The pathogenesis of Parkinson's disease (PD) has been linked to environmental factors, toxins, genetics, and peripheral inflammation. Importantly, intestinal inflammation like that seen in Crohn's disease (CD) or food allergies has been implicated in risk for neurodegeneration and late-onset PD. Further, CD and PD share genetic risk factors including gain-of-function leucine-rich repeat kinase 2 (LRRK2) mutations. Here, we aim to better understand how intestinal inflammation synergizes with Lrrk2 levels or kinase activation to promote neurodegeneration in young and old mice. We utilized bacterial artificial chromosome (BAC) mice overexpressing wildtype mouse Lrrk2 or mutant G2019S mouse Lrrk2 and compared them with C57B6J mice at baseline and under conditions of intestinal inflammation using dextran sodium sulfate (DSS) colitis models. While our data revealed regulation of the brain inflammatory state by Lrrk2, we did not observe age-dependent selective vulnerability or protection in Lrrk2 mouse lines in colitis protocols. Instead, DSS phenotypes were associated with increased nigrostriatal dysregulation in all genotypes independent of age. While Lrrk2 mutations appear to influence the genesis of peripheral inflammation, our data suggest that Lrrk2 activation due to a gain-of-function mutation does not exacerbate the effects of inflammation on nigrostriatal degeneration in this model.
Inflammatory activation is a major cause to nasal diseases, such as chronic rhinosinusitis and allergic rhinitis. However, in vitro research model to mimic the process of olfactory inflammation and to screen new therapeutic target is still lacking. We established three inflammatory models based on olfactory epithelium (OE) organoids, using lipopolysaccharide (LPS), TNFα treatment and doxycycline induction. The efficacy of these models was evaluated by immunostaining, RNA sequencing, qPCR, and functional assays. These inflammatory organoid models mimicked impairment in cell proliferation and neuronal genesis, and showed upregulation of inflammation-related signaling pathway and downregulation of cell cycle-related pathway. We identified that DNA damage inducible transcript 3 (Ddit3) was upregulated in all inflammatory organoid models. Ddit3 downregulation counteracted apoptosis, alleviated cell proliferation and neuronal differentiation, and recovered the functional response to odor stimulation in all three inflammatory organoid models. Ddit3 deficiency counteracted effect of LPS instillation by promoting cell proliferation, recovering neurogenesis, attenuating inflammation, and improving electrophysiological response to odor mixes in the OE. Single-cell RNA sequencing analysis showed that Ddit3 upregulation in mature olfactory sensory neurons of inducible inflammation model and patients with aging-related olfactory dysfunction correlated with endoplasmic reticulum stress and neuron apoptotic process. We established olfactory inflammation organoid models, and made use of these models to identify Ddit3 as a potential therapeutic target against inflammation-related olfactory neuronal loss and functional deficit.
General intelligence enables flexible problem solving across diverse contexts by minimizing uncertainty. Symbolic systems such as language extend this capacity, allowing humans to build social groups and construct world models beyond typical biological constraints. Previous research on linguistic communication within active inference has emphasized deep hierarchical models that ensure shared semantics between communicators. We argue that these models, while powerful, require extension to account for symbolic genesis, specifically using morality not only as uncertainty minimization across cultural niches, but also as the mechanism that created the virtual space enabling symbolic cognition. Our ancestors transcended dyadic modeling by implementing cultural layers through novel model selection, enabling in-group signaling and hierarchical social organization through psychological typing. This rendered the generative process endogenous (self-referential). Our emotional and impulsive tendency toward morality, we argue, enabled the deeper level of abstraction and the stable third-party triangulated perspective necessary for symbolic thought. This framework can be evaluated through simulations similar to recent active inference literature and provides a foundation for building generally intelligent systems aligned with human cultural values.
Oncogenic tyrosine kinase activity of BCR::ABL1 is causally associated with chronic phase (CP) of chronic myeloid leukemia (CML) and its inhibition by tyrosine kinase inhibitors (TKIs) induces remission in majority of patients. However, in the terminal blast crisis (BC) phase, 80% patients are resistant to TKIs. Forty percent among them are resistant despite inhibition of BCR::ABL1 activity by TKIs and in earlier study, we observed similar antithesis in K562 cells resistant to TKI-imatinib. We demonstrated active BCR::ABL1 signaling downstream of inactivated BCR::ABL1 and its causal association with resistance. This study explores the involvement of ITGB1, integrin with significant role in genesis of CML and differentially expressed in resistant K562 cells, in mediation of atypical activation of BCR::ABL1 pathway and thus resistance. Imatinib-sensitive and resistant K562 cells as well as sensitive cells with ITGB1 knockdown (KD) to mimic resistant cells, were analyzed for proteome and phosphoproteome by mass spectrometry and kinome was profiled by quantification of kinase activities in an array-based assay. The commonality between differentially expressed proteins (DEPs) identified in resistant cells and ITGB1-KD cells together with ITGB1 interactors, identified from ITGB1-immunoprecipitate by mass spectrometry, provided a comprehensive sketch of ITGB1-mediated signaling in resistant cells. The proteins identified as key players in ITGB1-mediated activation of BCR::ABL1 signaling were validated in K562 and KU812 cells, CD34+ cells from patient samples and their functional significance was assessed by inhibition studies in K562 cells. It was observed that the reduced levels of ITGB1 in resistant cells activated BCR::ABL1 downstream signaling kinases- p38MAPK and ERK. Though not influenced by ITGB1, LYN was active in resistant cells. Inhibition studies revealed that p38MAPK, ERK and LYN regulate the activity of each other, thereby explaining ITGB1-independent activation of LYN. The three kinases in turn activate members of CDK, MAPK, AKT and PKC families while ERK alone modulates EPH activity. Thus, reduction in level of ITGB1 in resistant cells leads to activation of ERK and p38MAPK belonging to BCR::ABL1 pathway, despite inactivation of BCR::ABL1, which in turn leads to activation of LYN. Together, these kinases activate members of vital pro-survival pathways, thereby imparting imatinib resistance in CML-BC cells.
Fatigue is one of the most prevalent and debilitating symptoms in individuals with multiple sclerosis (MS). We recorded somatosensory high-frequency oscillatory (HFO) thalamocortical activity in a group of MS patients without history of optic neuritis (ON). Furthermore, we examined if, like what was previously observed in response to visual stimuli, patients exhibit diminished amplitude habituation, and whether this may further exacerbate fatigue in individuals with MS. Twenty patients diagnosed with relapsing-remitting MS were prospectively enrolled. The MS cohorts were compared with a cohort of 20 healthy volunteers (HV). Fatigue Severity Scale (FSS) was employed to evaluate the trait levels of reported fatigue. We assessed the N20 somatosensory evoked potentials (SSEPs) parameters and N20-P25 amplitude habituation, and, following the application of a band-pass filter (450-750 Hz), we evaluated electrophysiological parameters of pre- and post-synaptic HFOs. The latency and amplitude of the N20 SSEP and its habituation do not exhibit significant differences between MS patients and HVs. MS patients exhibited delayed latency of negative oscillatory maximum and reduced maximum peak-to-peak amplitude of the pre-synaptic HFOs (all p < 0.01). In patients, post-synaptic HFOs showed a significant delayed latency and a trend towards a reduction in the maximal peak-to-peak amplitude. The pre-synaptic HFO latency of the negative oscillatory maximum, reflecting thalamocortical activity, shows a correlation with the FSS in MS patients (r = 0.522, p = 0.018). No significant ophthalmological anomalies were identified. Our data revealed a significant reduction and slowing of somatosensory thalamocortical network activity in MS patients without history of ON. Furthermore, our findings showed that fatigue levels may be affected by slowed thalamocortical activity, but not by habituation of cortical responses. Our findings suggest a potential role of the thalamo-cortical network on the genesis of MS-related fatigue.
The human vascular network is a highly dynamic, complex and organ-specific microenvironment essential for organ homeostasis. Traditional 2D cell cultures fail to capture its complex intercellular interactions, tissue-specific architectures, and mechanobiological cues. Blood vessel organoids (BVOs) generated from human induced pluripotent stem cells (hiPSCs) replicate the structure and function of blood vessels. Because hiPSCs preserve the donor's telomere length and epigenetic memory, BVOs may preserve the genesis memory, opening up a completely new avenue for the study of vascular disorders. In this review, we systematically outline the methods for in vitro blood vessel generation and explore how vascularizing parenchymal organoids actively drives tissue maturation while overcoming hypoxic limitations. We assess the vital transition from biochemical induction to biomechanical integration, highlighting how microfluidic organ-on-a-chip (OoC) platforms resolve the lineage-specific media dilemma and impose the physiological shear stress necessary for definitive vascular maturation. Furthermore, we comprehensively summarize the applications of BVOs as personalized preclinical avatars across diverse pathologies, including diabetic vasculopathy, cerebrovascular and cardiovascular diseases, tumor immune evasion, hereditary anomalies, and infectious vasculotropism. Finally, we address critical current bioengineering constraints-notably incomplete vessel maturation, the absence of functional lymphatic systems, and the lack of immunocompetent microenvironments-providing strategic future perspectives to accelerate the translation of BVOs in precision and regenerative medicine.
As employee turnover intensifies and the talent shortage grows, boomerang employment-the phenomenon of former employees returning to their previous organizations-has become increasingly common. However, theoretical understanding of how this behavior occurs remains limited. This study aims to explore the formation mechanisms of workplace boomerang behavior and construct a theoretical model to explain this process. Employing a grounded theory approach, we collected data from two sources: online secondary materials and semi-structured interviews with former employees who had returned to their previous companies. The data were systematically analyzed through open coding, axial coding, and selective coding to identify core categories and their interrelationships. Anchoring factors (rational, emotional, matching, normative) and driving factors (career, contextual, cognitive) shape boomerang intention (cognitive commitment and behavioral enactment), ultimately leading to boomerang behavior. Organizational opportunities (talent gaps, value assessments, industry ecology) are critical for enabling boomerang behavior. Our work makes the following theoretical advancements. First, by systematically examining how boomerang behavior emerges, this study shifts the analytical focus from "outcome analysis" to "process genesis." Second, by investigating the critical role of the former organization in the formation of boomerang behavior, this study builds a "bilateral interaction" decision model. Third, by framing boomerang behavior as a distinct form of situated job choice, this study addresses the explanatory shortcomings of traditional job-choice theories in this context.
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser202/Ser396/Ser404 phosphorylations of TAU and formation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser202/Ser396/Ser404 phosphorylations and genesis of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAUSer202/Ser396/Ser404 oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser202/Ser396/Ser404 phosphorylations and generation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
GABAA and protein hypotheses aside, the lipid theory remains the most influential account of anaesthetic effects in modern pharmacology. An apparent aspect of the lipoidal model's continued dominance is its long historical pedigree, frequently aligned with a process of steady refinement from Bibra and Harless to Hermann, Pohl, and finally Meyer/Overton. This paper problematizes this continuum by placing the genesis of a short-lived experimental entity-protagon-at the centre of the transition from the fat-solvation theory to the modern lipoidal theory of anaesthesia, which broadly identifies fat as a central mediating substance. A 'historical ontology' of protagon and an outline of the 19th century history of brain composition in relation to the early history of anaesthetic pharmacology, it treats the initial appearance of fat-oriented theories of anaesthesia as emergent of the focus on cerebral fat endemic to early 19th century organic principle analysis.
After February 1948, the new communist regime began to subordinate areas of life in Czechoslovakia to advocated political and ideological demands. Consequently, the unification of physical education and sports into Sokol was declared. In addition to institutional and legislative changes, the system of training for specialists was reorganized. The genesis of the Institute of Physical Education and Sport is reconstructed to illustrate organization and management of Czechoslovak physical education. The process of adopting the Soviet model of direct state control is described in the context of the geographic, historical, economic, and social specifics of a given territory. This research was based on the study of archival documents from the provenance of the State Committee and the State Office for Physical Education and Sport. This paper examines the intentions of the competent authorities, the circumstances of the foundation, mission, application of graduates and the content of studies at the Institute.
Natural polymers can be engineered into nanoscale "molecular traps", the bioMIPs, by the technique of molecular imprinting, which is a template-directed synthesis to generate selective binding sites in a crosslinked matrix. To date, bioMIPs are synthesized in solution by nano-aggregation of the polymeric units around a template, yielding to selective meta-biomaterials. Yet, the in-solution process limits the uniformity and scale-up of the bioMIPs. Here we report the first solid-phase synthesis (SPS) of interleukin-6 (IL-6) selective bioMIPs made of Gelatin methacryloyl (GelMA) and establish design rules for producing monomodal bioMIPs from protein building blocks. SPS synthesis is based on the oriented immobilization of the template to a solid support. SPS nucleation was studied on a plasmonic surface permitting real-time monitoring of bioMIP genesis. Subsequently, it was translated into a prototype reactor for scaling up the production. Guided by Flory-Huggins-De Gennes theory, we mapped the synthetic space by varying GelMA concentration, density and architecture of the surface-immobilized templates, and nucleation-time. The formed SPS bioMIPs were structurally and functionally characterized. Compared with analogous bioMIPs prepared by in-solution imprinting, SPS bioMIPs displayed a low picomolar dissociation constant, surpassing the in-solution ones by 3 orders of magnitude; showed ∼1 ng/μg IL-6 uptake in human serum, i.e., ∼45-fold increase with respect to in-solution ones, underscoring robust selective recognition under physiologically relevant conditions. Overall, the SPS strategy enables template-free isolation of high-quality bioMIPs and provides a practical route toward manufacturing cytokine-targeting nanotraps for inflammation-modulating biomedical applications.
While the advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based technologies has democratized the genesis of precise mutations, there is a need for more sophisticated tools to enable large-scale DNA manipulations, advancing genome editing across medicine, biotechnology, and agriculture. The success of Cas9 and Cas12 has hinged on the generation of precise DNA nicks and double-stranded breaks (DSBs), enabling local sequence mutagenesis, albeit of a limited size range. Emerging effectors combining Cas with other enzymatic functions, such as CRISPR-associated transposons and site-specific recombinases, enable larger integrations. Sophisticated combinations such as programmable addition via site-specific targeting element (PASTE), prime-editing-assisted site-specific integrase gene editing (PASSIGE), and prime-editing-mediated recombination of opportune target (PrimeRoot) expand payload options and DSB-free editing modalities, with translational potential for next-generation crop breeding in sustainable agriculture and the development of gene and cell therapies in personalized medicine.
Congenital heart disease is among the most common fetal abnormalities and birth defects. Despite identifying numerous risk factors influencing its onset, a comprehensive understanding of its genesis and management across diverse populations remains limited. Recent advancements in machine learning have demonstrated the potential for leveraging patient data to enable early congenital heart disease detection. Over the past seven years, researchers have proposed various data-driven and algorithmic solutions to address this challenge. This paper presents a systematic review of congenital heart disease recognition using machine learning, conducting a meta-analysis of 432 references from leading journals published between 2018 and 2025. A detailed investigation of 74 scholarly works highlights key factors, including databases, algorithms, applications, and solutions. Additionally, the survey outlines reported datasets used by machine learning experts for congenital heart disease recognition. Using a systematic literature review methodology, this study identifies critical challenges and opportunities in applying machine learning to congenital heart disease.
Cancer remains as the most feared human disease and embodies deep psychological and physical suffering (1). It is one of the unsolved medical problems nowadays and constitutes a heavy burden not only for the individual and his family but also for health systems worldwide (2). In this context, cancer prevention and early diagnosis and treatment is of cardinal importance; hence, identification of cancer risk factors in the genesis of human cancer is an urgent necessity. Among these deleterious influences, obesity and aberrantly increased growth hormone receptor (GHR) signaling have been identified as two of the most relevant factors in the etiology of malignancy (3, 4). Considering the above premises, attempts at effectively and safely treating patients with cancer are within the noblest aims in medicine and science. At present, radical surgery, radio and chemotherapy, targeted therapy, and immunotherapy are the basis for dealing with this widespread issue (5). Nevertheless, and especially in several types of cancer, all efforts are ineffective (6). In consequence, strategies to discover new medicines aimed at safely and effectively treating individuals affected by cancer are needed. Similarly, adjuvant methods aimed at making more effective use of standard therapies are required. Contextually, a new experimental approach to dealing with melanoma, liver cancer, pancreatic cancer, and cholangiocarcinoma, some of the most lethal malignancies in humans, has been developed based on the previous discovery of a GHR antagonist used for acromegaly and its mode of action (7, 8). Development of new drugs for cancer treatment is partially based on observations in humans who have a distinct phenotype that combines obesity -the most epidemiologic risk factor in cancer etiology- along with absent growth hormone receptor (GHR) signaling (4, 9).
To report a case of AA developing during golimumab and leflunomide treatment for seropositive rheumatoid arthritis, with subsequent improvement following initiation of selective Janus kinase 1 (JAK1) inhibition. A 55-year-old woman developed progressive, non-scarring alopecia while rheumatoid arthritis disease activity remained well controlled. Clinical and trichoscopic findings were consistent with AA, and laboratory investigations were unremarkable. The patient received serial intralesional triamcinolone at approximately 4-8 week intervals over a 14-month period, with progression in Severity of Alopecia Tool (SALT) score from approximately 20 to 50. Alopecia developed and progressed despite ongoing TNF-α inhibitor therapy and serial intralesional corticosteroids. Upadacitinib was initiated for rheumatoid arthritis management and escalated from 15 mg to 30 mg. Hair regrowth was observed within six weeks, with SALT improving to approximately 15 by three months. Although spontaneous remission and delayed corticosteroid effects cannot be excluded, the timing and magnitude of improvement support a temporal association with JAK1 inhibition. This case highlights a pragmatic therapeutic consideration when alopecia arises during TNF-α inhibitor therapy.
The recently introduced cardiovascular-kidney-metabolic (CKM) syndrome captures the close interplay between metabolic risk factors, chronic kidney disease, and cardiovascular disease, but insufficiently reflects the important additional role of the liver. Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide, is strongly associated with cardiovascular events, kidney disease progression, and all-cause mortality, yet remains frequently under-recognized in routine clinical practice. We propose the concept of a cardiovascular-kidney-liver-metabolic syndrome (CKLMS) and present a multidisciplinary, primary care-centered framework for its assessment and management. Based on expert consensus and current evidence, the framework integrates cardiovascular, renal, hepatic, and metabolic risk stratification using accessible, validated tools feasible in primary care, including blood pressure and lipid profiling, assessment of kidney function and albuminuria, non-invasive liver fibrosis testing, and systematic screening for diabetes and obesity. Management emphasizes early lifestyle intervention, use of pharmacological therapies with multi-organ benefit, and clearly defined referral pathways to specialist care. Primary care professionals are positioned as coordinators of longitudinal, patient-centered, multidisciplinary management. Early, integrated identification and treatment of CKLMS in primary care represents a pragmatic and effective strategy to prevent disease progression, reduce cardiovascular and kidney events, and improve long-term outcomes.
Keloid is a skin fibrosis disease characterized by continuous deposition of extracellular matrix and invasive expansion of the lesion. Hypochlorous acid (HOCl), an important member of the reactive oxygen family, has been proven to participate in the activation process of fibroblasts in various fibrosis diseases. However, the dynamic changes in keloid have not been fully explored. Herein, we constructed an activatable near-infrared fluorogenic (NIRF) probe DQFCl-HOCl for visualizing HOCl and exploring its association with the pathological activity of keloid. DQFCl-HOCl featured NIRF emission, rapid response, nanomolar-level detection sensitivity, and excellent selectivity. In cell models, DQFCl-HOCl could image exogenous and endogenous HOCl. More importantly, the HOCl fluorescence signal in keloid fibroblasts was markedly higher than that in normal dermal fibroblasts, and it decreased after intervention with RepSox or triamcinolone acetonide (TA). In a patient-derived xenograft model, DQFCl-HOCl could distinguish keloid tissue in mice and dynamically visualize the therapeutic effect of TA. Additionally, transcriptomic coexpression network analysis combined with Western blot results indicated that redox regulation pathways were closely coupled with the fibrotic signaling network centered on TGF-β. This work provided a new chemical imaging tool for tracing the redox microenvironment of keloid and evaluating therapeutic response.
Current classifications used for total knee arthroplasty (TKA) are static and fail to capture the dynamic behavior of the limb during gait. This study introduces a novel intraoperative method to measure dynamic hip-knee angle (dHKA) using an intra-articular device coupled with a computer-assisted orthopaedic surgery (CAOS) system. This device applies a quasi-constant distraction force throughout the knee joint range of motion. A machine learning (ML) model was utilized to identify natural data groupings and develop a classification based on patient-specific dHKA profiles. We analyzed dHKA before and after the femoral cut (tibia-first TKA workflow) and assessed how often post-cut clusters matched pre-cut clusters across surgeons. A total of 1,890 tibia-first TKA cases performed by 11 surgeons were reviewed. For each case, HKA angles were recorded at 12 flexion angles (0 to 120°) before and after the femoral cut. Using pre-cut data, a 12-dimensional map was created with each dimension representing the degree of HKA at a specific flexion angle. A K-means clustering model was trained on data collected before the tibial cut to identify alignment profiles. The trained model was then applied to data collected after the tibial cut for comparison. A subset of 141 TKA cases from a single surgeon who had one-year Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS Jr.) scores was analyzed to explore the association between cluster preservation and early functional outcomes. Clustering evaluation identified four clusters and an 8-dimensional feature space as optimal. Pre-cut/post-cut cluster distributions were cluster one (15.3%/14.2%), cluster two (35.9%/30.1%), cluster three (34.2%/35.6%), and cluster four (14.5%/20.2%). Cluster one was characterized as valgus and neutral, cluster two as neutral, cluster three as low to moderate varus, and cluster four as moderate to high varus. Overall, 69.4% of the cases retained the same cluster post-cut, with surgeon-specific match rates ranging from 61 to 88%. In the outcomes subset, 72.3% preserved their pre-cut cluster. Preservation was associated with greater KOOS Jr. improvement, with cluster-specific significance observed in low-to-moderate varus knees. This study demonstrates the first use of unsupervised ML to classify intraoperative dHKA profiles captured with a force-controlled intra-articular device and CAOS system. This enables real-time feedback and offers a foundation for an automated alignment classification guidance in personalized TKA.
Qapqal Xibe Autonomous County is located in the central Yili Basin of Xinjiang. It possesses significant potential for geothermal resource development, but the lack of in-depth research on deep geothermal genetic mechanisms and refined resource evaluation restricts its large-scale utilization. Therefore, this paper integrates regional geological surveys, borehole thermometry, geophysical exploration, and hydrochemical and isotopic tracing to reveal the formation mechanism of the geothermal field. Furthermore, it quantitatively evaluates the resource potential and analyzes uncertainties by combining the volumetric method, analytical method, and Monte Carlo simulations. The results indicate that the shallow geothermal gradient is 2.2 °C/100 m, while the deep gradient increases to 3.8 °C/100 m. The Gagestai Fault and its secondary faults serve as dominant channels for deep thermal fluid migration. The Cretaceous Donggou Formation and the Jurassic Badaowan Formation constitute a dual-layer high-quality reservoir, with measured reservoir temperatures of 42.50 °C and 91.25 °C, respectively. Isotopic and hydrochemical analyses infer that the geothermal water mainly originates from atmospheric precipitation and snowmelt in mountainous areas. After long-distance deep circulation, cation exchange, and heating by the basement heat source, the fluid upwells along the faults to accumulate, forming a typical layered confined fault-controlled geothermal system. Resource evaluation, verified by Monte Carlo simulations, demonstrates that the volumetric method exhibits higher robustness at the current exploration stage. The total recoverable heat in the study area is 8.19 × 1016 J, classifying it as a medium-sized geothermal field. Rational development of these resources could save approximately 2.75 × 106 tons of standard coal and reduce CO2 emissions by about 7.315 × 106 tons. This study provides key parameters and a scientific basis for geothermal resource development in the Yili Basin, holding significant practical value for promoting the clean energy industry in Xinjiang and achieving the "dual carbon" goals.
Cancer risks of individuals heterozygous for an ATM pathogenic or predicted pathogenic variant (PV/PPV) remain imprecise to guide optimal clinical management. Therefore, we aimed to estimate these risks in different family settings. Data were collected on 141 ataxia-telangiectasia families, 398 Hereditary Breast and Ovarian Cancer families and 96 families with a history of pancreatic cancer enrolled in French nation-wide epidemiological studies CoF-AT2, TUMOSPEC or GENESIS. Hazard ratios (HR) and cumulative risks were estimated using a modified segregation analysis method. An increased risk of breast and pancreatic cancers was observed for PV/PPV heterozygotes, and HRs were similar in the three family sets. When combined, HR were 4.0 (95%CI:2.9-5.6) for female breast cancer, 6.6 (95%CI:3.6-12.1) for female pancreatic cancer, and 2.8 (95%CI:1.4-5.5) for male pancreatic cancer. In birth cohort 1960-1969, female heterozygotes had a cumulative risk of breast cancer of 9.9% (95%CI:7.1%-13%) by age 50, and of 40% (95%CI:31%-51%) by age 80. Their risk of pancreatic cancer by age 80 was 8.1% (95%CI:4.3%-14%). The risk of male pancreatic cancer by age 80 was 5.1% (95%CI:2.4%-9.3%). No increased risk of ovarian and prostate cancers was observed. Our findings will help in the clinical management of families where an ATM PV/PPV segregates.