Holistic food system innovation strategies can close up to 80% of China's domestic protein gaps while reducing global environmental impacts.

China's imports of livestock feed, particularly protein-rich feeds, pose challenges to global environmental sustainability. Achieving protein self-sufficiency for food and feed in China without exceeding environmental boundaries requires integrated measures and optimization of China's food system. Here we propose holistic food system innovation strategies consisting of three components-technological innovation, integrated spatial planning and demand-side options-to reduce protein import dependency and promote global environmental sustainability. We find that food system innovations can close almost 80% of China's future protein gaps while reducing 57-85% of agricultural import-embodied environmental impacts. Deploying these innovations would also reduce greenhouse gas emissions (22-27%) and people's harmful exposure to ammonia (73-81%) compared with the baseline scenario in 2050. Technological innovations play a key role in closing protein gaps, while integrated crop-livestock spatial planning is imperative for achieving environmental and health targets.

Dimethylamine Copper(I) Halide Single Crystals: Structure, Physical Properties, and Scintillation Performance.

Hybrid copper(I) halides have garnered a significant amount of attention as potential substitutes in luminescence and scintillation applications. Herein, we report the discovery and crystal growth of new zero-dimensional compounds, (C2H8N)3Cu2I5 and (C2H8N)4Cu2Br6. The bromide and iodide have a triclinic structure with space group P1̅ and an orthorhombic structure with space group Pnma, respectively. (C2H8N)3Cu2I5 exhibits cyan emission peaking at 504 nm with a photoluminescence quantum yield (PLQY) of 34.79%, while (C2H8N)4Cu2Br6 shows yellowish-green emission peaking at 537 nm with a PLQY of 38.45%. The temperature-dependent photoluminescence data of both compounds were fitted to theoretical models, revealing that nonradiative intermediate states significantly affect thermal quenching and antiquenching. Electron-phonon interactions, the origin of emission line width broadening and peak shifting, were also investigated via fittings. The scintillation properties of (C2H8N)3Cu2I5 were evaluated, and an X-ray imaging device was successfully fabricated using (C2H8N)3Cu2I5. This work demonstrates the potentiality of copper halides in lighting and X-ray imaging applications.

Preparation of Radiolabeled Zolbetuximab Targeting CLDN18.2 and Its Preliminary Evaluation for Potential Clinical Applications.

Claudin18.2 (CLDN18.2), due to its high expression in various gastric cancer tissues, is considered an optimal target for antitumor drug molecules. In this study, we obtained the labeled compounds of [125I]I-zolbetuximab using the Iodogen method. Under the optimum labeling conditions, the molar activity of [125I]I-zolbetuximab was 1.75 × 102 GBq/µmol, and the labeling efficiency was more than 99%. The labeled compounds exhibited excellent in vitro stability in both phosphate buffer saline (PBS, pH = 7.4) and fetal bovine serum systems (FBS) (radiochemical purity >90% at 72 h). The uptake percentage of [125I]I-zolbetuximab in MKN45-CLDN18.2 cells is 24.69 ± 0.84% after 6 h. The saturation binding assay and specificity assay further demonstrated the high specificity of [125I]I-zolbetuximab for CLDN18.2. The long retention at the tumor site and rapid metabolic clearance at other organ sites of [125I]I-zolbetuximab were observed in small-animal SPECT-CT imaging. The same trend was also observed in the biodistribution study. Due to the excellent targeting ability of zolbetuximab for CLDN18.2, [125I]I-zolbetuximab exhibits strong specific binding and retention with cells and tumors highly expressing CLDN18.2. However, the balance between mAb's longer cycle time in vivo and targeting binding and retention ability should be intensively considered for using this kind of radiopharmaceutical in the diagnosis and treatment of CLDN18.2-positive gastric cancer.

Contrasting effects of NADPH oxidases on the fungal hyphae growth and immune responses in Pleurotus ostreatus.

Pleurotus ostreatus is one of the most consumed mushroom species, as it serves as a high-quality food, favors a rich secondary metabolism, and has remarkable adaptability to the environment and predators. In this study, we investigated the function of two key reactive oxygen species producing enzyme NADPH oxidase (PoNoxA and PoNoxB) in P. ostreatus hyphae growth, metabolite production, signaling pathway activation, and immune responses to different stresses. Characterization of the Nox mutants showed that PoNoxB played an important role in the hyphal formation of the multicellular structure, while PoNoxA regulated apical dominance. The ability of P. ostreatus to tolerate a series of abiotic stress conditions (e.g., osmotic, oxidative, membrane, and cell-wall stresses) and mechanical damage repair was enhanced with PoNoxA over-expression. PoNoxB had a greater responsibility in regulating the polysaccharide composition of the cell wall and methyl jasmonate and gibberellin GA1 biosynthesis, and improved mushroom resistance against Tyrophagus putrescentiae. Moreover, mutants were involved in the jasmonate and GA signaling pathway, and toxic protein defense metabolite production. Our findings shed light on how the oyster mushroom senses stress signals and responds to adverse environments by the complex regulators of Noxs.

Case Report: Scalp pityriasis versicolor may be a neglected problem.

Pityriasis versicolor, a common skin fungal infection, is typically observed on trunk and limb skin. Here, we highlight an unusual presentation: scalp involvement, often overlooked due to its asymptomatic, mildly scaly patches. We report four pediatric cases, emphasizing the potential underestimation of this scalp variant. This case series underscores the importance of considering this diagnosis in patients with unexplained scalp hypopigmentation, especially in males with short hair who may readily notice these subtle changes. The report contributes to the understanding of this variant's clinical presentation and emphasizes the need for awareness among clinicians to ensure accurate diagnosis and appropriate management.

A novel multi-feature fusion attention neural network for the recognition of epileptic EEG signals.

Epilepsy is a common chronic brain disorder. Detecting epilepsy by observing electroencephalography (EEG) is the main method neurologists use, but this method is time-consuming. EEG signals are non-stationary, nonlinear, and often highly noisy, so it remains challenging to recognize epileptic EEG signals more accurately and automatically. This paper proposes a novel classification system of epileptic EEG signals for single-channel EEG based on the attention network that integrates time-frequency and nonlinear dynamic features. The proposed system has three novel modules. The first module constructs the Hilbert spectrum (HS) with high time-frequency resolution into a two-channel parallel convolutional network. The time-frequency features are fully extracted by complementing the high-dimensional features of the two branches. The second module constructs a grayscale recurrence plot (GRP) that contains more nonlinear dynamic features than traditional RP, fed into the residual-connected convolution module for effective learning of nonlinear dynamic features. The third module is the feature fusion module based on a self-attention mechanism to assign optimal weights to different types of features and further enhance the information extraction capability of the system. Therefore, the system is named HG-SANet. The results of several classification tasks on the Bonn EEG database and the Bern-Barcelona EEG database show that the HG-SANet can effectively capture the contribution degree of the extracted features from different domains, significantly enhance the expression ability of the model, and improve the accuracy of the recognition of epileptic EEG signals. The HG-SANet can improve the diagnosis and treatment efficiency of epilepsy and has broad application prospects in the fields of brain disease diagnosis.

Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth.

Cancer cells undergo major epigenetic alterations and transcriptomic changes, including ectopic expression of tissue- and cell-type-specific genes. Here, we show that the germline-specific RNA helicase DDX4 forms germ-granule-like cytoplasmic ribonucleoprotein granules in various human tumors, but not in cultured cancer cells. These cancerous DDX4 complexes contain RNA-binding proteins and splicing regulators, including many known germ granule components. The deletion of DDX4 in cancer cells induces transcriptomic changes and affects the alternative splicing landscape of a number of genes involved in cancer growth and invasiveness, leading to compromised capability of DDX4-null cancer cells to form xenograft tumors in immunocompromised mice. Importantly, the occurrence of DDX4 granules is associated with poor survival in patients with head and neck squamous cell carcinoma and higher histological grade of prostate cancer. Taken together, these results show that the germ-granule-resembling cancerous DDX4 granules control gene expression and promote malignant and invasive properties of cancer cells.

Identification of Matrine as a Kirsten rats Arcomaviral oncogene homolog inhibitor alleviating chemotherapy-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) represents a prevailing and severe clinical concern, characterized by limited availability of clinically effective treatment strategies. Current evidence endorses matrine's potential as a neuroprotective and analgesic agent for CIPN. Nevertheless, the precise targets and mechanisms of action of matrine remain insufficiently explored, impeding comprehensive pharmacological investigation and clinical application. OBJECTIVE: This study endeavors to elucidate the analgesic and neuroprotective effects of matrine in mice with vincristine-induced neuropathic pain. A focal point is the identification of matrine's specific target and the underlying molecular mechanisms governing its analgesic and neuroprotective actions. METHODS: To discern matrine's analgesic effects in CIPN mice, we conducted behavioral experiments encompassing the Von Frey filament test and Hargreaves Test. Furthermore, we conducted electrophysiological and histopathological assessments involving HE staining, Nissl staining, and Fluoro-Jade B staining to evaluate matrine's effects on neuroprotection within dorsal root ganglia and the spinal cord of CIPN mice. Sequentially, thermal shift assay, GTP hydrolysis assay, and nucleotide exchange assay were executed to validate matrine's inhibitory effects on KRAS. Molecular docking and site-directed mutagenesis experiments were implemented to identify the precise binding pocket of matrine on KRAS. Lastly, matrine's inhibitory effects on downstream signaling pathways of KRAS were confirmed through experiments conducted at animal model. RESULTS: Matrine exhibited a notable increase in mechanical withdrawal threshold and thermal withdrawal latency in vincristine-treated mice. This compound substantially ameliorated the neurofunctional blockade associated with sensory and motor functions induced by vincristine. Moreover, matrine mitigated pathological damage within DRG and the L4-L5 spinal cord regions. The study's MST experiments indicated matrine's substantial elevation of KRAS's melting temperature. The GTP hydrolysis and nucleotide exchange assays revealed concentration-dependent inhibition of KRAS activity by matrine. Molecular docking provided insight into the binding mode of matrine with KRAS, while site-directed mutagenesis verified the specific binding site of matrine on KRAS. Lastly, matrine's inhibition of downstream Raf/Erk1/2 and PI3K/Akt/mTOR signaling pathways of KRAS was confirmed in VCR mice. CONCLUSION: Compared to previous studies, our research has identified matrine as a natural inhibitor of the elusive protein KRAS, often considered "undruggable." Furthermore, this study has revealed that matrine exerts its therapeutic effects on chemotherapy-induced peripheral neuropathy (CIPN) by inhibiting KRAS activation, subsequently suppressing downstream signaling pathways such as Raf/Erk1/2 and PI3K/Akt/mTOR. This investigation signifies the discovery of a novel target for matrine, thus expanding the potential scope of its involvement in KRAS-related biological functions and diseases. These findings hold the promise of providing a crucial experimental foundation for forthcoming drug development initiatives centered around matrine, thereby advancing the field of pharmaceutical research.

CBP60b clade proteins are prototypical transcription factors mediating immunity.

Transcriptional reprogramming is critical for plant immunity. Several calmodulin (CaM)-binding protein 60 (CBP60) family transcription factors (TFs) in Arabidopsis (Arabidopsis thaliana), including CBP60g, Systemic Acquired Resistance Deficient 1 (SARD1), CBP60a, and CBP60b, are critical for and show distinct roles in immunity. However, there are additional CBP60 members whose function is unclear. We report here that Arabidopsis CBP60c-f, four uncharacterized CBP60 members, play redundant roles with CBP60b in the transcriptional regulation of immunity responses, whose pCBP60b-driven expression compensates the loss of CBP60b. By contrast, neither CBP60g nor SARD1 is inter-changeable with CBP60b, suggesting clade-specific functionalization. We further show that function of CBP60b clade TFs relies on DNA-binding domains (DBDs) and CaM-binding domains, suggesting that they are downstream components of calcium signaling. Importantly, we demonstrate that CBP60s encoded in earliest land plant lineage Physcomitrium patens and Selaginella moellendorffii, are functionally homologous to Arabidopsis CBP60b, suggesting that the CBP60b clade contains the prototype TFs of the CBP60 family. Furthermore, tomato and cucumber CBP60b-like genes rescue the defects of Arabidopsis cbp60b and activate the expression of tomato and cucumber SALICYLIC ACID INDUCTION DEFICIIENT2 (SID2) and ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) genes, suggesting that immune response pathways centered on CBP60b are also evolutionarily conserved. Together, these findings suggest CBP60b clade transcription factors are functionally conserved in evolution and positively mediate immunity.

Multiplex assays reveal anti-EBV antibody profile and its implication in detection and diagnosis of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression.

Knowledge, Attitudes, and Practices about Hyperuricemia and Gout in Community Health Workers and Patients with Diabetes.

Hyperuricemia exhibits a high incidence among individuals with diabetes; however, the significance of hyperuricemia and gout is often underestimated. This study aimed to assess the knowledge, attitude, and practice of hyperuricemia and gout among community health workers and patients with diabetes. Two questionnaires were designed to investigate knowledge, attitudes, and practices of hyperuricemia and gout among community health workers and patients with diabetes in Chenghua District, Chengdu, from August 2021 to January 2022. A total of 709 community health workers were included, whose average score was 17.74/30. Approximately half of general practitioners (GPs) demonstrated knowledge regarding the target serum uric acid levels for hyperuricemia and gout. Only 11.2% of GPs were fully aware of the preferred medicine for acute gout. The majority of GPs (86.7%) demonstrated limited awareness regarding the contraindications associated with colchicine, while a significant proportion (65.1%) lacked knowledge about the specific classes of drugs that inhibit uric acid synthesis. Among the 508 patients with diabetes included in this survey, 32.3% demonstrated awareness of hyperuricemia, while 60.8% exhibited knowledge regarding gout. The average score attained by these individuals was recorded at 7.21 out of a total of 26 points. The majority of patients with diabetes (87.8%) held the mistaken belief that hyperuricemia definitely led to the development of gout. Almost 66% agreed that a massage or a hot compress could be used when acute gouty arthritis attacks. The knowledge rate of hyperuricemia and gout among community health workers was moderate, while it was low in patients with diabetes.

Lightweight Electrolyte Design for Li/Sulfurized Polyacrylonitrile (SPAN) Batteries.

Sulfurized polyacrylonitrile (SPAN) recently emerges as a promising cathode for high-energy lithium (Li) metal batteries owing to its high capacity, extended cycle life, and liberty from costly transition metals. As the high capacities of both Li metal and SPAN lead to relatively small electrode weights, the weight and specific energy density of Li/SPAN batteries are particularly sensitive to electrolyte weight, highlighting the importance of minimizing electrolyte density. Besides, the large volume changes of Li metal anode and SPAN cathode require inorganic-rich interphases that can guarantee intactness and protectivity throughout long cycles. This work addresses these crucial aspects with an electrolyte design where lightweight dibutyl ether (DBE) is used as a diluent for concentrated lithium bis(fluorosulfonyl)imide (LiFSI)-triethyl phosphate (TEP) solution. The designed electrolyte (d = 1.04 g mL-1) is 40%-50% lighter than conventional localized high-concentration electrolytes (LHCEs), leading to 12%-20% extra energy density at the cell level. Besides, the use of DBE introduces substantial solvent-diluent affinity, resulting in a unique solvation structure with strengthened capability to form favorable anion-derived inorganic-rich interphases, minimize electrolyte consumption, and improve cell cyclability. The electrolyte also exhibits low volatility and offers good protection to both Li metal anode and SPAN cathode under thermal abuse.

A global assessment of glyphosate and AMPA inputs into rivers: Over half of the pollutants are from corn and soybean production.

Glyphosate is widely used in agriculture for weed control; however, it may pollute water systems with its by-product, aminomethylphosphonic acid (AMPA). Therefore, a better understanding of the flows of glyphosate and AMPA from soils into rivers is required. We developed the spatially explicit MARINA-Pesticides model to estimate the annual inputs of glyphosate and AMPA into rivers, considering 10 crops in 10,226 sub-basins globally for 2020. Our model results show that, globally, 880 tonnes of glyphosate and 4,090 tonnes of AMPA entered rivers. This implies that 82 % of the river inputs were from AMPA, with glyphosate accounting for the remainder. Over half of AMPA and glyphosate in rivers globally originated from corn and soybean production; however, there were differences among sub-basins. Asian sub-basins accounted for over half of glyphosate in rivers globally, with the contribution from corn production being dominant. South American sub-basins accounted for approximately two-thirds of AMPA in rivers globally, originating largely from soybean production. Our findings constitute a reference for implementing and supporting effective control strategies to achieve Sustainable Development Goals 2 and 6 (food production and clean water, respectively) simultaneously in the future.

Somatic GNA11/GNAQ variants in a cohort of Chinese children with phakomatosis pigmentovascularis.

Importance: Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G-protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective: To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods: We performed whole-exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep-targeted sequencing was conducted to validate the somatic mutations. A genotype-phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results: Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype-phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation: Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

Revealing the role of interlayer spacing in radioactive-ion sieving of functionalized graphene membranes.

Functionalization of graphene enables precise control over interlayer spacing during film formation, thereby enhancing the separation efficiency of radioactive ions in graphene membranes. However, the systematic impact of interlayer spacing of graphene membranes on radioactive-ion separation remains unexplored. This study aims to elucidate how interlayer spacing in functionalized graphene membranes affects the separation of radioactive ions. Utilizing polyamidoxime (PAO) to modify graphene oxide, we controlled the interlayer spacing of graphene membranes. Experimental results indicate that tuning interlayer spacing enables control of the permeation flux of radioactive ions (UO22+ 1.01 × 10-5-8.32 × 10-5 mol/m2·h, and K+ remains stable at 3.60 × 10-4 mol/m2·h), and the K+/UO22+ separation factors up to 36.2 at an interlayer spacing of 8.8 Å. Using density functional theory and molecular dynamics simulations, we discovered that the effective separation is mainly determined via interlayer spacing and the quantity of introduced functional groups, explaining the anomalous high permeation flux of target ions at low interlayer spacing (4.3 Å). This study deepens our comprehension of interlayer spacing within nanoconfined spaces for ion separation and recovery via graphene membranes, offering valuable insights for the design and synthesis of high-performance nanomembrane materials.

An optimized crop-livestock system can achieve a safe and just planetary boundary for phosphorus at the sub-basin level in China.

The contribution of crop and livestock production to the exceedance of the planetary boundary for phosphorus (P) in China is still unclear, despite the country's well-known issues with P fertilizer overuse and P-related water pollution. Using coupled models at sub-basin scales we estimate that livestock production increased the consumption of P fertilizer fivefold and exacerbated P losses twofold from 1980 to 2017. At present, China's crop-livestock system is responsible for exceeding what is considered a 'just' threshold for fertilizer P use by 30% (ranging from 17% to 68%) and a 'safe' water quality threshold by 45% (ranging from 31% to 74%) in 25 sub-basins in China. Improving the crop-livestock system will keep all sub-basins within safe water quality and just multigenerational limits for P in 2050.

Multi-walled carbon nanotubes affect yield, antioxidant response, and rhizosphere microbial community of scented rice under combined cadmium-lead (Cd-Pb) stress.

Rice production is threatened by heavy metal stress. The use of multi-walled carbon nanotubes (MWCNTs) in agriculture has been reported in previous studies. We aimed to quantify the impact of MWCNTs on the growth and physiological characteristics of scented rice under cadmium (Cd) and lead (Pb) stresses. Therefore, a pot experiment was conducted, two scented rice varieties Yuxiangyouzhan and Xiangyaxiangzhan were used as materials grown under different concentrations of MWCNTs (0, 100, and 300 mg kg-1 recorded as CK, CNPs100, and CNPs300, respectively). The yield, antioxidant response, and rhizosphere microbial community of scented rice were studied. The results showed that compared with the CK treatment, the CNPs100 and CNPs300 treatments increased leaf dry weight by 17.95%-56.22% at the heading stage, and the H2O2 content in leaves decreased significantly by 36.64%-42.27% at the maturity stage. Under CNPs100 treatment, the grain yield of two scented rice varieties increased significantly by 17.54% and 27.40%, respectively. The MWCNTs regulated the distribution of the Cd and Pb in different plant tissues. The content of Cd (0.11-0.20 mg kg-1) and Pb (0.01-0.04 mg kg-1) in grain were at a safety level (<0.2 mg kg-1). Moreover, MWCNTs increased soil microbial community abundance and altered community composition structure under Cd-Pb stress, which in turn improved agronomic traits and quality of scented rice. Overall, this study suggested that the application of MWCNTs regulates the growth, yield, physiological response, and soil microbial community, the genotypes response effect of scented rice to MWCNTs is needed further studied.

BLA-involved circuits in neuropsychiatric disorders.

The basolateral amygdala (BLA) is the subregion of the amygdala located in the medial of the temporal lobe, which is connected with a wide range of brain regions to achieve diverse functions. Recently, an increasing number of studies have focused on the participation of the BLA in many neuropsychiatric disorders from the neural circuit perspective, aided by the rapid development of viral tracing methods and increasingly specific neural modulation technologies. However, how to translate this circuit-level preclinical intervention into clinical treatment using noninvasive or minor invasive manipulations to benefit patients struggling with neuropsychiatric disorders is still an inevitable question to be considered. In this review, we summarized the role of BLA-involved circuits in neuropsychiatric disorders including Alzheimer's disease, perioperative neurocognitive disorders, schizophrenia, anxiety disorders, depressive disorders, posttraumatic stress disorders, autism spectrum disorders, and pain-associative affective states and cognitive dysfunctions. Additionally, we provide insights into future directions and challenges for clinical translation.