S100A8/A9-activated IFNγ+ NK cells trigger ß-cell necroptosis in hepatitis B virus-associated liver cirrhosis.

BACKGROUND AND AIMS: Hepatitis B virus (HBV)-associated liver cirrhosis (LC), a common condition with high incidence and mortality rates, is often associated with diabetes mellitus (DM). However, the molecular mechanisms underlying impaired glucose regulation during HBV-associated LC remain unclear. METHODS: Data from 63 patients with LC and 62 patients with LC-associated DM were analysed. Co-culture of NK cells and islet ß cell lines were used to study the glucose regulation mechanism. A mouse model of LC was used to verify the effect of S100A8/A9 on the glucose regulation. RESULTS: Higher levels of interferon (IFN)-γ derived from natural killer (NK) cells and lower levels of insulin emerged in the peripheral blood of patients with both LC and DM compared with those from patients with LC only. IFN-γ derived from NK cells facilitated ß cell necroptosis and impaired insulin production. Furthermore, S100A8/A9 elevation in patients with both LC and DM was found to upregulate IFN-γ production in NK cells. Consistently, in the mouse model for LC, mice treated with carbon tetrachloride (CCL4) and S100A8/A9 exhibited increased blood glucose, impaired insulin production, increased IFN-γ, and increased ß cells necroptosis compared with those treated with CCL4. Mechanistically, S100A8/A9 activated the p38 MAPK pathway to increase IFN-γ production in NK cells. These effects were diminished after blocking RAGE. CONCLUSION: Together, the data indicate that IFN-γ produced by NK cells induces ß cell necroptosis via the S100A8/A9-RAGE-p38 MAPK axis in patients with LC and DM. Reduced levels of S100A8/A9, NK cells, and IFN-γ could be valuable for the treatment of LC with DM. Accumulation of S100A8/A9 in patients with LC may indicate the emergence of DM.

Preparation of Monodispersed Nanofibrous Gelatin Microspheres Using Homebuilt Microfluidics.

Gelatin, a protein derivative from collagen, is a versatile material with promising applications in tissue engineering. Among the various forms of gelatin scaffolds, nanofibrous gelatin microspheres (NFGMs) are attracting research efforts due to their fibrous nature and injectability. However, current methods for synthesizing nanofibrous gelatin microspheres (NFGMs) have limitations, such as wide size distributions and the use of toxic solvents. To address these challenges, the article introduces a novel approach. First, it describes the creation of a microfluidic device using readily available supplies. Subsequently, it outlines a unique process for producing monodispersed NFGMs through a combination of the microfluidic device and thermally induced phase separation (TIPS). This innovative method eliminates the need for sieving and the use of toxic solvents, making it a more ecofriendly and efficient alternative.

Emergence of Debye Scaling in the Density of States of Liquids under Nanoconfinement.

In the realm of nanoscience, the dynamic behaviors of liquids at scales beyond the conventional structural relaxation time, τ, unfold a fascinating blend of solid-like characteristics, including the propagation of collective shear waves and the emergence of elasticity. However, in classical bulk liquids, where τ is typically of the order of 1 ps or less, this solid-like behavior remains elusive in the low-frequency region of the density of states (DOS). Here, we provide evidence for the emergent solid-like nature of liquids at short distances through inelastic neutron scattering measurements of the low-frequency DOS in liquid water and glycerol confined within graphene oxide membranes. In particular, upon increasing the strength of confinement, we observe a transition from a liquid-like DOS (linear in the frequency ω) to a solid-like behavior (Debye law, ∼ω2) in the range of 1-4 meV. Molecular dynamics simulations confirm these findings and reveal additional solid-like features, including propagating collective shear waves and a reduction in the self-diffusion constant. Finally, we show that the onset of solid-like dynamics is pushed toward low frequency along with the slowing-down of the relaxation processes upon confinement. This nanoconfinement-induced transition, aligning with k-gap theory, underscores the potential of leveraging liquid nanoconfinement in advancing nanoscale science and technology, building more connections between fluid dynamics and materials engineering.

Hepatic arterial infusion of GEMOX plus systemic gemcitabine chemotherapy combined with lenvatinib and PD-1 inhibitor in large unresectable intrahepatic cholangiocarcinoma.

PURPOSE: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC). METHODS: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0. RESULTS: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs. CONCLUSIONS: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC.

Fast, sensitive detection of protein homologs using deep dense retrieval.

The identification of protein homologs in large databases using conventional methods, such as protein sequence comparison, often misses remote homologs. Here, we offer an ultrafast, highly sensitive method, dense homolog retriever (DHR), for detecting homologs on the basis of a protein language model and dense retrieval techniques. Its dual-encoder architecture generates different embeddings for the same protein sequence and easily locates homologs by comparing these representations. Its alignment-free nature improves speed and the protein language model incorporates rich evolutionary and structural information within DHR embeddings. DHR achieves a >10% increase in sensitivity compared to previous methods and a >56% increase in sensitivity at the superfamily level for samples that are challenging to identify using alignment-based approaches. It is up to 22 times faster than traditional methods such as PSI-BLAST and DIAMOND and up to 28,700 times faster than HMMER. The new remote homologs exclusively found by DHR are useful for revealing connections between well-characterized proteins and improving our knowledge of protein evolution, structure and function.

Axillary lymph node removal in de novo metastatic breast cancer.

Background: Several prospective studies have found that local surgical resection did not improve the survival of patients with de novo metastatic breast cancer (dnMBC). However, a significant portion of dnMBC patients still undergo local surgery, and the role of axillary lymph node dissection (ALND) in dnMBC patients remains unclear. This study aimed to investigate the effect of ALND in patients with dnMBC. Methods: We included patients diagnosed with dnMBC between 2010 and 2020 using the data from the Surveillance, Epidemiology, and End Results program. The Chi-square test, binomial logistic regression, propensity score matching (PSM), Kaplan-Meier method, and multivariate Cox proportional models were employed for statistical analysis. Results: A total of 6,838 patients were identified, with 5,562 (81.3%) in the ALND group and 1,276 (18.7%) in the non-ALND group. Being diagnosed in later years emerged as an independent predictive factor related to the receipt of ALND (P=0.003). Before PSM, the 5-year breast cancer-specific survival (BCSS) was 51.1% and 38.2% in those with and without ALND, respectively (P<0.001). The 5-year overall survival (OS) was 45.9% and 32.3% in those with and without ALND, respectively (P<0.001). ALND was identified as an independent prognostic factor related to better BCSS (P<0.001) and OS (P<0.001) compared to the non-ALND group. Similar findings were observed after PSM. The outcomes were significantly better in the ALND group than in the non-ALND group in most subgroups. However, the number of removed lymph nodes did not show a significant association with BCSS (P=0.27) and OS (P=0.29). Conclusions: Our study suggests that ALND is associated with improved survival outcomes in dnMBC patients. These findings advocate for a re-evaluation of the role of surgical interventions in dnMBC, emphasizing the need for personalized treatment strategies that consider the potential benefits of ALND.

Unconventional Thermophotonic Charge Density Wave.

Charge-order states of broken symmetry, such as charge density wave (CDW), are able to induce exceptional physical properties, however, the precise understanding of the underlying physics is still elusive. Here, we combine fluctuational electrodynamics and density functional theory to reveal an unconventional thermophotonic effect in CDW-bearing TiSe_{2}, referred to as thermophotonic-CDW (tp-CDW). The interplay of plasmon polariton and CDW electron excitations give rise to an anomalous negative temperature dependency in thermal photons transport, offering an intuitive fingerprint for a transformation of the electron order. Additionally, the demonstrated nontrivial features of tp-CDW transition hold promise for a controllable manipulation of heat flow, which could be extensively utilized in various fields such as thermal science and electron dynamics, as well as in next-generation energy devices.

Effects of potassium diformate on growth performance, apparent digestibility of nutrients, serum biochemical indices, and intestinal microflora in Cherry Valley ducks.

This study was performed to investigate the effects of potassium diformate (KDF) on growth performance, apparent digestibility of nutrients, serum biochemical indices, and intestinal microflora of Cherry Valley ducks. In total, 144 female healthy 1-day-old Cherry Valley ducks were divided into 3 groups with 6 replicates per group and 8 ducks per replicate according to the principle of similar body weight. The control group was fed a basic diet. In the 2 experimental groups, 0.8% and 1.2% KDF was added to the basic diet, respectively. The trial period was 6 wk and the pretrial period was 3 wk. The final weight and ADG were significantly higher in the 0.8% KDF group than in the control group (P < 0.05). The feed-to-gain ratio was significantly lower in both KDF groups than in the control group (P < 0.05). The apparent digestibility of CP was significantly higher in both KDF groups than in the control group (P < 0.05). The apparent digestibility of calcium was also significantly higher in the 0.8% KDF group (P < 0.05). The serum levels of alkaline phosphatase, cholesterol, and total protein were significantly lower in the 0.8% KDF group than in the control group (P < 0.05), the IgM content was significantly higher (P < 0.05), the low-density lipoprotein cholesterol, triglyceride, and urea levels were significantly lower (P < 0.01), and the glucose level was significantly higher (P < 0.01). The serum total protein level was significantly higher in the 1.2% KDF group than in the control group (P < 0.05). The relative abundance of Firmicutes and Patescibacteria in the gut of ducks was significantly higher in the 0.8% KDF group than in the control group (P < 0.05), the relative abundance of unclassified Erysipelotrichaceae and Lactobacillus was significantly higher (P < 0.01), and the relative abundance of Fusobacteriota was significantly lower (P < 0.05). However, the relative abundance of Firmicutes in the gut of ducks was significantly higher in the 1.2% KDF group than in the control group (P < 0.05). The relative abundance of unclassified Erysipelotrichaceae and Clostridium sensu stricto 1 was significantly higher (P < 0.01), as was the relative abundance of Fusobacteriota and Proteobacteria (P < 0.05). These findings indicate that the addition of 0.8% KDF to the diet can improve the growth performance of Cherry Valley ducks, promote the absorption of nutrients, change the structure of the microflora in the cecum, and increase the relative abundance of dominant bacteria. It was also shown that there was a significant difference between the 0.8% and 1.2% KDF levels which suggest that the safety margin for overdosing is quite low.

The SPARC-related modular calcium binding 1 (Smoc1) regulated by androgen is required for mouse gubernaculum development and testicular descent.

ABSTRACT: Testicular descent occurs in two consecutive stages: the transabdominal stage and the inguinoscrotal stage. Androgens play a crucial role in the second stage by influencing the development of the gubernaculum, a structure that pulls the testis into the scrotum. However, the mechanisms of androgen actions underlying many of the processes associated with gubernaculum development have not been fully elucidated. To identify the androgen-regulated genes, we conducted large-scale gene expression analyses on the gubernaculum harvested from luteinizing hormone/choriogonadotropin receptor knockout (Lhcgr KO) mice, an animal model of inguinoscrotal testis maldescent resulting from androgen deficiency. We found that the expression of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (Smoc1) was the most severely suppressed at both the transcript and protein levels, while its expression was the most dramatically induced by testosterone administration in the gubernacula of Lhcgr KO mice. The upregulation of Smoc1 expression by testosterone was curtailed by the addition of an androgen receptor antagonist, flutamide. In addition, in vitro studies demonstrated that SMOC1 modestly but significantly promoted the proliferation of gubernacular cells. In the cultures of myogenic differentiation medium, both testosterone and SMOC1 enhanced the expression of myogenic regulatory factors such as paired box 7 (Pax7) and myogenic factor 5 (Myf5). After short-interfering RNA-mediated knocking down of Smoc1, the expression of Pax7 and Myf5 diminished, and testosterone alone did not recover, but additional SMOC1 did. These observations indicate that SMOC1 is pivotal in mediating androgen action to regulate gubernaculum development during inguinoscrotal testicular descent.

Relationship between intraoperative hypothermia and hyperthermia with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery.

Background: Surgical patients often experience intraoperative hypothermia or hyperthermia. However, the relationship of intraoperative hypothermia and hyperthermia with postoperative pulmonary infection (PPI) and surgical site infection (SSI) is unclear. Here, we conducted a retrospective cohort study to address these issues. Methods: Adult patients who underwent major non-cardiac surgery under general anesthesia were eligible for the study and were recruited. Three indices of core body temperature under hypothermia (<36°C) and hyperthermia (>37.3°C) were calculated as mentioned in the following: absolute value (0C), duration of exposure (min), and area under the curve (AUC,°C× min). The outcomes were in-hospital PPI and SSI. The risk-adjusted association of intraoperative hypothermia and hyperthermia with PPI and SSI was determined. Results: The absolute value (the nadir value of hypothermia and the peak value of hyperthermia) was not associated with PPI and SSI. PPI was associated with (1) duration: hypothermia >90 min [adjusted odds ratio (aOR): 1.425, 95% confidence interval (CI): 1.131-1.796] and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >3,198 (aOR: 1.390, 95%CI: 1.128-1.731) and hyperthermia >7,945 (aOR: 2.045, 95%CI: 1.138-3.676). SSI was associated with (1) duration: hypothermia > 195 min (aOR: 2.900, 95%CI: 1.703-4.937) and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >6,946 (aOR: 2.665, 95%CI: 1.618-4.390), hyperthermia >7,945 (aOR: 2.619, 95%CI: 1.625-4.220). Interactions were not observed between hyperthermia and hypothermia on the outcomes. Conclusions: It was observed that intraoperative hypothermia and hyperthermia are associated with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery.

On the temperature dependence of the density of states of liquids at low energies.

We report neutron-scattering measurements of the density of states (DOS) of water and liquid Fomblin in a wide range of temperatures. In the liquid phase, we confirm the presence of a universal low-energy linear scaling of the experimental DOS as a function of the frequency, g ( ω ) = a ( T ) ω , which persists at all temperatures. The low-frequency scaling of the DOS exhibits a sharp jump at the melting point of water, below which the standard Debye's law, g ( ω ) ∝ ω 2 , is recovered. On the contrary, in Fomblin, we observe a continuous transition between the two exponents reflecting its glassy dynamics, which is confirmed by structure measurements. More importantly, in both systems, we find that the slope a(T) grows with temperature following an exponential Arrhenius-like form, a ( T ) ∝ exp ( - ⟨ E ⟩ / T ) . We confirm this experimental trend using molecular dynamics simulations and show that the prediction of instantaneous normal mode (INM) theory for a(T) is in qualitative agreement with the experimental data.

Fuzi lizhong pills alter microbial community compositions and metabolite profiles in ulcerative colitis rat with spleen-kidney yang deficiency syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic inflammatory bowel condition that is frequently related with Spleen-Kidney Yang Deficiency Syndrome (SKYD) in Chinese medicine. Fuzi Lizhong Pill (FLZP), a traditional medicine for SKYD, has been utilized in China for generations, although the exact mechanism by which it treats UC is unknown. AIM OF THE STUDY: The goal of this study is to further understand FLZP's therapeutic mechanism in SKYD-associated UC. MATERIALS AND METHODS: To investigate the impact of FLZP on SKYD-associated UC, we used a comprehensive method that included serum metabolomics and gut microbiota profiling. The chemical composition of FLZP was determined using mass spectrometry. UC rats with SKYD were induced and treated with FLZP. Serum metabolomics and 16S rRNA microbial community analysis were used to evaluate FLZP's effects on endogenous metabolites and gut microbiota, respectively. Correlation analysis investigated the association between metabolites and intestinal flora. A metabolic pathway analysis was undertaken to discover putative FLZP action mechanisms. RESULTS: FLZP contains 109 components, including liquiritin (584.8176 µg/g), benzoylaconine (16.3087 µg/g), benzoylhypaconine (31.9583), and hypaconitine (8.1160 µg/g). FLZP predominantly regulated seven metabolites and eight metabolic pathways involved in amino acid and nucleotide metabolism, with an emphasis on energy metabolism and gastrointestinal digestion. FLZP also influenced intestinal flora variety, increasing probiotic abundance while decreasing pathogenic bacteria prevalence. An integrated investigation identified associations between changes in certain gut flora and energy metabolism, specifically the tricarboxylic acid (TCA) cycle. CONCLUSIONS: FLZP successfully cures UC in SKYD rats by regulating amino acid and energy metabolism. Its positive effects may include altering microbiota composition and metabolite profiles in UC rats with SKYD. These findings shed light on FLZP's mode of action and its implications for UC management.

Decoupling of the onset of anharmonicity between a protein and its surface water around 200 K.

The protein dynamical transition at ~200 K, where the biomolecule transforms from a harmonic, non-functional form to an anharmonic, functional state, has been thought to be slaved to the thermal activation of dynamics in its surface hydration water. Here, by selectively probing the dynamics of protein and hydration water using elastic neutron scattering and isotopic labeling, we found that the onset of anharmonicity in the two components around 200 K is decoupled. The one in protein is an intrinsic transition, whose characteristic temperature is independent of the instrumental resolution time, but varies with the biomolecular structure and the amount of hydration, while the one of water is merely a resolution effect.

Simple, Efficient, and Scalable Structure-Aware Adapter Boosts Protein Language Models.

Fine-tuning pretrained protein language models (PLMs) has emerged as a prominent strategy for enhancing downstream prediction tasks, often outperforming traditional supervised learning approaches. As a widely applied powerful technique in natural language processing, employing parameter-efficient fine-tuning techniques could potentially enhance the performance of PLMs. However, the direct transfer to life science tasks is nontrivial due to the different training strategies and data forms. To address this gap, we introduce SES-Adapter, a simple, efficient, and scalable adapter method for enhancing the representation learning of PLMs. SES-Adapter incorporates PLM embeddings with structural sequence embeddings to create structure-aware representations. We show that the proposed method is compatible with different PLM architectures and across diverse tasks. Extensive evaluations are conducted on 2 types of folding structures with notable quality differences, 9 state-of-the-art baselines, and 9 benchmark data sets across distinct downstream tasks. Results show that compared to vanilla PLMs, SES-Adapter improves downstream task performance by a maximum of 11% and an average of 3%, with significantly accelerated convergence speed by a maximum of 1034% and an average of 362%, the training efficiency is also improved by approximately 2 times. Moreover, positive optimization is observed even with low-quality predicted structures. The source code for SES-Adapter is available at https://github.com/tyang816/SES-Adapter.

PETA: evaluating the impact of protein transfer learning with sub-word tokenization on downstream applications.

Protein language models (PLMs) play a dominant role in protein representation learning. Most existing PLMs regard proteins as sequences of 20 natural amino acids. The problem with this representation method is that it simply divides the protein sequence into sequences of individual amino acids, ignoring the fact that certain residues often occur together. Therefore, it is inappropriate to view amino acids as isolated tokens. Instead, the PLMs should recognize the frequently occurring combinations of amino acids as a single token. In this study, we use the byte-pair-encoding algorithm and unigram to construct advanced residue vocabularies for protein sequence tokenization, and we have shown that PLMs pre-trained using these advanced vocabularies exhibit superior performance on downstream tasks when compared to those trained with simple vocabularies. Furthermore, we introduce PETA, a comprehensive benchmark for systematically evaluating PLMs. We find that vocabularies comprising 50 and 200 elements achieve optimal performance. Our code, model weights, and datasets are available at https://github.com/ginnm/ProteinPretraining . SCIENTIFIC CONTRIBUTION: This study introduces advanced protein sequence tokenization analysis, leveraging the byte-pair-encoding algorithm and unigram. By recognizing frequently occurring combinations of amino acids as single tokens, our proposed method enhances the performance of PLMs on downstream tasks. Additionally, we present PETA, a new comprehensive benchmark for the systematic evaluation of PLMs, demonstrating that vocabularies of 50 and 200 elements offer optimal performance.

Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19.

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls was performed, excluding patients previously treated with glucocorticoids. Several SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity of mineralocorticoids and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls, excluding those that affected adrenal function. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with those in SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with exacerbation of inflammation, differentiation and the presence of dual-ZG/ZF identity cells. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of adrenal axis and the corticosteroid sensitivity.

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

New recognition of the heart-brain axis and its implication in the pathogenesis and treatment of PTSD.

Post-traumatic stress disorder (PTSD) is a complex psychological disorder provoked by distressing experiences, and it remains without highly effective intervention strategies. The exploration of PTSD's underlying mechanisms is crucial for advancing diagnostic and therapeutic approaches. Current studies primarily explore PTSD through the lens of the central nervous system, investigating concrete molecular alterations in the cerebral area and neural circuit irregularities. However, the body's response to external stressors, particularly the changes in cardiovascular function, is often pronounced, evidenced by notable cardiac dysfunction. Consequently, examining PTSD with a focus on cardiac function is vital for the early prevention and targeted management of the disorder. This review undertakes a comprehensive literature analysis to detail the alterations in brain and heart structures and functions associated with PTSD. It also synthesizes potential mechanisms of heart-brain axis interactions relevant to the development of PTSD. Ultimately, by considering cardiac function, this review proposes novel perspectives for PTSD's prophylaxis and therapy.