of Henan Province (2025ZKY016).

    Disclosure

    The authors report no conflicts of interest in this work.

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    59. Huang Z. Effects of Yiaikang capsule on Th17/Treg cells and their key transcription factors in HIV/AIDS patients. Master. 2015.

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    64. Renjun LI. Study on oral administration of Astragalus polysaccharide and ginseng stem saponin to enhance foot-and-mouth disease vaccine and intestinal mucosal immunity. Doctor. 2017.

    65. Sang F, Li Q, Qian J, et al. Discussion on the Protective Effect of Yiaikang Capsule onIntestinal Mucosal Barrier Injury of HlV/AlDS Based onPermeability and Tight Junction. J Emergency Traditional Chin Med. 2018;27(05):769–772.

    66. Yang Q. To explore the clinical efficacy of Yiaikang capsule in the intervention of HIV/AIDS spleen-centered deficiency syndrome and its influence on intestinal flora based on the theory of “spleen-centered protection”. Master. 2024.

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    68. Ji S, Xu Y, Han D, et al. Changes in Lipid Indices in HIV+ Cases on HAART. Biomed Res Int. 2019;2019:2870647. doi:10.1155/2019/2870647

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    70. Shen J, Ren Z, Li Q, et al. Effect of YAK-containing serum on genes related to lipid metabolism induced by Ritonavir in Hep G2 cells. Lishizhen Med Materia Med Res. 2019;30(01):77–80.

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    77. Chen Z, Y SUN, Zhang X, et al. The effect of antiretroviral treatment combined traditional Chinese medicine on the reconstruction of immune function in AIDS patients. Chin J AIDS & STD. 2022;28(10):1132–1135. doi:10.13419/j.cnki.aids.2022.10.04

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    86. Jin Y, Zhang M, Ma Y, et al. Effects of Chinese Medicine on the Survival of AIDS patients administered second-line ART in rural areas of china: a retrospective cohort study based on real-world data. Evid Based Complement Alternat Med. 2022;2022:5103768. doi:10.1155/2022/5103768

    87. Xu QL, Guo HJ, Jin YT, et al. Advantages of Chinese Medicine for Patients with acquired immunodeficiency syndrome in rural central China. Chin J Integr Med. 2018;24(12):891–896. doi:10.1007/s11655-017-2418-8

    88. Fu L. Siwu Xiaofeng decoction mainly treated 30 cases of chronic AIDS rash. Traditional Chin Med Res. 2013;26(09):16–18.

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    93. Zhang H, Xu Z, Hua C. Yiaikang capsule combined with Zhisou powder treated 48 cases of AIDS patients with cough. Clin J Traditional Chin Med. 2017;29(11):1890–1892. doi:10.16448/j.cjtcm.2017.0627

    94. Shao C. Clinical study of Yiaikang capsule combined with Biejia Decoction Pill on HIV/HCV co-infection. master. 2018.

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  • Chelsea 2-1 Palmeiras (5 Jul, 2025) Game Analysis

    Chelsea 2-1 Palmeiras (5 Jul, 2025) Game Analysis

    An 83rd-minute Weverton own goal from a deflected Malo Gusto cross gave Chelsea a nervy 2-1 win over a spirited Palmeiras side in the Club World Cup quarter-finals at Lincoln Financial Field on Friday.

    Cole Palmer also got on the scoresheet in the first half for Chelsea, who move on to face more Brazilian opposition in Fluminense in New York on Tuesday with a place in the final on the line.

    Palmeiras roared back after halftime with teenage winger Estêvão, who is soon to join Chelsea, equalising in the 53rd minute with a stunning strike from a tight angle.

    “Tough game as we expected,” said Chelsea manager Enzo Maresca. “First half, I think we were a little bit better compared to the second half, we controlled the game much better.

    “But then they scored and the game changed but at the end we scored and I think we deserved to win. Congratulations to the players, because they have been very good.”

    Chelsea started the match well despite missing key defensive midfield duo Moisés Caicedo and Romeo Lavia, with 21-year-old Andrey Santos making his first start some two and a half years after joining the club.

    They controlled possession and repeatedly threatened through Pedro Neto, who caused chaos for Palmeiras defence down the right flank.

    Palmer struck in the 16th minute, receiving a pass from Trevoh Chalobah on the edge of the box and gliding past three defenders with ease before dispatching a precise left-footed strike into the bottom corner.

    Despite their dominance, Chelsea squandered several opportunities, including Christopher Nkunku’s glaring miss in the 34th minute when he blasted over with only goalkeeper Weverton to beat.

    Palmeiras, missing key defenders Joaquin Piquerez, Gustavo Gómez and Murilo, struggled to contain Chelsea’s fluid attack in the first half but emerged from the break with renewed energy.

    They nearly equalised when Bruno Fuchs headed narrowly wide from a corner before Estevao worked his magic with an effort that should be a strong candidate for goal of the tournament so far.

    The 18-year-old showcased his immense talent by cutting in from the right, gliding past Levi Colwill and smashing an unstoppable shot from a tight angle that flew over keeper Robert Sánchez and off the underside of the crossbar.

    “Happy because we won, happy because he scored, so it’s a perfect night,” Maresca said of his new signing.

    Just when Palmeiras looked at their most dangerous, though, Chelsea found the winner down the other end.

    Gusto found space down the left and his attempted cross deflected off defender Fuchs and wrongfooted Weverton, the ball bouncing off the goalkeeper’s back and into the net to end Palmeirasdreams of an all-Brazilian semi-final.

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  • Why Rematch is the surprise hit of 2025 for esports – Esports Insider

    1. Why Rematch is the surprise hit of 2025 for esports  Esports Insider
    2. “The essence of football is not in the rules”: Rematch’s creative director on nailing that five-a-side feeling and making a game “about kicking a ball rather than kicking heads in”  GamesRadar+
    3. I spent 75 hours unlocking every trophy in Elden Ring Nightreign, only for Rematch to steal its thunder with a single hat trick  MSN

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  • Favorites and Sleepers: Mid-Ohio

    Favorites and Sleepers: Mid-Ohio

    Reigning Mid-Ohio Sports Car Course winner Pato O’Ward snapped the Team Penske/Chip Ganassi Racing domination on the 2.258-mile track last year by giving Arrow McLaren its first victory there.

    But Chip Ganassi Racing driver Alex Palou enters this weekend as the driver to beat. The three-time NTT INDYCAR SERIES champion is undefeated on natural road courses in 2025 with wins at The Thermal Club, Barber Motorsports Park, Indianapolis Motor Speedway road course and Road America. He’s also on a four-race podium streak at Mid-Ohio, including a 2023 victory and runner-up finish last year.

    Can anyone stop the points leader in Sunday’s 90-lap race?

    If so, it may take a village.

    Typically, Mid-Ohio Sports Car Course has been a track that has featured organization-wide dominance; if someone tops Palou, look for their teammate to be close by.

    Since 1990, a one-two team finish has occurred 138 times in NTT INDYCAR SERIES competition. Mid-Ohio has produced a series-leading 16 of those occurrences, double the next best of eight at the former Belle Isle Park circuit in Detroit.

    Here are the favorites and sleepers for The Honda Indy 200 at Mid-Ohio Presented by the All-New 2026 Passport airing at 1 p.m. ET Sunday on FOX, the FOX Sports app and the INDYCAR Radio Network.

    Favorites

    Scott McLaughlin (No. 3 Odyssey Battery Team Penske Chevrolet)

    McLaughlin has three straight top-five finishes at Mid-Ohio, including a 2022 win in which he led 45 laps. He finished third last season, the third straight year a Team Penske driver finished in that spot, with Will Power doing so in 2022 and 2023. On natural road course races this season, McLaughlin finished 27th, third, fourth and 12th, respectively, showing he’s a serious contender when the car is right.

    Pato O’Ward (No. 5 Arrow McLaren Chevrolet)

    Last year’s winner led 24 of 80 laps en route to the victory, but history isn’t on his side as no driver has gone back-to-back at Mid-Ohio since Scott Dixon in 2011-12. However, O’Ward has flashed natural road course speed this season with podiums at The Thermal Club and the IMS road course. He also earned NTT P1 Award honors and led 51 laps at The Thermal Club and finished sixth at Barber Motorsports Park.

    Scott Dixon (No. 9 PNC Bank Chip Ganassi Racing Honda)

    Dixon has six wins in 19 Mid-Ohio Sports Car Course starts. His recent finishes include fourth, fifth, second and 27th, respectively. Chip Ganassi Racing has also produced the second-place finisher each of the last four years via Marcus Ericsson (2021), Palou (2022, 2024) and Dixon (2023).

    Alex Palou (No. 10 Open AI Chip Ganassi Racing Honda)

    Mid-Ohio Sports Car Course has been a great track for Palou, who has three straight top-two finishes on the track, including a victory in 2023. There’s not much more to say for the three-time series champion, who leads second-place Kyle Kirkwood by 93 in the standings.

    Will Power (No. 12 Verizon Team Penske Chevrolet)

    Power led 206 combined laps with seven top-four finishes in his last 10 Mid-Ohio starts. While he finished 11th last year, he battled a sickness that compromised his ability to push his car beyond its limits. He finished sixth this season at The Thermal Club, fifth at Barber, third on the IMS road course and 14th at Road America.

    Sleepers

    Christian Lundgaard (No. 7 Arrow McLaren Chevrolet)

    Lundgaard, in his last two Mid-Ohio starts driving for Rahal Letterman Lanigan Racing, qualified fifth and ninth and finished fourth and seventh, respectively. This season, his first with Arrow McLaren, he has shown podium speed on natural road courses, with finishes of third and second at Thermal and Barber, before dipping to 16th and 24th at the IMS road course and Road America, respectively. Arrow McLaren proved it can win here, and Lundgaard is more than capable.

    Graham Rahal (No. 15 Fifth Third Bank Honda)

    Mid-Ohio Sports Car Course is Rahal’s home track and is a place where he has performed well. Rahal has completed 99.7 percent of his laps (1,521 out of 1,525) and produced 10 top-10 finishes in his last 12 tries. He qualified second in 2023 and finished seventh after a slow final pit stop dropped him in the finishing order. Rahal has finished 11th, 14th, sixth and 20th on natural road courses this season.

    Kyle Kirkwood (No. 27 Andretti Global Honda)

    The only driver not named Alex Palou to win this season, with three in total, is chasing his first natural road course victory. Kirkwood is 0-for-24 on this type of track but is trending upward and improving nearly every season at like venues. At Mid-Ohio, he has finished 26th, 17th and eighth, respectively. Kirkwood finished fourth two weekends ago at Road America.

    Louis Foster (No. 45 Mi-Jack Honda)

    He finished first and second, respectively, at Mid-Ohio in USF Pro 2000 competition in 2022. He then earned his first career INDY NXT by Firestone victory on this track in 2023 and repeated last year during his 10-win championship season. Foster earned NTT P1 Award honors in the last race at Road America, and his best finishes during his rookie season are 11th at both the IMS and Road America road courses. He has qualified 10th, 12th, third and first, respectively, on natural road courses, too.

    Felix Rosenqvist (No. 60 SiriusXM Honda)

    Rosenqvist earned his first career podium at Mid-Ohio by finishing runner-up to Dixon in 2019. He placed runner-up in the last race, at Road America. On natural road course tracks this season, Rosenqvist has three top-10 finishes in four tries.


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  • Melbourne Instruments’ Roto-Control gets Bitwig Studio integration following 2.0 firmware update

    Melbourne Instruments’ Roto-Control gets Bitwig Studio integration following 2.0 firmware update

    Announced earlier this year at NAMM 2025, Melbourne Instruments’ Roto-Control is a MIDI controller with a difference.

    Equipped with eight motorized knobs – first seen on the company’s NINA synth – that instantly recall parameter values when opening new projects or plugins, Roto-Control also offered Ableton Live integration straight out of the box.

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  • How Iranian missile strike on Israel impacts Europe

    How Iranian missile strike on Israel impacts Europe

    Israel’s historic military operation in Iran delivered significant achievements whose complete impact will only emerge over time, whether through the elimination of key officials in the Islamic Republic’s leadership or through meaningful damage to its nuclear capabilities. However, this powerful operation triggered devastating retaliation that killed Israelis and scarred the nation with widespread destruction – damage that extends far beyond Israel’s borders affecting numerous European countries, and specifically, the European Commission.

    We joined European Union Ambassador to Israel Dimiter Tzantchev during his visit to the Weizmann Institute of Science, among the hardest-hit locations from Iranian ballistic missile attacks, as part of a tour of strike sites nationwide. Two missiles rendered five buildings unusable, affecting research conducted by at least 52 research groups. The cancer research center suffered the worst damage, with laboratories now entombed beneath mountains of debris.

    The destroyed Cancer Research Center at the Weizmann Institute (Photo: Adi Nirman)

    “We truly experienced the five stages of grief,”  Dr. Leeat Yankielowicz-Keren, who heads a team investigating connections between the immune system and cancer. Her laboratory housed cutting-edge, exclusive equipment essential to her Weizmann research team’s work – all completely destroyed. “We obtained special permission to enter the building today, and several people wept. The devastation is beyond belief. One of my students, a reserve combat soldier who served in Gaza, insisted he would rappel through windows to salvage what he could, though we told him ‘nothing’s left.’ He was really in denial.”

    Another laboratory that became unusable as a result of the blast belongs to Dr. Ranit Kedmi, who studies the immune system. “I only opened my laboratory two years ago,” she shared.” Both research teams share a crucial commonality – they were enabled by European Research Council (ERC) grants, financed through the European Commission. The destruction of these laboratories means Iranian strikes directly impact European interests.

    Dr. Yankielowicz-Keren stresses the consequences reach even further internationally. “During the first week [after the attack], I had to spend at least an hour every day replying to emails from all over the world – people offering to help, people offering to send students, people showing compassion,” she said. “After October 7th, I didn’t feel the same kind of solidarity. I think that this time the scientific community and particularly the cancer community experienced this as their own loss. It’s not a Weizmann-specific research – it’s our understanding of cancer that got pushed back years because of this, on a global level.”

    The environmental research building that was destroyed as a result of the blast wave at the Weizmann Institute (Photo: Adi Nirman)

    The Weizmann Institute ranks among the world’s top research facilities. Though based in Israel, its research teams include students from across the globe. “Scientists excel at problem-solving,” Dr. Kedmi observed, describing how a South Korean student in her team chose to remain in Israel and help rebuild the damaged laboratory despite the wartime reality in Israel. Meanwhile, a colleague from Heidelberg, Germany, offered his laboratory facilities to one of Yankelvitz-Keren’s students to continue crucial research.

    While the determination shown by these research teams and their female leaders inspires admiration, the growing global recognition of Weizmann’s damage cannot be overlooked. Worldwide discourse often reduces to either supporting or opposing Israel, missing the global ripple effects created when the Weizmann Institute becomes a target, impacting the European Research Council, scientists across the world, and potentially life-saving medical advances.

    The destruction of patient rooms at Soroka Medical Center, 2 floors below the missile strike point (Photo: Adi Nirman)

    The tour naturally included Soroka Hospital, the Negev region’s sole medical facility. We were granted special access to examine the damage in the northern surgical building, which sustained a direct upper-floor hit. Exceptional preparation and threat assessment by Soroka personnel enabled patient evacuation one day before the strike that completely destroyed that floor and caused the floor below to collapse.

    Broken elevator shafts at Soroka Medical Center (Photo: Adi Nirman)

    The strike’s severity and the ballistic missile’s warhead power became evident through the extensive ground-floor damage. Shattered ceilings and walls, demolished elevator shafts, displaced door frames, and patient rooms reduced to rubble fragments intensified as we ascended through the building’s floors. Medical staff that was inside the building during the attack followed proper defensive protocols and escaped injury.

    Destruction two floors below the missile strike point at Soroka Medical Center (Photo: Adi Nirman)

    “Anywhere else worldwide, we would transfer all patients to alternative hospitals and spend a year recovering,” Soroka Hospital Director Dr. Shlomi Kodesh told Ambassador Tzantchev. Remarkably, the hospital resumed 80% of operations surrounded by destruction and blast damage, in extremely difficult conditions for both patients and medical personnel alike. “We need tens of millions of dollars,” Dr. Kodesh emphasized, highlighting the critical importance of maintaining Soroka’s operations as southern Israel’s only hospital. “The Negev deserves better,” he concluded.

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  • PM Sharif discusses trade, investment and regional ties with ECO leaders on summit sidelines

    PM Sharif discusses trade, investment and regional ties with ECO leaders on summit sidelines

    Eight killed in Karachi building collapse, exposing city’s crisis of unsafe housing


    KARACHI: A five-story residential building collapsed in Karachi’s densely populated Lyari neighborhood on Friday, killing at least eight people and trapping many others, in yet another tragedy underscoring the city’s crisis of unsafe, aging structures.


    Rescue workers, aided by local residents, scrambled to pull people from the debris of the Fotan Mansion building, recovering both bodies and injured survivors. The collapse took place around 10:30 a.m., jolting the community.


    “I suddenly woke up … it felt like there were tremors, like an earthquake,” said Salman Ahmed, who was sleeping in a nearby building at the time of the incident and later rescued two children.


    “At the moment the building collapsed, nothing was visible,” he recalled. “There was so much dust and smoke that no one could understand what had happened. “We could hear voices coming from underneath [the rubble].”


    It was not immediately clear how many families lived in the building, but residents estimated that around 40 people were inside when it collapsed. Many of the occupants were members of the low-income Hindu minority community.


    As of Friday evening, a large rescue operation was still underway, with cranes clearing debris and rescuers working against time to reach those still trapped beneath the rubble.


    “They handed me a three-month-old baby girl, she was alive,” said Maya Sham, a relative of a family living in the building. “Right now, two of their sons and three daughters-in-law are still trapped. But we can still hear voices from inside.”


    The collapse devastated families like that of Megbhai, a member of the Hindu community, which largely resided in the building.


    Karachi Mayor Murtaza Wahab confirmed that six people had died and eight were rescued alive. He said the building had long been on the city’s “danger list.”


    “This building was declared dangerous, and a couple of notices were issued to the occupants to vacate because of its structure,” Wahab told Arab News at the site. “But unfortunately, people chose to risk their lives, and they did not vacate.”


    Pakistan’s largest city — home to over 20 million people — faces a chronic housing shortage. Many low-income residents live in dilapidated buildings that have escaped regular maintenance. Authorities have declared nearly 588 buildings dangerous in Karachi, most in the congested Old City area.


    According to the Sindh Building Control Authority (SBCA), Fotan Mansion had been declared unsafe as far back as 2012.


    “This building was declared dangerous by the SBCA in 2012 and had been served multiple notices over the years,” SBCA spokesperson Shakeel Dogar told Arab News. “Before the recent rains, public announcements were also made in the area, but unfortunately, no one was willing to vacate,” he said, adding that it was the responsibility of the district administration to enforce the SBCA’s evacuation directives.


    Mayor Wahab said rescue efforts remained the top priority, with accountability and investigation to follow.


    “Our administration, our machinery is here on the ground,” he said. “Once we’re done with the rescue aspect, we will focus on who was responsible for this negligence or omission.”


    RECURRING TRAGEDY


    Friday’s incident is the latest in a string of deadly building collapses in Karachi.


    In February 2020, a five-story building collapsed in Rizvia Society, killing at least 27 people. The following month, another residential structure came down in Gulbahar, claiming 16 lives.


    In June 2021, a three-story building in Malir collapsed, killing four. And just last year, in August, a building collapse in Qur’angi led to at least three deaths.


    Most of these structures had either been declared unsafe or were built without proper approval.


    Experts say that despite repeated disasters, there has been little progress in enforcing building codes or relocating residents from hazardous structures.


    “The incident of the building collapse in Lyari is deeply tragic,” said Muhammad Hassan Bakhshi, chairman of the Association of Builders and Developers of Pakistan (ABAD). “It is alarming that despite having a list of dangerous buildings, the SBCA did not take action to get them evacuated.”


    He urged the Sindh government to reassess buildings citywide and equip rescue teams with modern tools and technology.


    With hundreds of buildings still listed as unsafe, authorities now face mounting pressure to prevent future disasters.


    “The way out is that we must follow what the law says,” said Mayor Wahab when asked if anyone would be held accountable. “If citizens don’t listen to us, the political leadership and the administration have to play their part to convince those people.”


    “Nobody wants to leave their house… but we must learn from our mistakes and ensure no such untoward incident takes place in the future,” he said.

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  • Baker McKenzie advised Axia Vegetable Seeds on the sale of its shares to DENSO Corporation | Newsroom

    Baker McKenzie advised Axia Vegetable Seeds on the sale of its shares to DENSO Corporation | Newsroom

    Axia Vegetable Seeds, headquartered in the Netherlands, is a leading breeding company of high-quality tomato seeds for greenhouses globally. The acquisition marks a significant step in DENSO’s strategic expansion into the AgriTech sector.

    By combining Axia’s strengths with DENSO’s automation and environmental-control technologies to industrialize farming, the partnership aims to develop and globally deploy innovative solutions for stable food production and supply. The acquisition is DENSO’s second investment in the agriculture sector in the Netherlands, following its earlier acquisition of a Dutch enterprise specializing in horticultural facility management.

    Moving forward, DENSO and Axia Vegetable Seeds will collaborate to combine industrial technology with seed development to create high-quality seeds suitable for automated farming approaches and climate adaptation. Additionally, by leveraging DENSO’s image recognition and AI technologies, the two companies aim to shorten the development period of new seeds and bring higher value-added seeds to market more quickly.

    “We are proud to have supported Axia Vegetable Seeds in this transaction. The deal reflects the growing convergence of agriculture and advanced technology, and we are excited to see the innovation this partnership will bring to the global food system,” says Mo Almarini, lead of the Baker McKenzie team.

    The Baker McKenzie team, led by Corporate M&A partner Mo Almarini, included Laila Kouchi, Max Nederlof, Alexis Gavriilidis, Frederique Peeters, Koen Bos, Willem Jan Treuren and Anastasia Boonen-Vaes, with valuable support from Carolina Cordero di Vonzo (Baker McKenzie Italy) bringing specific expertise in Plant Variety Rights and other colleagues in Chicago, Istanbul, Rome, Madrid, Mexico City and New York..

    Further information is available on the respective websites:
    DENSO: DENSO Acquires Axia Vegetable Seeds to Realize Sustainable Agriculture | Newsroom | News | DENSO Global Website

    About Axia Vegetable Seeds
    Axia Vegetable Seeds is an independent seed breeding company based in the Netherlands, specializing in the breeding and development of high-quality vegetable varieties with a strong focus on tomato. With a strong foundation in R&D and deep understanding of growers’ needs, Axia Vegetable Seeds delivers innovation to the greenhouse horticulture industry worldwide.

    About DENSO CORPORATION
    DENSO is a global automotive parts manufacturer that provides advanced automotive technologies, systems, and products. Leveraging the core technologies it has developed through its experience in automotive components, DENSO is expanding the scope of its value offerings to include factory automation, food distribution, agriculture, and more. Through automated harvesting using robots equipped with sensing technologies and through digital-based cultivation environment control, DENSO is working toward the industrialization of farms.

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  • AI Tool Accurately Predicts Prostate Cancer Outcomes Across Racial Groups

    AI Tool Accurately Predicts Prostate Cancer Outcomes Across Racial Groups

    Mack Roach III, MD, professor of radiation oncology, medical oncology, and urology at the University of California, San Francisco, discusses the development and evaluation of a multimodal artificial intelligence (AI) algorithm designed to predict prostate cancer outcomes and its performance across racial subgroups.

    According to Roach, the motivation behind the study stemmed from a longstanding controversy in prostate cancer: the role of race in determining outcomes. While prostate cancer incidence is 1.5 to 2 times higher among Black men compared with other racial groups, the question of whether biological differences contribute to disparities in outcomes has been widely debated.

    “For many years, there have been different opinions about whether there is an inherent biologic factor or not, and so it is important for us to distinguish between the incidence of the disease and the biologic behavior of a disease once it is diagnosed,” he explains.

    To address this, researchers turned to a high-quality data set derived from prospective phase 3 randomized clinical trials. These trials ensured uniform treatment protocols, patient stratification, and systematic follow-up. “The value of that resource,” Roach explains, “is that the quality of care and the eligibility are controlled in such a way that biases do not really enter into the quality of treatment.” Importantly, variables such as insurance coverage, treatment type, and dose were standardized, which allowed for more accurate analysis of outcomes by race.

    This dataset provided a unique opportunity to test whether AI could not only enhance prognostic accuracy, but also maintain fairness across racial groups. The AI model analyzed digitized biopsy slides along with clinical features like prostate-specific antigen, tumor grade, and stage, uncovering subtle prognostic indicators not readily visible to human pathologists.

    The study, published in JCO Clinical Cancer Informatics, demonstrated that the algorithm accurately predicted outcomes such as recurrence and metastasis and did so without introducing racial bias. The results support the broader application of AI in oncology while reinforcing the importance of diverse, well-controlled data in developing equitable predictive tools.

    REFERENCE:
    Roach M 3rd, Zhang J, Mohamad O, et al. Assessing algorithmic fairness with a multimodal artificial intelligence model in men of African and non-African origin on NRG oncology prostate cancer phase III trials. JCO Clin Cancer Inform. 2025;9:e2400284. doi:10.1200/CCI-24-00284

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  • Don’t miss the Pleiades shine with Venus in the predawn sky on July 5

    Don’t miss the Pleiades shine with Venus in the predawn sky on July 5

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    Venus will appear as a bright morning star close to the ‘Seven Sisters’ of the Pleiades open cluster. | Credit: Alan Dyer/VW Pics/UIG via Getty Images

    Early risers are in for a celestial treat on July 5, when Venus appears as a bright ‘morning star’ alongside the magnificent Pleiades open star cluster in the eastern sky just before dawn.

    Stargazers in the U.S. can see Venus rising around 3 a.m. local time, with the Pleiades star cluster visible as a smudge of light under dark sky conditions less than 7 degrees to Venus’ upper left. To estimate that distance, hold a clenched fist at arm’s length; it spans roughly 10 degrees of sky.

    The cosmic duo will be visible for around two and a half hours before the glare of the rising sun hides the Pleiades from view. While the cluster is known to contain a multitude of blue-white stars, our naked-eye view of the Pleiades from Earth is largely dominated by its seven brightest members : Alcyone, Asterope, Celaeno, Electra, Taygete, Merope and Maia. The light from these stars is best viewed away from city lights and becomes easier to detect when the star cluster is in the periphery of your vision, where the cells that excel at night vision are at their densest.

    The seven brightest stars can be picked out using a pair of 10×50 binoculars, while a telescope with an aperture of 4 inches or greater will reveal more of the cluster’s thousand-strong stellar population.

    A map of the night sky with Venus and Uranus

    See Venus close to the Pleiades in the predawn hours. | Credit: Chris Vaughn

    Venus, meanwhile, is stunning to view with the naked eye alone, shining at magnitude -3.9. However, pointing a telescope with an aperture of 2.4 inches or greater with a magnification of 50x or more will allow you to pick out its moon-like phases, according to telescope-maker Celestron.

    TOP TELESCOPE PICK:

    Celestron - NexStar 4SE Telescope

    Celestron – NexStar 4SE Telescope

    Want to see the planets of our solar system for yourself? The Celestron NexStar 4SE is ideal for beginners wanting quality, reliable and quick views of celestial objects. For a more in-depth look at our Celestron NexStar 4SE review.

    But wait, there’s more! The ice giant Uranus is also present in the sky on July 5, positioned almost directly between Venus and the Pleiades. However, its relatively dim magnitude of +5.8 makes it incredibly challenging to spot with the naked eye. Remember, magnitude is the system astronomers use to keep track of how bright an object appears in our night sky. The lower the number is, the brighter the object. The human eye is capable of spotting objects brighter than magnitude +6.5 in dark sky conditions.

    To see Uranus’ tiny aqua disk you’ll need a telescope with an 8-inch aperture. However, even then it will appear as little more than a blue point of light hanging against the starfield beyond.

    Editor’s Note: If you capture a picture of Venus with the Pleiades and want to share it with Space.com’s readers, then please send your photo(s), comments, name and location to spacephotos@space.com.

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