Fragmentation Techniques Research Articles

Development of Top-Down Mass Spectrometry Strategies in the Chromatographic Time Scale (LC-TD-MS) for the Extended Characterization of an Anti-EGFR Single-Domain Antibody-Drug Conjugate in Both Reduced and Nonreduced Forms.

Even though mAbs have attracted the biggest interest in the development of therapeutic proteins, next-generation therapeutics such as single-domain antibodies (sdAb) are propelling increasing attention as new alternatives with appealing applications in different clinical areas. These constructs are small therapeutic proteins formed by a variable domain of the heavy chain of an antibody with multiple therapeutic and production benefits compared with their mAb counterparts. These proteins can be subjected to different bioconjugation processes to form single-domain antibody-drug conjugates (sdADCs) and hence increase their therapeutic potency, and akin to other therapeutic proteins, nanobodies and related products require dedicated analytical strategies to fully characterize their primary structure prior to their release to the market. In this study, we report for the first time the extensive sequence characterization of a conjugated anti-EGFR 14 kDa sdADC by using state-of-the-art top-down mass spectrometry strategies in combination with liquid chromatography (LC-TD-MS). Mass analysis revealed a highly homogeneous sample with one conjugated molecule. Subsequently, the reduced sdADC was submitted to different fragmentation techniques, namely, higher-energy collisional dissociation, electron-transfer dissociation, and electron-transfer higher-energy collision dissociation, allowing to unambiguously assess the conjugation site with 24 diagnostic fragment ions and 85% of global sequence coverage. The sequence coverage of the nonreduced protein was significantly lower (around 16%); however, the analysis of the fragmentation spectra corroborated the presence of the intramolecular disulfide bridge along with the localization of the conjugation site. Altogether, our results pinpoint the difficulties and challenges associated with the fragmentation of sdAb-derived formats in the LC time scale due to their remarkable stability as a consequence of the intramolecular disulfide bridge. However, the use of complementary activation techniques along with the identification of specific ion fragments allows an improved sequence coverage, the characterization of the intramolecular disulfide bond, and the unambiguous localization of the conjugation site.

Study of the Effects of Different Dielectric Environments on the Characteristics of Electro-Explosive Discharge of Metal Wires and Shock Waves

The electrical explosive fragmentation technique has attracted widespread attention due to its environmental friendliness and high efficiency. However, the mechanism by which dielectrics influence rock fragmentation remains unclear. This study innovatively selected seven types of environmentally friendly dielectrics to systematically investigate their roles in the metallic wire electrical explosive rock fragmentation process. By precisely characterizing the crack morphology of concrete blocks, shock wave–strain responses, and discharge signal characteristics, the diverse mechanisms by which different dielectrics modulate rock fragmentation were revealed. The results indicate that oxide dielectrics release energy continuously through thermochemical reactions, highly conductive solutions accelerate energy deposition, and reductant suspensions generate strong secondary shock waves—all significantly outperforming tap water in terms of rock fragmentation performance. Notably, the energy deposition efficiency shows a nonlinear relationship with fragmentation effectiveness, influenced by factors such as energy release modes, dielectric composition, and bubble dynamics. The energy conversion mechanism of the electrical explosive rock fragmentation process studied in this paper provides a theoretical foundation for the fine-tuning, customization, and greening of electrical explosive rock fragmentation strategies in engineering practice.

Elucidating Tertiary Structures of Affibody in Vacuo Using Genetic Code Expansion and FRIPS Mass Spectrometry.

Radical-directed protein fragmentation techniques, particularly free radical-initiated peptide sequencing (FRIPS) mass spectrometry (MS), offer significant potential for elucidating protein structures in the gas phase. This study presents a novel approach to protein structural analysis in vacuo, combining FRIPS MS with genetic code expansion (GCE) technology. By incorporating unnatural amino acids (UAAs) at specific sites within an Affibody protein, we effectively introduced a radical precursor at six distinct positions. The study explores structural information derived from radical-directed fragmentations by analyzing the proximity and pathways of radical transfer within the protein's tertiary structure. Our findings reveal that in the lowest charge state (+5), the Affibody retains a folded conformation resembling its native structure, with significant radical-directed fragmentations occurring through both "through-sequence" and "through-space" mechanisms. These results demonstrate the potential of FRIPS MS to provide residue-specific insights into protein folding and structural information in the gas phase, paving the way for a more detailed protein structure analysis.

Modeling the propagation of hydraulic fractures in reservoirs with natural fracture networks using high aspect ratio interface elements

The application of hydraulic fracturing in unconventional reservoirs is a technique widely used to overcome the problem of low permeability in porous media. However, there are complex factors involved in understanding this technique, since the propagation of hydraulic fractures can be impacted by factors such as the state of stress in situ and the distribution of natural fractures, which may have different lengths, inclination angles and aperture values. Thus, based on the continuum mechanics and using the finite element method, this paper seeks to simulate the effect of hydraulic fracturing in porous media with a complex natural fractures network under the influence of different stress states. The modeling of the problem considers a fully coupled approach for solving the hydro-mechanical problem, with the Darcy’s law governing the fluid flow in the porous media and by the classical cubic law inside the fractures. For the representation of natural and hydraulic fractures, High Aspect Ratio Interface Finite Elements (HAR-IEs) associated with a suitable tensile damage model are used and inserted into the regular mesh via the Mesh Fragmentation Technique (MFT). The results obtained are validated with the literature and show that the model is capable of reproducing the complex scenarios of propagation and interaction between multiple fractures.

The effects of mild traumatic brain injury induced by a low‐intensity blast exposure on phosphoproteome networks and cognitive function influenced by mutant tau overexpression

AbstractBackgroundThis study was to elucidate the impact of blast‐induced neurotrauma (BINT) on phosphoproteome networks and cognition in a genetically heterogeneous population of mice (rTg4510) with the human tau P301L mutation linked to Alzheimer’s disease‐related dementia (ADRD) including frontotemporal dementia.MethodMild traumatic brain injury was induced in rTg4510 mice exposed to a single low‐density blast (LIB) at an upright position. After assessment of cognitive function by the automated‐Home Cage Monitoring (aHCM) system, frontal cortex tissue was collected at 40 days post‐injury. The label‐free tandem mass spectrometry using the data‐independent acquisition and parallel accumulation‐serial fragmentation techniques for quantitative proteomics and weighted peptide co‐expression‐network analysis (WpCNA) approaches were used to evaluate phosphoproteomes in association with synaptic function and learning ability.ResultIn this study, blast‐exposed rTg4510 mice demonstrated a lower learning index, using the CognitionWall test by aHCM, compared to all other groups including non‐carrier unexposed sham controls. Among total 17,637 phosphopeptides identified, 706 and 550 were significantly changed in rTg4510 and non‐carrier LIB‐exposed mice relative to unexposed sham controls, respectively. Using WpCNA, we found phosphopeptide networks tied to associative learning and mossy‐fiber pathways, which predicted learning outcomes. Phosphopeptide expression in these networks were inversely related to learning and linked to synaptic dysfunction, cognitive decline, and dementia. LIB selectively increased pSer262 Tau in rTg4510, a site implicated in initiating tauopathy.ConclusionThis study unveils the relationship between ADRD genetic susceptibility, BINT, and cognitive decline, thus offering potential pathways as therapeutic targets for precision medicine to alleviate the disease burden among those affected by BINT.

Optimizing the Appropriate Mode of the Pulse-modulated Holmium Laser in a Pop-dusting Benchtop Model.

To investigate the effectiveness of different holmium:yttrium-aluminum-garnet (Ho:YAG) laser modes for lithotripsy in the "dusting era" and identify the optimal laser mode for producing stone fragments measuring ≤0.5mm. We used plaster of Paris-made artificial stones crushed into 2-3 mm pieces, weighing 1g in total. The primary endpoint was the mass of stone fragments ≤0.5mm produced by different laser modes. The secondary endpoints were size categories, fragment mass, and changes in irrigation fluid temperature. The Lumenis Pulse 120H Ho:YAG laser, with a 200-μm fiber, was used in 3 modes (Moses contact [MC], Moses distance [MD], and long pulse [LP], all at 0.5J×80Hz). Laser lithotripsy involved a 20-second exposure with a 10-second pause for 15 cycles, conducted 7 times per mode while measuring the maximum irrigation fluid temperatures for each cycle. The MC mode demonstrated superior performance in producing fragments ≤0.5mm (P =.0034) compared with the MD mode. No notable differences were observed for other size categories. The MD and LP modes showed higher rates of mass loss in fluid (MD, P =.023; LP, P =.046) compared with the MC mode. In addition, the increase in irrigation fluid temperature was more pronounced in the MD and LP modes than in the MC mode (MD, P =.015; LP, P =.010). In renal stone lithotripsy during the "dusting era," the MC mode is preferable for generating smaller stone fragments ≤0.5mm. These insights are valuable for optimizing stone fragmentation techniques.

DigFrag as a digital fragmentation method used for artificial intelligence-based drug design

Fragment-Based Drug Design (FBDD) plays a pivotal role in the field of drug discovery and development. The construction of high-quality fragment libraries is a critical step in FBDD. Conventional fragmentation approaches often rely on rigid rules and chemical intuition, limiting their adaptability to diverse molecular structures. The rapid development of Artificial Intelligence (AI) technology offers a transformative opportunity to rethink traditional methods. Here, we present DigFrag, a digital fragmentation method that highlights important substructures by focusing locally within the molecular graph. In addition, we feed the fragments segmented by machine intelligence and human expertise into the deep generative model to compare the preference for data from different sources. Experimental results show that the structural diversity of fragments segmented by DigFrag is higher, and more desirable compounds are generated based on these fragments. These results also demonstrate that data generated based on AI methods may be more suitable for AI models. Moreover, a user-friendly platform called MolFrag (https://dpai.ccnu.edu.cn/MolFrag/) is developed based on various fragmentation techniques to support molecular segmentation.

How Technical Advances Changed the Concept of Antibodies.

Shaped by advances in scientific instrumentation and experimental techniques, the concept of antibody has undergone profound transformations throughout the history of immunology. Serological assays, separation techniques, protein fragmentation techniques, molecular biology techniques, and other methodological innovations did not only serve to produce data on the structure and function of these molecules but, by framing antibodies into a unique facet of experimental investigation, were effectively redefining and reconceptualizing these molecules for the scientific community. The characteristics and properties of antibodies observed in experimental settings were often directly extrapolated to their presumed nature in living organisms, as exemplified by the literal identification of antibodies with a gamma electrophoretic fraction in the 1930s. Stemming from parallel advances in related fields such as molecular biology and biochemistry, the introduction of novel techniques was driving shifts in the field of immunology, establishing novel frameworks of theoretical conceptualization and understanding. Technological innovation in experimental techniques continues to shape our view of these molecules, driving progress in both basic immunology and therapeutic applications.

Comparison of different fragmentation techniques for the production of true-to-life microplastics

Microplastics are small plastic particles found widely in the environment, posing significant challenges as diverse environmental contaminants. Their pervasive presence and potential impacts on ecosystems and human health underscore the importance of research in this field. However, working with microplastics in the laboratory and field can be challenging due to the difficulty in creating particles that are similar to those found in the environment. The advancement of research in this area is, therefore, dependent on the availability of reference materials or representative test materials that can simulate real-world conditions. One of the biggest challenges in creating more relevant test microplastics is investigating processes that can mimic as close as possible the environmental counterpart. To tackle this challenge, we have explored three distinct cryogenic grinding techniques for generating microplastics on a laboratory scale (ultracentrifugal mill, immersion blender, mixer mill). The resulting products were examined, and the advantages and limitations of the technologies were analyzed to gain deeper insights into the correlation between the various techniques utilized and the distinctive characteristics of the “true-to-life” microplastics produced. This allows us to tailor the production of test materials to the specific research questions they are intended to address. Furthermore, by understanding the characteristics of true-to-life microplastics, we can gain insights into their behavior under various environmental conditions. This knowledge can help in developing better methods for detecting and monitoring microplastics in the environment, as well as developing more effective mitigation strategies to reduce their impact.

Advances in Mass Spectrometry Fragmentation Techniques for Peptide and Protein Characterization: CID to ETD

Mass spectrometry (MS) has transformed the field of proteomics by enabling the precise analysis of proteins and peptides at the molecular level. The heart of this analysis is the process of fragmentation, which plays a pivotal role in elucidating amino acid sequence, identifying post-translational modifications (PTMs), and characterizing structural features. Peptides and proteins are first ionized and then subjected to fragmentation techniques such as Collision-Induced Dissociation (CID), Electron-Transfer Dissociation (ETD), and Electron-Capture Dissociation (ECD). These techniques induce fragmentation along the peptide backbone, generating characteristic fragment ions (b and y ions, c and z ions) that reflect the sequence of amino acids. The mass-to-charge (m/z) ratios of these fragment ions provide crucial data for de novo sequencing and PTM identification. Furthermore, fragmentation patterns can reveal insights into protein folding, interactions, and dynamics. This article provides the detailed view of mass fragmentation techniques in peptides and proteins, highlighting its importance in advancing proteomic research and its applications in fields ranging from biomarker discovery to drug development.

Michael Tippett: Specification of the Work for Orchestra and Soprano "Byzantia"

The purpose of the research is to reveal the deep image-sound layers and features of the Irish bardic tradition in the work of M. Tippett through the prism of the work for orchestra and soprano "Byzantium". The methodological basis of the research is historical-conceptual, hermeneutic method and comparative analysis of factual data based on the works of Thomas Weiskel, David Clark, Edward Venn, and Meirion Bowen. Scientific novelty. For the first time in the Ukrainian art history segment, M. Tippett's work for orchestra and soprano "Byzantium" was analysed with an emphasis on the dramaturgy of the composition, cyclical elements, metaphorical sound images, symbolism and characteristic features of the musical and poetic tradition of Irish bards. Conclusions. Biographical collisions of M. Tippett influenced his creative aspirations and attitude to the surrounding world. M. Tippett's aesthetic views are a dialogue between romantic aspirations and sceptical realism of the modern era. Michael Tippett's musical language absorbed both tradition and the entire palette of accumulated world musical experience, as well as duality of meanings, symbolism, imagery and conflict. The work analyses the composition for orchestra and soprano "Byzantium" by M. Tippet, which is based on the mosaic of images, the logical sequence of musical motifs, and cyclicity. It is necessary to highlight the fragmentary nature of musical sections, variable motifs, the presence of contrasting material, the symbolism of magical, changing life force as secular ephemerality, the destruction of the musical text using the technique of expansion and fragmentation. Thus, the composition "Byzantium" is a reincarnation of Irish cultural nationalism in the aspect of traditional forms of bardic poetry. The musical language of M. Tippett in the work "Byzantium" is based on the forms crystallised by the work of L. Beethoven and updated by the musical context of modern and postmodern.

Strategies for Top-Down Hydrogen Deuterium Exchange-Mass Spectrometry: A Mini Review and Perspective.

Hydrogen deuterium-exchange mass spectrometry (HDX-MS) is commonly used in the study of protein dynamics and protein interactions. By measuring the isotopic exchange of backbone amide hydrogens in solution, HDX-MS offers valuable structural insights into challenging biological systems. Traditional HDX-MS approaches utilize bottom-up (BU) proteomics, in which deuterated proteins are digested before MS analysis. BU-HDX enables the characterization of proteins with various sizes in simple protein mixtures or complex biological samples such as cell lysates. However, BU methods are inherently limited by the inability to resolve protein sub-populations arising from different protein conformations, such as those arising from post-translational modifications (PTMs). Alternatively, top-down (TD) HDX-MS detects the global deuterium uptake at the intact proteoform level, allowing direct probing of structural changes due to protein-protein interactions, PTMs, or conformational changes. Combining TD-HDX-MS with electron-based fragmentation techniques, such as electron capture dissociation (ECD) and electron transfer dissociation (ETD), has demonstrated the feasibility of studying intact protein interactions with amino acid-level resolution. Here, we present a brief overview of methodologies, limitations, and applications of TD-HDX-MS using direct infusion techniques and LC-based approaches. Furthermore, we conclude with a perspective on the future directions for TD-HDX-MS.

A 3D-Planned Inward Fragmentation Technique for the Removal of Impacted Mandibular Third Molars: A Case Series.

Background/Objectives: The extraction of impacted mandibular third molars (M3Ms) carries significant risks, especially regarding the inferior alveolar nerve (IAN). This study aimed to evaluate the effectiveness of a 3D-planned inward fragmentation technique (3Dp-IFT) to improve surgical outcomes, reduce complications, and preserve bone structure in cases involving complex M3M impactions. Methods: Twenty-three patients aged between 18 and 36 years requiring M3M removal were included. Preoperative planning involved the use of cone-beam computed tomography (CBCT) for precise localization of the furcation area, followed by the creation of a 3D navigation template using PlastyCAD software version 1.7. The surgical procedure was performed under local anesthesia, with meticulous endoscopic assistance to ensure accurate access and minimize trauma. Postoperative outcomes, such as bone loss, pain, swelling, and mouth opening range, were carefully measured. The data were systematically organized and analyzed descriptively using Microsoft Excel. Results: No disturbances to the IAN or lingual nerve were observed. The mean buccal bone loss was 2.2 mm, with a standard deviation of 1.2 mm. Postoperative pain and swelling were generally low, with significant reductions within the first week. The use of the 3D navigation template significantly improved surgical access, enhancing safety and minimizing complications. Conclusions: The 3Dp-IFT technique represents a significant advancement in the minimally invasive removal of M3M by allowing precise access to critical anatomical areas while minimizing bone loss and postoperative complications. This approach is particularly beneficial for complex cases involving M3M near the IAN, thereby improving surgical safety and patient outcomes.

Current status and future perspectives for endoscopic treatment of local complications in chronic pancreatitis.

Chronic pancreatitis is a progressive disease characterized by irregular fibrosis, cellular infiltration, and parenchymal loss within the pancreas. Chronic pancreatitis treatment includes lifestyle modifications based on disease etiology, dietary adjustments appropriate for each stage and condition, drug therapy, endoscopic treatments, and surgical treatments. Although surgical treatments of symptomatic chronic pancreatitis provide good pain relief, endoscopic therapies are recommended as the first-line treatment because they are minimally invasive. In recent years, endoscopic therapy has emerged as an alternative treatment method to surgery for managing local complications in patients with chronic pancreatitis. For pancreatic stone removal, a combination of extracorporeal shock wave lithotripsy and endoscopic extraction is used. For refractory pancreatic duct stones, intracorporeal fragmentation techniques, such as pancreatoscopy-guided electrohydraulic lithotripsy and laser lithotripsy, offer additional options. Interventional endoscopic ultrasound has become the primary treatment modality for pancreatic pseudocysts, except in the absence of disconnected pancreatic duct syndrome. This review focuses on the current status of endoscopic therapies for common local complications of chronic pancreatitis, including updated information in the past few years.

Towards a universal method for middle-down analysis of antibodies via proton transfer charge reduction-Orbitrap mass spectrometry.

Modern mass spectrometry technology allows for extensive sequencing of the ~ 25kDa subunits of monoclonal antibodies (mAbs) produced by IdeS proteolysis followed by disulfide bond reduction, an approach known as middle-down mass spectrometry (MD MS). However, the spectral congestion of tandem mass spectra of large polypeptides dramatically complicates fragment ion assignment. Here, we report the development and benchmark of an MD MS strategy based on the combination of different ion fragmentation techniques with proton transfer charge reduction (PTCR) to simplify the gas-phase sequencing of mAb subunits. Applied on the liquid chromatography time scale using an Orbitrap Tribrid mass spectrometer, PTCR produces easy-to-interpret mass spectra with limited ion signal overlap. We demonstrate that the accurate estimation of the number of charges submitted to the Orbitrap mass analyzer after PTCR allows for the detection of charge-reduced product ions over a wide mass-over-charge (m/z) window with low parts per million m/z accuracy. Therefore, PTCR-based MD MS analysis increases not only sequence coverage, number of uniquely identified fragments, and number of assigned complementary ion pairs, but also the general confidence in the assignment of subunit fragments. This data acquisition method can be readily applied to any class of mAbs without an apparent need for optimization, and benefits from the high resolving power of the Orbitrap mass analyzer to return sequence coverage of individual subunits exceeding 80% in a single run, and > 90% when just two experiments are combined.

The interplay between bounded ranks of tensors arising from partitions

AbstractLet be integers. Using a fragmentation technique, we characterise ‐tuples of non‐empty families of partitions of such that it suffices that an order‐ tensor has bounded ‐rank for each for it to have bounded ‐rank. On the way, we prove power lower bounds on suitable products of diagonal tensors, providing a qualitative answer to a question of Naslund.

Comparative analysis of feature annotation methods for SESI-HRMS in exhaled breath analysis

Secondary electrospray ionization coupled to high-resolution mass spectrometry (SESI-HRMS) is a powerful method for the analysis of exhaled breath in real time. However, feature annotation is challenging due to the flow-injection nature of the technique. To evaluate alternative methods for enhancing feature annotation, a study was conducted where the exhaled breath of sixteen subjects was condensed and analyzed using dynamic headspace vacuum in-trap extraction gas chromatography-mass spectrometry (DHS-V-ITEX-GC–MS) and liquid chromatography coupled to mass spectrometry (LC-MS) using polar and reverse-phase conditions along with a data-independent MS2-acquisition method based on multiple injections. The annotation results obtained from these methods were compared to those from SESI-HRMS. The use of these techniques on breath condensate is unprecedented. The GC–MS method primarily detected compounds of exogenous origin, particularly additives in oral hygiene products like menthol. On the other hand, LC-MS detected a vast number of features, especially with the utilized data-independent acquisition method. Chemical classes to these features were assigned in-silico. In positive ion mode, mostly amino acids and amines were detected, while the largest group in negative ion mode consisted of carboxylic acids. Approximately 25% and 5% of SESI features had a corresponding match with LC-MS and GC–MS. While both GC–MS and LC-MS methods partially overlapped with the SESI features, there was limited overlap of both in the mass-to-charge range from 150 to 200. In conclusion, both GC–MS and LC-MS analysis of breath condensate can serve as supplementary tools for annotating features obtained from SESI-MS. However, to increase confidence in the annotation results, combining these methods with additional on-line fragmentation techniques is recommended.

Identification and screening of umami peptides from skipjack tuna (Katsuwonus pelamis) hydrolysates using EAD/CID based micro-UPLC-QTOF-MS and the molecular interaction with T1R1/T1R3 taste receptor

In this study, the enzymatic hydrolysates of skipjack tuna, Katsuwonus pelamis, were purified by ultrafiltration and further identified through micro-ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (micro-UPLC-QTOF-MS). The potential umami peptides were identified using both conventional collision-induced dissociation (CID) and novel electron-activated dissociation (EAD) fragmentation techniques. Nine novel umami peptides with iUmami-SCM > 588 were screened. Sensory evaluation and electronic tongue analysis were performed to confirm the taste characteristics of the umami peptides, indicating that these umami peptides all exhibited varying degrees of umami taste. Molecular docking and molecular dynamics simulation were utilized to investigate the interaction with T1R1/T1R3 taste receptors. The docking results revealed that Asp234, Ser23, Glu231, and Ile237 appeared most frequently in all docking sites and formed stable complexes through hydrogen bonding and electrostatic interactions. Furthermore, molecular dynamics simulation allowed for a more comprehensive analysis of their interactions within a dynamic environment, providing a deeper understanding of the umami perception mechanism involving umami peptides and receptors.

Mixed fragmentation technique for securing structured data using multi-cloud environment (MFT-SSD)

Large data storage security is a topic of great interest to researchers, particularly in the age of big data where preserving data from theft, unauthorized access, and storage failure has become a crucial concern. To safeguard such data, encryption/decryption approaches have been employed, which are time-consuming and inefficient. The aim of this study is to develop a method, namely Mixed Fragmentation Technique for Securing Structured Data using Multi-Cloud Environment (MFT-SSD), for protecting large-scale data stored in a multi-cloud environment. This prevents insider attacks by adopting a mixed fragmentation approach to split the data into three files. For example, healthcare data is will be distributed among many clouds, each of which stores a partially unrecognized fraction of data without the need for an encryption or decryption layer. Comparing MFT-SSD to various encryption/decryption algorithms, our results show significant improvement; hence, the total performance of big data security is also improved.

Modeling the effect of material heterogeneity on the thermo-mechanical behavior of concrete using mesoscale and stochastic field approaches

The adverse impact of high temperatures on concrete is a well-recognized issue that can lead to significant mechanical deterioration and structural integrity loss. Factors such as aggregate type, cement composition, temperature, duration of exposure, and moisture content can substantially influence the fire resistance of concrete. To simulate and better understand the effects arising from the heterogeneity of concrete in a fire situation, a mesoscale approach is proposed, using the Mesh Fragmentation Technique (MFT) to assess the complex thermo-mechanical behavior of concrete. The MFT introduces high aspect ratio interface elements to model crack propagation and interfacial transition zones by means of an appropriated tensile damage constitutive law. In this extended framework, a fully-coupled thermo-mechanical model is proposed. The modeling approach includes considerations of both macroscopic and mesoscopic scales, in which the coarse aggregate, mortar matrix and interfacial transition zones are represented. Besides, a stochastic distribution is assumed for the material properties to account for the lower scale heterogeneity. The main novelty proposed in this study consists in the synergy of mesoscale and stochastic approaches that are herein combined to model the effect of heterogeneity on the concurrent macro-mesoscale thermo-mechanical behavior of concrete. To validate the numerical model’s capabilities in capturing thermally induced cracks, benchmark cases and a simulation of a bending beam exposed to elevated temperatures are presented. The results demonstrate the potential of the proposed approach in predicting the behavior of concrete subjected to thermal loading and the role played by heterogeneity in the thermally induced cracking.