A targeted therapy already transforming treatment for hypertrophic cardiomyopathy (HCM) may be effective across a broader range of disease-causing genetic mutations than previously understood, according to new preclinical research published in Nature Cardiovascular Research.
The study identifies a previously unknown molecular mechanism underlying one of the most common inherited forms of HCM and demonstrates that the cardiac myosin inhibitor mavacamten—the first targeted therapy available for this condition—can reverse disease-associated changes, even when the underlying biology differs from that of the patients for whom the drug was originally developed.
HCM affects approximately one in 200 to 500 people and is the leading cause of sudden cardiac death in young adults and athletes. The disease is characterized by abnormal thickening of the heart muscle, impaired relaxation, and excessive contractility, which can ultimately lead to heart failure, arrhythmias, and sudden cardiac death.
Most inherited cases are caused by variants in either MYH7, which encodes the molecular motor myosin, or MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), an important regulator of cardiac muscle contraction.
While truncating mutations in MYBPC3 reduce levels of cMyBP-C and promote excessive myosin activity, much less has been known about how missense mutations—which preserve protein levels but alter protein function—drive disease.
To investigate this question, researchers generated a knock-in mouse model carrying the R502W missense mutation, one of the most common pathogenic MYBPC3 variants found in patients with HCM. Unlike mice lacking cMyBP-C, the R502W animals maintained normal amounts and localization of the protein yet still developed hallmark features of hypertrophic cardiomyopathy, including cardiac hypertrophy, fibrosis, impaired cardiac function, and hypercontractility.
“Our findings support that mutation-induced loss of interactions between the central domains of cMyBP-C and myosin is a molecular pathomechanism in HCM that can be targeted by myosin inhibitors,” the authors write.
Rather than reducing protein abundance, the mutation weakened the interaction between cMyBP-C and myosin, shifting more myosin molecules into an active structural state capable of generating contraction. The mutation also increased calcium sensitivity, together producing excessive contractile force.
Importantly, these abnormalities arose through a mechanism distinct from the loss-of-protein pathway associated with truncating MYBPC3 mutations.
Despite these divergent disease mechanisms, treatment with mavacamten significantly reduced pathological remodeling in both the R502W mice and animals lacking cMyBP-C. The drug also restored a more normal inactive structural state of myosin in mutant heart muscle and reduced excessive contraction in engineered human heart tissues carrying the same mutation.
“Hence, our data and evidence in the literature suggest that mavacamten is equally effective for carriers of any pathogenic variant in MYH7 or MYBPC3,” the authors conclude. The findings may help explain why genetic differences alone are unlikely to account for the variable clinical responses observed in patients receiving mavacamten.
The work also has implications beyond current therapies. Because some emerging gene therapies aim to replace cMyBP-C rather than correct mutant protein function, the authors suggest those approaches may be less effective for patients carrying missense mutations such as R502W. By contrast, gene-editing strategies capable of directly correcting single-base mutations may prove particularly promising.
The researchers also propose that the newly developed mouse model more closely resembles the relatively mild progression of human hypertrophic cardiomyopathy than previous models based on complete cMyBP-C deficiency, making it a valuable platform for testing future therapies and studying disease biology.
Looking ahead, the investigators suggest that most patients carrying pathogenic MYBPC3 variants could potentially benefit from myosin inhibition regardless of the mutation’s underlying molecular mechanism.
“Our preclinical data indicate that all carriers of pathogenic variants in MYBPC3, arguably the most common cause of HCM, may similarly benefit from myosin inhibition regardless of diverging specific pathomechanisms,” the authors conclude. They add that the limited effectiveness of mavacamten observed in some patients is “probably due to reasons other than the specific HCM variants they carry,” including disease stage, environmental influences, or other genetic factors.
Background: Asynchronous online forums provide flexible, accessible peer support for many people living with dementia and carers. Moderators are central to the functioning of these communities, yet little is known about their experiences. Objective: This study explored the experiences of individuals moderating an online dementia forum, including their motivations, perceived benefits, challenges, and suggestions for improvements. Methods: Moderators from a UK-based online dementia support forum were recruited using purposive sampling via forum administrators. Between January and March 2025, 5 moderators, all with dementia care experience, participated in remote semistructured interviews. Interview topics included pathways into moderation, perceptions of the moderator role, experiences of supporting forum members, challenges encountered, perceived personal benefits, and views on the future development of online support communities. Interviews were transcribed verbatim and analyzed using reflexive thematic analysis. Results: Four themes were produced: (1) “from support seeker to support provider”: moderators primarily identified as community members rather than authority figures, following a trajectory from receiving support as a carer to actively facilitating community support; (2) “understanding through shared experience”: lived experience of dementia was seen as essential for empathy, credibility, and sensitive responses, though sometimes prompted strong emotional reactions; (3) “giving back and gaining in return”: moderation offered purpose, structure, and social connection, particularly postretirement and following transition out of caring; (4) “balancing growth with community preservation”: forum expansion increased workload, spam management demands, and safeguarding responsibilities, and moderators were cautious about social media–style features and artificial intelligence–generated content undermining the effectiveness of support exchanges. Conclusions: Moderators play a crucial, value-driven role in sustaining dementia support forums, extending beyond administrative duties. The findings suggest that moderators occupy a distinctive position as both recipients and providers of peer support, drawing on experiential expertise to maintain trust and community cohesion. Forum growth and technological innovations present opportunities and challenges, highlighting the need to balance scalability with authenticity in online support communities.
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The U.S. Food and Drug Administration has cleared CoRegen’s Investigational New Drug (IND) application for CRG-150, allowing the company to initiate a first-in-human Phase I/IIa clinical trial of its autologous CRISPR-engineered regulatory T (Treg) cell therapy in patients with advanced solid tumors. The study will evaluate safety and preliminary efficacy in metastatic triple-negative breast cancer (TNBC), metastatic HR-positive/HER2-negative breast cancer, and metastatic prostate cancer at leading academic cancer centers.
The clearance advances into the clinic an immunotherapy strategy that differs fundamentally from existing cell therapies. Rather than engineering cytotoxic lymphocytes to recognize tumor antigens, CRG-150 uses CRISPR gene editing to reprogram regulatory T cells (Tregs), with the goal of reversing the immunosuppressive tumor microenvironment and restoring endogenous antitumor immunity.
The approach emerged from more than three decades of research at Baylor College of Medicine on steroid receptor coactivator-3 (SRC-3), a transcriptional regulator that sits upstream of numerous immune signaling pathways. According to CoRegen, CRISPR-mediated disruption of SRC-3 fundamentally alters Treg biology, removing one of the mechanisms tumors use to evade immune surveillance.
Suneet Varma, Chairman of the Board at CoRegen [Baylor College of Medicine]
“What was fantastic about this discovery was that it allowed us to engineer a regulatory T cell to knock out SRC-3,” said Suneet Varma, chairman of the board of CoRegen. “By knocking out SRC-3, we have essentially removed the cloak of invisibility that cancer was hiding behind. Once you remove that cloak of invisibility, the tumor is recognized by the immune system, and CD4-positive T cells, CD8-positive T cells, and natural killer cells flood the tumor.”
The company reports that preclinical studies in multiple murine solid tumor models demonstrated durable tumor eradication following treatment with SRC-3-disrupted regulatory T cells. Investigators subsequently rechallenged animals with the original tumor and observed rapid elimination consistent with immunologic memory. In additional experiments, mice challenged with different tumor types, including pancreatic cancer after initial treatment of triple-negative breast cancer, also mounted antitumor responses, suggesting that the mechanism may not depend on a single tumor antigen or histology. Those findings now await validation in humans.
“This is a new, never-been-done-before approach to immuno-oncology,” Varma said. “We’ve cured many, many mice. But we need to now treat and cure humans. There’s a lot of work between here and there.”
Reversing the biology of immune suppression
Since the identification of FOXP3 as the master transcription factor governing regulatory T-cell development more than two decades ago, Tregs have become recognized as essential regulators of immune homeostasis. By suppressing excessive immune activation, they prevent autoimmunity and maintain peripheral tolerance. The same biology, however, is frequently co-opted by cancer. Many solid tumors recruit or expand Tregs within the tumor microenvironment, where they suppress cytotoxic T lymphocytes and natural killer (NK) cells, limiting endogenous antitumor immunity and contributing to resistance against immunotherapy.
That dual biology has made Tregs both attractive and challenging therapeutic targets. Most clinical development in the field has focused on harnessing their suppressive properties. Multiple companies are developing autologous, allogeneic, and CAR-engineered Treg therapies for autoimmune diseases, inflammatory disorders, and transplantation, where augmenting immune tolerance is desirable. By contrast, relatively few cell therapy programs have sought to manipulate Tregs in oncology because selectively disrupting their immunosuppressive function without broadly compromising immune regulation has proven difficult.
For example, last week, the FDA approved Orca Bio’s Tregzi, an unmodified donor-derived cell therapy designed as an alternative to traditional matched-donor stem cell transplantation for blood cancer patients. The therapy uses three purified donor cell populations—including regulatory T cells, conventional T cells, and hematopoietic stem and progenitor cells—selected to preserve immune control while supporting blood system recovery. By leveraging naturally occurring immune-regulating cells, Tregzi aims to reduce complications such as chronic graft-versus-host disease, marking a key milestone for the broader effort to harness Tregs as a next-generation approach in cancer treatment.
Sonal Gupta, MD, PhD, Chief Medical Officer at CoRegen [CoRegen]
CoRegen’s strategy is to alter Treg biology directly through CRISPR-mediated disruption of SRC-3, a steroid receptor coactivator that functions as a transcriptional regulator upstream of numerous immune signaling pathways. Sonal Gupta, MD, PhD, chief medical officer of CoRegen, explained that SRC-3 occupies a regulatory position upstream of numerous genes involved in immune signaling, including pathways associated with immune checkpoint regulation. “What we do is use CRISPR editing to knock out the SRC-3 gene,” Gupta told Inside Precision Medicine. “That changes the biology of regulatory T cells.”
She compares unmodified Tregs to “bouncers at a nightclub,” preventing immune cells from entering tumors. Following gene editing, the cells no longer maintain that suppressive phenotype, allowing endogenous immune cells to infiltrate the tumor microenvironment. Unlike checkpoint inhibitors, which interrupt individual inhibitory pathways such as PD-1/PD-L1 or CTLA-4, the company hypothesizes that reprogramming Tregs through SRC-3 disruption may produce broader remodeling of tumor immune suppression.
The therapy is also differentiated from CAR T cells. “CAR T cells directly kill the cancer cells by targeting something on the cancer cell, and, in our case, we genetically modify regulatory T cells,” said Gupta. “Regulatory T cells play a very important role in the tumor microenvironment. They basically do not allow the endogenous immune system to kill the cancer. When we gene-modify them the way we do, they allow the endogenous immune system to enter and kill the cancer cells.”
From laboratory discovery to first-in-human testing
The origins of CRG-150 trace back more than three decades to the laboratory of the late Bert W. O’Malley, MD, at Baylor College of Medicine. O’Malley, widely regarded as one of the founders of molecular endocrinology, spent much of his career studying steroid receptor coactivators (SRCs), proteins that regulate large transcriptional networks controlling cellular behavior.
According to Varma, bringing that body of work together with advances in regulatory T-cell biology transformed a long-running academic research program into a therapeutic platform. “Our goal was to take this tremendous body of evidence and receptor biology and move what was in an academic laboratory into a biotech environment where we could demonstrate the potential impact in patients,” he said.
CRG-150 begins with collection of autologous peripheral blood cells rather than bone marrow. Regulatory T cells are isolated, edited using CRISPR to disrupt SRC-3, expanded ex vivo, and then reinfused into the patient.
Gupta believes beginning with an autologous product provides the strongest opportunity to demonstrate proof of concept. “Autologous really is the gold standard,” she said. “Because the cells come from the patient, they’ve already been exposed to the tumor antigens.”
Another potentially important distinction is the absence of lymphodepleting chemotherapy prior to treatment. Current CAR T therapies typically require depletion of endogenous lymphocytes before infusion, adding toxicity and limiting outpatient administration. “Unlike CAR T cells, these patients do not have to undergo depletion and have their immune system knocked out before receiving therapy,” Gupta said. “There is potential for this therapy to actually be outpatient.”
Varma noted that because the therapy relies on a standard blood collection rather than more invasive procedures, the collection process should also be broadly accessible. “Not all autologous therapies are created equal,” he said. “We wanted the process to be as simple as possible and the vein-to-vein time as manageable as possible.”
The company has partnered with Lonza under a multi-year manufacturing agreement to support clinical production. Varma said manufacturing consistency formed an important component of the IND package reviewed by the FDA. “The FDA concurred that we had achieved what we needed to achieve to proceed,” he said.
Gupta added that recent advances in Treg manufacturing have substantially improved the feasibility of clinical development. “Being able to expand regulatory T cells to generate sufficient doses for patients has been a very important advance,” she said.
Testing a new therapeutic paradigm
Historically, novel oncology therapies enter clinical testing in heavily pretreated patients before moving into earlier treatment settings if efficacy is demonstrated. Varma believes CRG-150 may ultimately challenge that paradigm because its mechanism depends on mobilizing endogenous immunity. “We would really benefit from a healthier immune system, since that’s what we’re activating,” he said. “Scientifically, it suggests the therapy should ultimately be used earlier.”
The initial study, however, appropriately begins in advanced disease. The Phase I/IIa trial will use a dose-escalation and cohort-expansion design. Phase I will establish safety and identify the recommended Phase II dose, followed by expansion cohorts evaluating preliminary efficacy in metastatic TNBC, HR-positive/HER2-negative breast cancer, and metastatic prostate cancer. According to Gupta, the long-term objective is to generate sufficient data to support discussions with the FDA regarding a subsequent registration study.
The company reports strong interest from academic investigators participating in the study. “We’ve had more interest from clinical sites than we can currently support,” Varma said.
The FDA clearance positions CoRegen within a rapidly evolving landscape of engineered immune cell therapies. Most current Treg programs are directed toward restoring immune tolerance in autoimmune disease or transplantation, whereas oncology developers have largely focused on engineered effector cells such as CAR T cells, T-cell receptor-engineered T cells, and tumor-infiltrating lymphocytes. CRG-150 occupies a distinct niche by seeking to reprogram, rather than expand or eliminate, regulatory T cells within the tumor microenvironment.
The company is already exploring future iterations of the platform, including allogeneic products and in vivo approaches, as well as expansion into additional tumor types including pancreatic cancer, glioblastoma, melanoma, colorectal cancer, and non-small cell lung cancer. For now, however, the focus is on determining whether a strategy that has generated durable immune responses across multiple preclinical solid tumor models can safely translate into patients. The Phase I/IIa trial will provide the first opportunity to answer that question.
Background: Manual chart abstraction from electronic health records is a critical step in clinical outcomes research but is time-intensive and prone to human error. Advances in artificial intelligence (AI), particularly large language models, offer the potential to automate the extraction of structured data from unstructured clinical documentation with improved efficiency and consistency. Objective: This study aimed to evaluate the accuracy and efficiency of an AI-assisted approach for extracting patient-reported outcomes from clinical notes compared with traditional human abstraction. Methods: We conducted a retrospective study of 26 patients treated with low-dose radiation therapy for osteoarthritis. Human reviewers abstracted numeric rating scale (NRS; 0‐10) pain scores at baseline, the end of treatment, and the first follow-up, and von Pannewitz score (VPS; 0‐4) improvement scores at posttreatment time points. A HIPAA (Health Insurance Portability and Accountability Act)–compliant generative pretrained transformer–based AI system was prompted to extract the same end points from clinical notes. Concordance was assessed using exact match rates, the intraclass correlation coefficient for the NRS, and weighted Cohen κ for the VPS. The time required for AI vs manual abstraction was recorded. The AI system was not trained or fine-tuned on study data, and performance was evaluated directly against human abstraction to reflect real-world deployment. Results: The AI system demonstrated high concordance with human abstraction, achieving an exact match rate of 92% for the NRS (95% CI 84‐96; intraclass correlation coefficient=0.96) and 94% for the VPS (95% CI 84‐98; κ=0.91). All discrepancies were minor, and no spurious values were generated. The AI system identified 1 clinically relevant data point missed during manual review. Average abstraction time per patient decreased from approximately 30 minutes to 2 minutes, representing time savings of >90%. The system also captured trends in analgesic use, but these results were not statistically significant, including reductions without escalation. Conclusions: AI-assisted data abstraction demonstrated high concordance with human review in this single-institution cohort while substantially reducing the time requirements. These findings support the feasibility of AI-assisted abstraction workflows, although further validation across larger and more diverse datasets is needed.
According to the World Health Organization (WHO), tuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb), is the world’s deadliest single-agent caused infection, responsible for 1.23 million deaths in 2024. The bacterium’s outer cell membrane is difficult hard to penetrate, making few drugs effective in treating the disease.
“Mtb is unique,” said Sloan Siegrist, PhD, associate professor of microbiology at UMass Amherst. “Not only does it have two membranes that protect the cell from antimicrobial chemical compounds that we might use to kill it, its outer membrane is unlike any other biological barrier out there.”
Siegrist’s lab specializes in finding vulnerabilities in the mycomembrane to develop drugs that can effectively treat tuberculosis. However, traditional drug discovery has relied on low throughput experimental screens. In 2023, Siegrist, in collaboration with Marcos Pires, PhD, professor of chemistry at the University of Virginia, published Peptidoglycan Accessibility Click-Mediated AssessmeNt (PAC-MAN), a method that can test many compounds in parallel.
“Marcos and I wanted to harness measurements of known chemicals to predict compound uptake for unknown chemicals, so we brought in computational biologists and chemists, including my colleague Anna Green, PhD, from UMass Amherst’s Manning College of Information and Computer Sciences,” said Siegrist.
Green uses computation to understand patterns in biological compounds. “Small molecules can be particularly difficult to analyze computationally,” she says. “Because they come in all different sizes with a wide range of molecular connections, you can’t describe them with a single measurement, by weight, say, or size.”
Green and colleagues designed a machine learning model, the Mycobacterial Permeability neural Network (MycoPermeNet), trained on the PAC-MAN screening data. The model can predict how readily a compound permeates the mycomembrane from its chemical structure alone and points to the physical properties that help a compound penetrate Mtb’s defenses.
“The mycomembrane lets some molecules through and keeps others out,” says Green. “There must be something about this membrane, and about the chemistry of each molecule, that decides which ones get in—and our combined tools help us figure out which ones can get through, and why.”
Knowing that the protein tissue kallikrein-1 (KLK1) is effective in treating ischemic diseases is one thing. Manufacturing it as a recombinant protein has been quite another. So, when DiaMedica Therapeutics cracked the manufacturing aspect, it was well on its way toward commercializing KLK1 therapeutics.
The manufacturing breakthrough came when researchers realized that protein activity (which is essential for therapeutic benefit) was linked to certain glycosylation patterns. DiaMedica engineered the molecule to reflect those glycosylations and also made two changes to the amino acid sequence to improve manufacturability. “Then we partnered with Catalent,” Rick Pauls, president and CEO, says. “We are using its GPEx® technology with CHO cells,” which produces more cells within the same timeframe and thus lowers manufacturing costs.
Tenacity in action
This happened neither easily nor quickly. To understand the measure of this achievement, we need to look at DiaMedica’s history.
KLK1 came to DiaMedica’s attention because of liver research. “A liver physiologist cut the vagus nerve [which regulates liver metabolism] and discovered that the rats, effectively, became diabetic,” Pauls recounts. “We hypothesized that when a healthy person consumed a meal, the liver releases something that acts as an insulin sensitizer. We did some basic work and identified KLK1 as that insulin sensitizer.”
The company was founded in 2004 to develop a KLK1 therapeutic for complications related to Type II diabetes. Those trials failed. “It’s a long story,” says Pauls, that left the company “pretty close to bankrupt.”
DiaMedica, though, was tenacious. “We knew there was a human urine form of this protein that had been used for a few decades in Asia to treat acute ischemic stroke, and a porcine form treating hypertension for decades as well,” Pauls recalls. DiaMedica had the protein and the manufacturing know-how to produce active, recombinant proteins, and—with KLK1 levels low in stroke patients—a reason to pivot.
Ischemic stroke and preeclampsia
Its lead compound, DM199 (rinvecalinase alfa), is enrolling patients in Phase II/III trials for acute ischemic stroke. Called the ReMEDy2 trial, the company anticipates an interim readout near year’s end. Additionally, Phase I and II studies for preeclampsia and Phase II studies for fetal growth restriction are underway.
“This is protein restoration,” Pauls says. It targets ischemic stroke patients who have missed the three-to-four-hour post-stroke treatment window for tissue plasminogen activator (tPA) therapeutics or mechanical thrombectomy. Those patients constitute approximately 80% of acute ischemic strokes today, so “there is a huge unmet medical need,” Pauls says.
DM199 works by restoring normal levels of the KLK1 protein. KLK1, in turn, is thought to enhance the production of nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor. Pouring through their own preclinical and clinical results, the DiaMedica team noticed that DM199 consistently enhanced blood circulation and lowered blood pressure.
That realization drove the team to also target preeclampsia, a hypertensive disease of pregnancy that Pauls says may be the company’s most exciting application for investors.
Unlike approved blood pressure therapeutics, DM199 does not cross the placental barrier, a critical safety feature that protects the fetus. After examining early clinical data, DiaMedica scientists also realized that increasing blood flow to the placenta could target the root cause of the disease and perhaps gain another few weeks of crucial time in utero for the fetus.
“Today, there are no approved treatments. Mothers are given labetalol and nifedipine to control blood pressure and to extend the baby’s time in utero for only a few days.” Results are less than ideal, and the consequences can be severe.
Pauls says, “Some 40% of babies born before 28 weeks could have long-term disabilities, and 10 to 15% will have problems with eyesight for life. There’s been a real lack of drugs in development because developers are worried about harming the baby.”
An investigator-led Phase II clinical trial is enrolling. Later this year, the company plans to initiate its own Phase II study focused on early-onset preeclampsia after recently receiving regulatory clearance to start the study in Canada.
If the molecule eventually is approved for preeclampsia, DM199 seems poised to become, perhaps, the first approved treatment that offers the potential to extend gestational days and possibly address a root cause of preeclampsia.
Leveraging the pivot
Unlike many biopharmaceutical companies, DiaMedica has been able to bypass some of the usual first steps by leveraging existing studies on KLK1, as well as existing clinical data for stroke and preeclampsia.
That allows researchers to focus on humans without the translational issues inherent in animal studies. It also helps the company identify the human subgroups most likely to benefit from these treatments and the most appropriate dosing regimen early. “Having that clinical data helps de-risk our program and gives a better possibility of success,” Pauls says, because, as he points out, “Animals are not the same as people.”
Once the company pivoted to its current indications six or seven years ago, the challenge shifted from getting and manufacturing the active form of the protein to selecting the best indications and assembling the right team members.
“In the early days, maybe we didn’t have the right level of experience with limited capital,” he admits. Today, “we’ve been able to bring people on board who have brought drugs to market.”
Readouts due in 2027
Currently, the company is focused tightly on its clinical trials. The next step for DiaMedica is to get readouts from many of those, with five readouts on various aspects of the programs expected between now and the end of 2027. Each of those readouts will report on about 30 patients and will be factors in the design of a subsequent pivotal trial.
Additionally, an interim analysis of the first 200 patients in its acute ischemic stroke trial is expected by the end of the year, Pauls says. “If we see a drug effect that’s comparable to our Phase II trial or the data with the urine form (of KLK1) from China—which treats close to a million patients per year—we’ll be looking at completing enrollment the following quarter for stroke and then for preeclampsia. DiaMedica is dedicated to offering second chances to acute ischemic stroke patients and others who haven’t had them before, all while pivoting to new opportunities itself. Now, as trials advance, Pauls says, “I think this should be a straightforward path.”
DiaMedica Therapeutics
Location: 301 Carlson Parkway, Suite 210, Minneapolis, MN 55305
Phone: (763) 496-5192
Principal: Rick Pauls, president and CEO
Number of Employees: 35
Focus: DiaMedica is a clinical-stage company developing recombinant KLK1 protein restoration therapeutics for acute ischemic stroke, preeclampsia, fetal growth restriction, and other conditions with large unmet needs.
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If it feels like despite your employer offering health insurance you’re still paying a lot of money for health coverage and care, you’re not wrong. Bob Herman’s new series, Out of Pocket, Out of Reach, explores the impacts of soaring health care costs.
Electroencephalogram (EEG)-based emotion recognition faces significant generalization challenges in cross-subject and cross-session settings, primarily due to the inherent non-stationarity, individual differences, and semantic deficiency of EEG signals. To address these challenges and enhance the universality of affective brain-computer interface systems, this study proposes a novel unsupervised domain adaptation framework named Prototypical Graph-based Deep Label Propagation with Semantic Augmentation (PGDLP). PGDLP seamlessly integrates three core components—prototypical semantic augmentation, prototype-graph deep label propagation, and prototypical alignment—into an end-to-end optimized system. Specifically, class-wise multivariate normal distributions are constructed using source-domain feature statistics to augment target-domain features semantically, bridging the domain gap and mitigating semantic insufficiency. An adaptive similarity graph based on prototype-semantic distances is designed to optimize pseudo-label quality while reducing computational complexity. It is combined with linear projection and an exponential moving average (EMA) for dynamic refinement. Dual intra- and inter-domain alignment losses with an adaptive balance factor are introduced to enhance intra-class compactness and inter-domain transferability, thereby facilitating the learning of discriminative and domain-invariant features. Extensive experiments are conducted on three benchmark datasets (SEED, SEED-IV, DEAP) under four rigorous evaluation protocols (cross-subject cross-session, cross-subject single-session, within-subject cross-session, cross-database). Overall, PGDLP achieves superior recognition accuracy and generalization performance compared with most state-of-the-art methods across the majority of evaluation protocols. PGDLP also presents strong robustness against label noise, stable hyperparameter performance, and fast convergence. The results demonstrated that PGDLP outperforms state-of-the-art methods in recognition accuracy and generalization, with verified robustness to label noise, stable hyperparameters, and efficient convergence. This study provides a promising solution for unsupervised cross-domain EEG emotion recognition and offers valuable insights for domain adaptation research on other physiological signals.
IntroductionSaccadic eye movements are established biomarkers in neuroscience and clinical neurology, with video-oculography (VOG) serving as the gold standard for measurement. However, the high cost, bulky equipment, and poor portability of VOG systems restrict their clinical utility. Electrooculography (EOG) provides a practical alternative, but quantitative conversion of EOG-derived measurements into VOG-equivalent values remains insufficiently established. This study aimed to develop and validate a mathematically derived transformation model for estimating VOG-equivalent horizontal saccadic velocities from EOG recordings.MethodsFour healthy adults underwent simultaneous EOG and VOG recordings while performing controlled horizontal gaze shifts. Based on a current-source model of the corneal potential, an analytical relationship between EOG voltage velocity and angular eye velocity was derived. Multiple high-pass filter settings were systematically evaluated to identify optimal signal-processing conditions. Transformation equations were derived from the pooled horizontal-saccade dataset and further evaluated using leave-one-subject-out (LOSO) analysis.ResultsThe theoretical model predicted a linear relationship between EOG- and VOG-derived saccadic velocities. Among the tested filter settings, a 0.3 Hz high-pass combined with a 35 Hz low-pass filter yielded the best overall agreement. Under this condition, the final transformation model produced a common slope coefficient of 0.146 °/μV for both movement directions, with an additional direction-specific intercept of −82.37 °/s for rightward saccades. Converted EOG-derived velocities showed no significant differences from measured VOG-derived velocities. LOSO validation demonstrated stable transformation coefficients (mean slope = 0.147 °/μV, mean intercept = −82.47 °/s) and maintained agreement across individuals.ConclusionA biophysically derived and experimentally validated EOG-to-VOG transformation model can provide accurate estimates of horizontal saccadic velocity under appropriate filtering conditions. These findings support the feasibility of quantitative saccadic analysis using EOG, providing a practical alternative to VOG.
Non-Suicidal Self-Injury (NSSI) presents a significant public health challenge; however, its underlying neurobiological mechanisms remain insufficiently understood, limiting the development of targeted interventions. Emerging evidence suggests that NSSI exhibits core addictive features, such as compulsive urges and tolerance, which may be driven by dysfunctions in the brain’s reward circuitry. This review synthesizes current research on the neural overlaps between NSSI and addiction, specifically focusing on the dysregulation of the ventral striatum and prefrontal cortex. Based on this mechanistic framework, we propose the potential of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)—a high-dose, functional connectivity-guided transcranial magnetic stimulation protocol—as a precision treatment for NSSI. By targeting specific reward network deficits, SAINT may offer a novel, rapid-acting therapeutic strategy for patients who do not respond to conventional pharmacological or psychological interventions.
