Parkinsonism Following Chimeric Antigen Receptor T Cell Therapy.

This case report describes a 67-year-old woman who had received adoptive immunotherapy with chimeric antigen receptor T cells for multiple myeloma and was experiencing parkinsonism-like symptoms.

Clinical Presentation, Management, and Outcome in Neurolymphomatosis: A Systematic Review.

BACKGROUND AND OBJECTIVES: Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts, and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL. METHODS: A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Studies reporting individual patient data on cases with definitive NL diagnosis were included. Clinical, radiologic, pathologic, and outcome information were extracted. Univariable and multivariable survival analyses were performed using log-rank tests and Cox proportional hazard models. RESULTS: A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%), and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (>90%). Postmortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. The median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% CI 0.25-0.78; p = 0.005), performance status (ECOG <2, HR: 0.30; 95% CI 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters. DISCUSSION: Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Yet, diagnostic delays in primary NL remain common. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.

Factors influencing timely diagnosis in neurolymphomatosis.

BACKGROUND: Neurolymphomatosis refers to infiltration of the peripheral nervous system (PNS) by non-Hodgkin lymphoma (NHL). Diagnostic intervals in neurolymphomatosis and factors delaying diagnosis have not been evaluated. We therefore aimed to analyze diagnostic intervals in a large cohort. METHODS: The quality control database at Yale Cancer Center, Section of Neuro-Oncology, was searched for neurolymphomatosis cases diagnosed between 2001 and 2021. Univariate analyses were performed to identify parameters influencing diagnostic intervals. RESULTS: We identified 22 neurolymphomatosis cases including 7 with primary and 15 with secondary disease, which occurred a median (range: 4-144) of 16 months after initial NHL diagnosis. Patients typically presented with painful polyneuropathy (73%), that was asymmetrical and rapidly progressive. Diagnosis was based on PNS biopsy (50%) or integration of neuroimaging findings (50%) with NHL history and diagnostic cerebrospinal fluid examinations. Median interval from symptom onset to diagnosis was 3 months (range: 1-12). Secondary neurolymphomatosis compared to primary disease (median 2 vs. 6 months, p = 0.02), and cases with rapidly-progressive asymmetrical neuropathy as opposed to other presentations (median 2 vs. 6 months; p < 0.001) were diagnosed earlier. Upfront conventional CT compared to other modalities (median 2 vs. 5 months p = 0.04) and nerve root localization as opposed to other disease sites (median 1.5 vs. 4 months; p = 0.04) delayed diagnosis. CONCLUSIONS: NL type and localization, neuropathy course and distribution, and imaging modality selected for initial evaluation influence diagnostic intervals in neurolymphomatosis. Knowledge of this rare entity is critical for early suspicion, and diagnosis.

A unified generation-registration framework for improved MR-based CT synthesis in proton therapy.

BACKGROUND: The use of magnetic resonance (MR) imaging for proton therapy treatment planning is gaining attention as a highly effective method for guidance. At the core of this approach is the generation of computed tomography (CT) images from MR scans. However, the critical issue in this process is accurately aligning the MR and CT images, a task that becomes particularly challenging in frequently moving body areas, such as the head-and-neck. Misalignments in these images can result in blurred synthetic CT (sCT) images, adversely affecting the precision and effectiveness of the treatment planning. PURPOSE: This study introduces a novel network that cohesively unifies image generation and registration processes to enhance the quality and anatomical fidelity of sCTs derived from better-aligned MR images. METHODS: The approach synergizes a generation network (G) with a deformable registration network (R), optimizing them jointly in MR-to-CT synthesis. This goal is achieved by alternately minimizing the discrepancies between the generated/registered CT images and their corresponding reference CT counterparts. The generation network employs a UNet architecture, while the registration network leverages an implicit neural representation (INR) of the displacement vector fields (DVFs). We validated this method on a dataset comprising 60 head-and-neck patients, reserving 12 cases for holdout testing. RESULTS: Compared to the baseline Pix2Pix method with MAE 124.95 ± $\pm$ 30.74 HU, the proposed technique demonstrated 80.98 ± $\pm$ 7.55 HU. The unified translation-registration network produced sharper and more anatomically congruent outputs, showing superior efficacy in converting MR images to sCTs. Additionally, from a dosimetric perspective, the plan recalculated on the resulting sCTs resulted in a remarkably reduced discrepancy to the reference proton plans. CONCLUSIONS: This study conclusively demonstrates that a holistic MR-based CT synthesis approach, integrating both image-to-image translation and deformable registration, significantly improves the precision and quality of sCT generation, particularly for the challenging body area with varied anatomic changes between corresponding MR and CT.

Favorable Radiographic Response in a Patient With an Oligodendroglioma Treated With Azacitidine and Venetoclax for Acute Myeloid Leukemia.

The standard chemotherapy for treating oligodendrogliomas consists of a combination of procarbazine, lomustine, and vincristine (PCV). The combination of hypomethylating agents like azacitidine and BCL2 inhibitors like venetoclax has not been formally studied in the treatment of glial tumors. The combination of these two drugs is commonly used to treat acute myeloid leukemia (AML), with IDH-mutant disease being a particularly sensitive subtype. The use of azacitidine for the treatment of IDH-mutant gliomas has been reported in the literature, with mixed results that might suggest at least some benefits in a subtype of patients. It is also reported in the literature that the BCL2 gene is associated with treatment resistance and tumor recurrence in gliomas. Here, we present a patient with an oligodendroglioma who was treated with a conventional chemotherapy regimen for AML and, at the same time, had a favorable radiographic response to his brain tumor.

Sea Anemone Membrane Attack Complex/Perforin Superfamily Demonstrates an Evolutionary Transitional State between Venomous and Developmental Functions.

Gene duplication is a major force driving evolutionary innovation. A classic example is generating new animal toxins via duplication of physiological protein-encoding genes and recruitment into venom. While this process drives the innovation of many animal venoms, reverse recruitment of toxins into nonvenomous cells remains unresolved. Using comparative genomics, we find members of the Membrane Attack Complex and Perforin Family (MAC) have been recruited into venom-injecting cells (cnidocytes), in soft and stony corals and sea anemones, suggesting that the ancestral MAC was a cnidocyte expressed toxin. Further investigation into the model sea anemone Nematostella vectensis reveals that three members have undergone Nematostella-specific duplications leading to their reverse recruitment into endomesodermal cells. Furthermore, simultaneous knockdown of all three endomesodermally expressed MACs leads to mis-development, supporting that these paralogs have nonvenomous function. By resolving the evolutionary history and function of MACs in Nematostella, we provide the first proof for reverse recruitment from venom to organismal development.

Fundamentals of Arthroscopic Surgery Training and beyond: a reinforcement learning exploration and benchmark.

PURPOSE: This work presents FASTRL, a benchmark set of instrument manipulation tasks adapted to the domain of reinforcement learning and used in simulated surgical training. This benchmark enables and supports the design and training of human-centric reinforcement learning agents which assist and evaluate human trainees in surgical practice. METHODS: Simulation tasks from the Fundamentals of Arthroscopic Surgery Training (FAST) program are adapted to the reinforcement learning setting for the purpose of training virtual agents that are capable of providing assistance and scoring to the surgical trainees. A skill performance assessment protocol is presented based on the trained virtual agents. RESULTS: The proposed benchmark suite presents an API for training reinforcement learning agents in the context of arthroscopic skill training. The evaluation scheme based on both heuristic and learned reward functions robustly recovers the ground truth ranking on a diverse test set of human trajectories. CONCLUSION: The presented benchmark enables the exploration of a novel reinforcement learning-based approach to skill performance assessment and in-procedure assistance for simulated surgical training scenarios. The evaluation protocol based on the learned reward model demonstrates potential for evaluating the performance of surgical trainees in simulation.

Disability-adjusted life years from bone and joint infections associated with antimicrobial resistance: an insight from the 2019 Global Burden of Disease Study.

PURPOSE: Bone and joint infections, complicated by the burgeoning challenge of antimicrobial resistance (AMR), pose significant public health threats by amplifying the disease burden globally. We leveraged results from the 2019 Global Burden of Disease Study (GBD) to explore the impact of AMR attributed to bone and joint infections in terms of disability-adjusted life years (DALYs), elucidating the contemporary status and temporal trends. METHODS: Utilizing GBD 2019 data, we summarized the burden of bone and joint infections attributed to AMR across 195 countries and territories in the 30 years from 1990 to 2019. We review the epidemiology of AMR in terms of age-standardized rates, the estimated DALYs, comprising years of life lost (YLLs) and years lived with disability (YLDs), as well as associations between DALYs and socio-demographic indices. RESULTS: The GBD revealed that DALYs attributed to bone and joint infections associated with AMR have risen discernibly between 1990 and 2019 globally. Significant geographical disparities and a positive correlation with socio-demographic indicators were observed. Staphylococcus aureus infections, Group A Streptococcus, Group B Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter-related bone and joint infections were associated with the highest DALYs because of a high proportion of antimicrobial resistance. Countries with limited access to healthcare, suboptimal sanitary conditions, and inconsistent antibiotic stewardship were markedly impacted. CONCLUSIONS: The GBD underscores the escalating burden of bone and joint infections exacerbated by AMR, necessitating urgent, multi-faceted interventions. Strategies to mitigate the progression and impact of AMR should emphasize prudent antimicrobial usage and robust infection prevention and control measures, coupled with advancements in diagnostic and therapeutic modalities.

Venom trade-off shapes interspecific interactions, physiology, and reproduction.

The ability of an animal to effectively capture prey and defend against predators is pivotal for survival. Venom is often a mixture of many components including toxin proteins that shape predator-prey interactions. Here, we used the sea anemone Nematostella vectensis to test the impact of toxin genotypes on predator-prey interactions. We developed a genetic manipulation technique to demonstrate that both transgenically deficient and a native Nematostella strain lacking a major neurotoxin (Nv1) have a reduced ability to defend themselves against grass shrimp, a native predator. In addition, secreted Nv1 can act indirectly in defense by attracting mummichog fish, which prey on grass shrimp. Here, we provide evidence at the molecular level of an animal-specific tritrophic interaction between a prey, its antagonist, and a predator. Last, this study reveals an evolutionary trade-off, as the reduction of Nv1 levels allows for faster growth and increased reproductive rates.

ChromaX: a fast and scalable breeding program simulator.

SUMMARY: ChromaX is a Python library that enables the simulation of genetic recombination, genomic estimated breeding value calculations, and selection processes. By utilizing GPU processing, it can perform these simulations up to two orders of magnitude faster than existing tools with standard hardware. This offers breeders and scientists new opportunities to simulate genetic gain and optimize breeding schemes. AVAILABILITY AND IMPLEMENTATION: The documentation is available at https://chromax.readthedocs.io. The code is available at https://github.com/kora-labs/chromax.

Feasibility and Acceptability of an INtervention TO Increase MOBility in Older Hospitalized Medical Patients (INTOMOB): A Mixed-Methods Pilot Study.

Background: To reduce adverse outcomes of low hospital mobility, we need interventions that are scalable in everyday practice. This study assessed the feasibility and acceptability of the INTOMOB multilevel intervention addressing barriers to hospital mobility without requiring unavailable resources. Methods: The INTOMOB intervention, targeting older patients, healthcare professionals (HCPs) and the hospital environment, was implemented on acute general internal medicine wards of three hospitals (12/2022-03/2023). Feasibility and acceptability of the intervention were assessed and two types of accelerometers compared in a mixed methods study (patient and HCP surveys and interviews). Quantitative data were analyzed descriptively and qualitative data using a deductive approach. Results were integrated through meta-inferences. Results: Of 20 patients (mean age 74.1 years), 90% found the intervention helpful and 82% said the environment intervention (posters) stimulated mobility. The majority of 44 HCPs described the intervention as clear and helpful. There was no major implementation or technical issue. About 60% of patients and HCPs preferred a wrist-worn over an ankle-worn accelerometer. Conclusions: The INTOMOB intervention is feasible and well accepted. Patients' and HCPs' feedback allowed to further improve the intervention that will be tested in a cluster randomized trial and provides useful information for future mobility-fostering interventions.

An ancient pan-cnidarian microRNA regulates stinging capsule biogenesis in Nematostella vectensis.

An ancient evolutionary innovation of a novel cell type, the stinging cell (cnidocyte), appeared >600 million years ago in the phylum Cnidaria (sea anemones, corals, hydroids, and jellyfish). A complex bursting nano-injector of venom, the cnidocyst, is embedded in cnidocytes and enables cnidarians to paralyze their prey and predators, contributing to this phylum's evolutionary success. In this work, we show that post-transcriptional regulation by a pan-cnidarian microRNA, miR-2022, is essential for biogenesis of these cells in the sea anemone Nematostella vectensis. By manipulation of miR-2022 levels in a transgenic reporter line of cnidocytes, followed by transcriptomics, single-cell data analysis, prey paralysis assays, and cell sorting of transgenic cnidocytes, we reveal that miR-2022 enables cnidocyte biogenesis in Nematostella, while exhibiting a conserved expression domain with its targets in cnidocytes of other cnidarian species. Thus, here we revealed a functional basis to the conservation of one of nature's most ancient microRNAs.

Influence of timing of Levosimendan administration on outcomes in cardiac surgery.

Purpose: Though a subgroup analysis has shown improved survival for patients suffering severely reduced ventricular function undergoing coronary artery bypass grafting, RCTs were not able to demonstrate overall beneficial effects of perioperative Levosimendan in cardiac surgery. This might be due to Levosimendan's pharmacokinetics reaching a steady-state concentration only 4-8 h after administration. Thus, this study now analysed the influence of timing of Levosimendan administration on perioperative outcome in cardiac surgery patients preoperatively presenting with severely reduced ventricular function and therefore considered at high-risk for intra- or postoperative low cardiac output syndrome. We hypothesized that prolonged preoperative Levosimendan administration ("preconditioning") would reduce mortality. Methods: All adult patients undergoing cardiac surgery between 2006 and 2018 perioperatively receiving Levosimendan were included in this retrospective, observational cohort study (n = 498). Patients were stratified into 3 groups: Levosimendan started on the day prior to surgery ("preop"), Levosimendan started on the day of surgery ("intraop") or post ICU admission ("postop"). After propensity score matching (PSM) was performed, outcomes defined according to proposed standard definitions for perioperative outcome research were compared between groups. Results: After PSM, there were no significant differences in patients' characteristics, comorbidities and type/priority of surgery between groups. Compared to intraop or postop Levosimendan treatment, preop treated patients had significantly lower in-hospital-mortality (preop vs. intraop. vs. postop = 16,7% vs. 33,3% vs. 42,3%), duration of mechanical ventilation and rate of continuous renal replacement therapy. Conclusions: Prolonged preoperative treatment with Levosimendan of cardiac surgery patients preoperatively presenting with severely reduced left ventricular function might be beneficial in terms of postoperative outcome. Our results are in line with recent experts' recommendations concerning the prolonged perioperative use of Levosimendan. We strongly recommend that future randomized trials include this "preconditioning" treatment as an experimental arm.

The role of Plasmodium V-ATPase in vacuolar physiology and antimalarial drug uptake.

To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen Plasmodium falciparum employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.

Randomized Clinical Trials and Observational Tribulations: Providing Clinical Evidence for Personalized Surgical Pain Management Care Models.

Proving clinical superiority of personalized care models in interventional and surgical pain management is challenging. The apparent difficulties may arise from the inability to standardize complex surgical procedures that often involve multiple steps. Ensuring the surgery is performed the same way every time is nearly impossible. Confounding factors, such as the variability of the patient population and selection bias regarding comorbidities and anatomical variations are also difficult to control for. Small sample sizes in study groups comparing iterations of a surgical protocol may amplify bias. It is essentially impossible to conceal the surgical treatment from the surgeon and the operating team. Restrictive inclusion and exclusion criteria may distort the study population to no longer reflect patients seen in daily practice. Hindsight bias is introduced by the inability to effectively blind patient group allocation, which affects clinical result interpretation, particularly if the outcome is already known to the investigators when the outcome analysis is performed (often a long time after the intervention). Randomization is equally problematic, as many patients want to avoid being randomly assigned to a study group, particularly if they perceive their surgeon to be unsure of which treatment will likely render the best clinical outcome for them. Ethical concerns may also exist if the study involves additional and unnecessary risks. Lastly, surgical trials are costly, especially if the tested interventions are complex and require long-term follow-up to assess their benefit. Traditional clinical testing of personalized surgical pain management treatments may be more challenging because individualized solutions tailored to each patient's pain generator can vary extensively. However, high-grade evidence is needed to prompt a protocol change and break with traditional image-based criteria for treatment. In this article, the authors review issues in surgical trials and offer practical solutions.

Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL. In addition to novel insights into the pathobiology of EBV+ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.

Microendoscopic Surgery for Degenerative Disorders of the Cervical and Lumbar Spine: The Influence of the Tubular Workspace on Instrument Angulation, Clinical Outcome, Complications, and Reoperation Rates.

BACKGROUND: Long-term clinical outcomes with microendoscopic spine surgery (MESS) are poorly investigated. The effect of instrument angulation on clinical outcomes has yet to be assessed. METHODS: A total of 229 consecutive patients operated on via two MESS systems were analyzed. Instrument angulation for both MESS systems, which differ from each other regarding the working space for instruments, was assessed using a computer model. Patients' charts and endoscopic video recordings were reviewed to determine clinical outcomes, complications, and revision surgery rates. At a minimum follow-up of two years, clinical outcomes were assessed employing the Neck Disability Index (NDI) and Oswestry Disability Index (ODI). RESULTS: A total of 52 posterior cervical foraminotomies (PCF) and 177 lumbar decompression procedures were performed. The mean follow-up was six years (range 2-9 years). At the final follow-up, 69% of cervical and 76% of lumbar patients had no radicular pain. The mean NDI was 10%, and the mean ODI was 12%. PCF resulted in excellent clinical outcomes in 80% of cases and 87% of lumbar procedures. Recurrent disc herniations occurred in 7.7% of patients. The surgical time and repeated procedure rate were significantly lower for the MESS system with increased working space, whereas the clinical outcome and rate of complication were similar. CONCLUSIONS: MESS achieves high success rates for treating degenerative spinal disorders in the long term. Increased instrument angulation improves access to the compressive pathology and lowers the surgical time and repeated procedure rate.

The Imitation of the Ovarian Fatty Acid Profile of Superfertile Dummerstorf Mouse Lines during IVM of Control Line Oocytes Could Influence Their Maturation Rates.

Declining human fertility worldwide is an attractive research target for the search for "high fertility" genes and pathways to counteract this problem. To study these genes and pathways for high fertility, the superfertile Dummerstorf mouse lines FL1 and FL2 are two unique model organisms representing an improved fertility phenotype. A direct reason for this remarkable characteristic of increased litter size, which reaches >20 pups/litter in both FLs, is the raised ovulation rate by approximately 100%, representing an impressive record in this field. Dummerstorf high-fertility lines incarnate extraordinary and singular models of high-fertility for other species, mostly farm animals, with the aim of improving production and reducing costs. Our main goal is to describe the genetic and molecular pathways to reach their phenotypical excellence, and to reproduce them using the control population. The large litter size and ovulation rate in Dummerstorf lines are mostly due to an increase in the quality of their oocytes, which receive a different intake of fat and are composed of different types and concentrations of fatty acids. As the follicular microenvironment plays a fundamental role during the oocytes development, in the present manuscript, we tried to improve the in vitro maturation technique by mimicking the fatty acid profile of FLs oocytes during the IVM of control oocytes. Currently, the optimization of the IVM system is fundamental mostly for prepubertal girls and oncological patients whose main source of gametes to restore fertility may be their maturation in vitro. Our data suggest that the specific fatty acid composition of FLs COCs can contribute to their high-fertility phenotype. Indeed, COCs from the control line matured in IVM-medium supplemented with C14:0 (high in FL2 COCs) or with C20:0, C21:0, C22:0, and C23:0 (high in FL1 COCs), but also control oocytes without cumulus, whose concentration in long-chain FAs are "naturally" higher, showing a slightly higher maturation rate. These findings represent an important starting point for the optimization of the IVM system using FA supplementation.

Structural analysis of the Candida albicans mitochondrial DNA maintenance factor Gcf1p reveals a dynamic DNA-bridging mechanism.

The compaction of mitochondrial DNA (mtDNA) is regulated by architectural HMG-box proteins whose limited cross-species similarity suggests diverse underlying mechanisms. Viability of Candida albicans, a human antibiotic-resistant mucosal pathogen, is compromised by altering mtDNA regulators. Among them, there is the mtDNA maintenance factor Gcf1p, which differs in sequence and structure from its human and Saccharomyces cerevisiae counterparts, TFAM and Abf2p. Our crystallographic, biophysical, biochemical and computational analysis showed that Gcf1p forms dynamic protein/DNA multimers by a combined action of an N-terminal unstructured tail and a long helix. Furthermore, an HMG-box domain canonically binds the minor groove and dramatically bends the DNA while, unprecedentedly, a second HMG-box binds the major groove without imposing distortions. This architectural protein thus uses its multiple domains to bridge co-aligned DNA segments without altering the DNA topology, revealing a new mechanism of mtDNA condensation.