A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity of PPFIA3 variants in vivo, we generated transgenic fruit flies producing either human wild-type (WT) PPFIA3 or five missense variants using GAL4-UAS targeted gene expression systems. In the fly overexpression assays, we found that the PPFIA3 variants in the region encoding the N-terminal coiled-coil domain exhibited stronger phenotypes compared to those affecting the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 function is partially conserved in the fly. However, two of the tested variants failed to rescue the lethality at the larval stage and one variant failed to rescue lethality at the adult stage. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant-negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.

Targeting the tumor microenvironment for treating double-refractory chronic lymphocytic leukemia.

ABSTRACT: The introduction of BTK inhibitors and BCL2 antagonists to the treatment of chronic lymphocytic leukemia (CLL) has revolutionized therapy and improved patient outcomes. These agents have replaced chemoimmunotherapy as standard of care. Despite this progress, a new group of patients is currently emerging, which has become refractory or intolerant to both classes of agents, creating an unmet medical need. Here, we propose that the targeted modulation of the tumor microenvironment provides new therapeutic options for this group of double-refractory patients. Furthermore, we outline a sequential strategy for tumor microenvironment-directed combination therapies in CLL that can be tested in clinical protocols.

Selective Oxidation Using In Situ-Generated Hydrogen Peroxide.

ConspectusHydrogen peroxide (H2O2) for industrial applications is manufactured through an indirect process that relies on the sequential reduction and reoxidation of quinone carriers. While highly effective, production is typically centralized and entails numerous energy-intensive concentration steps. Furthermore, the overhydrogenation of the quinone necessitates periodic replacement, leading to incomplete atom efficiency. These factors, in addition to the presence of propriety stabilizing agents and concerns associated with their separation from product streams, have driven interest in alternative technologies for chemical upgrading. The decoupling of oxidative transformations from commercially synthesized H2O2 may offer significant economic savings and a reduction in greenhouse gas emissions for several industrially relevant processes. Indeed, the production and utilization of the oxidant in situ, from the elements, would represent a positive step toward a more sustainable chemical synthesis sector, offering the potential for total atom efficiency, while avoiding the drawbacks associated with current industrial routes, which are inherently linked to commercial H2O2 production. Such interest is perhaps now more pertinent than ever given the rapidly improving viability of green hydrogen production.The application of in situ-generated H2O2 has been a long-standing goal in feedstock valorization, with perhaps the most significant interest placed on propylene epoxidation. Until very recently a viable in situ alternative to current industrial oxidative processes has been lacking, with prior approaches typically hindered by low rates of conversion or poor selectivity toward desired products, often resulting from competitive hydrogenation reactions. Based on over 20 years of research, which has led to the development of catalysts for the direct synthesis of H2O2 that offer high synthesis rates and >99% H2 utilization, we have recently turned our attention to a range of oxidative transformations where H2O2 is generated and utilized in situ. Indeed, we have recently demonstrated that it is possible to rival state-of-the-art industrial processes through in situ H2O2 synthesis, establishing the potential for significant process intensification and considerable decarbonization of the chemical synthesis sector.We have further established the potential of an in situ route to both bulk and fine chemical synthesis through a chemo-catalytic/enzymatic one-pot approach, where H2O2 is synthesized over heterogeneous surfaces and subsequently utilized by a class of unspecific peroxygenase enzymes for C-H bond functionalization. Strikingly, through careful control of the chemo-catalyst, it is possible to ensure that competitive, nonenzymatic pathways are inhibited while also avoiding the regiospecific and selectivity concerns associated with current energy-intensive industrial processes, with further cost savings associated with the operation of the chemo-enzymatic approach at near-ambient temperatures and pressures. Beyond traditional applications of chemo-catalysis, the efficacy of in situ-generated H2O2 (and associated oxygen-based radical species) for the remediation of environmental pollutants has also been a major interest of our laboratory, with such technology offering considerable improvements over conventional disinfection processes.We hope that this Account, which highlights the key contributions of our laboratory to the field over recent years, demonstrates the chemistries that may be unlocked and improved upon via in situ H2O2 synthesis and it inspires broader interest from the scientific community.

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Ethical choice reversals.

Understanding the systematic ways that human decision making departs from normative principles has been important in the development of cognitive theory across multiple decision domains. We focus here on whether such seemingly "irrational" decisions occur in ethical decisions that impose difficult tradeoffs between the welfare and interests of different individuals or groups. Across three sets of experiments and in multiple decision scenarios, we provide clear evidence that contextual choice reversals arise in multiples types of ethical choice settings, in just the way that they do in other domains ranging from economic gambles to perceptual judgments (Trueblood et al., 2013; Wedell, 1991). Specifically, we find within-participant evidence for attraction effects in which choices between two options systematically vary as a function of features of a third dominated and unchosen option-a prima facie violation of rational choice axioms that demand consistency. Unlike economic gambles and most domains in which such effects have been studied, many of our ethical scenarios involve features that are not presented numerically, and features for which there is no clear majority-endorsed ranking. We provide empirical evidence and a novel modeling analysis based on individual differences of feature rankings within attributes to show that such individual variations partly explains observed variation in the attraction effects. We conclude by discussing how recent computational analyses of attraction effects may provide a basis for understanding how the observed patterns of choices reflect boundedly rational decision processes.

HSQC Spectra Simulation and Matching for Molecular Identification.

In the pursuit of improved compound identification and database search tasks, this study explores heteronuclear single quantum coherence (HSQC) spectra simulation and matching methodologies. HSQC spectra serve as unique molecular fingerprints, enabling a valuable balance of data collection time and information richness. We conducted a comprehensive evaluation of the following four HSQC simulation techniques: ACD/Labs (ACD), MestReNova (MNova), Gaussian NMR calculations (DFT), and a graph-based neural network (ML). For the latter two techniques, we developed a reconstruction logic to combine proton and carbon 1D spectra into HSQC spectra. The methodology involved the implementation of three peak-matching strategies (minimum-sum, Euclidean-distance, and Hungarian distance) combined with three padding strategies (zero-padding, peak-truncated, and nearest-neighbor double assignment). We found that coupling these strategies with a robust simulation technique facilitates the accurate identification of correct molecules from similar analogues (regio- and stereoisomers) and allows for fast and accurate large database searches. Furthermore, we demonstrated the efficacy of the best-performing methodology by rectifying the structures of a set of previously misidentified molecules. This research indicates that effective HSQC spectral simulation and matching methodologies significantly facilitate molecular structure elucidation. Furthermore, we offer a Google Colab notebook for researchers to use our methods on their own data (https://github.com/AstraZeneca/hsqc_structure_elucidation.git).

Novel Scorpion Toxin ω-Buthitoxin-Hf1a Selectively Inhibits Calcium Influx via CaV3.3 and CaV3.2 and Alleviates Allodynia in a Mouse Model of Acute Postsurgical Pain.

Venom peptides have evolved to target a wide range of membrane proteins through diverse mechanisms of action and structures, providing promising therapeutic leads for diseases, including pain, epilepsy, and cancer, as well as unique probes of ion channel structure-function. In this work, a high-throughput FLIPR window current screening assay on T-type CaV3.2 guided the isolation of a novel peptide named ω-Buthitoxin-Hf1a from scorpion Hottentotta franzwerneri crude venom. At only 10 amino acid residues with one disulfide bond, it is not only the smallest venom peptide known to target T-type CaVs but also the smallest structured scorpion venom peptide yet discovered. Synthetic Hf1a peptides were prepared with C-terminal amidation (Hf1a-NH2) or a free C-terminus (Hf1a-OH). Electrophysiological characterization revealed Hf1a-NH2 to be a concentration-dependent partial inhibitor of CaV3.2 (IC50 = 1.18 µM) and CaV3.3 (IC50 = 0.49 µM) depolarized currents but was ineffective at CaV3.1. Hf1a-OH did not show activity against any of the three T-type subtypes. Additionally, neither form showed activity against N-type CaV2.2 or L-type calcium channels. The three-dimensional structure of Hf1a-NH2 was determined using NMR spectroscopy and used in docking studies to predict its binding site at CaV3.2 and CaV3.3. As both CaV3.2 and CaV3.3 have been implicated in peripheral pain signaling, the analgesic potential of Hf1a-NH2 was explored in vivo in a mouse model of incision-induced acute post-surgical pain. Consistent with this role, Hf1a-NH2 produced antiallodynia in both mechanical and thermal pain.

Impact of Concomitant Traumatic Pancreatic and Colon Injuries on Outcomes.

BACKGROUND: Colon and pancreatic injuries have both long been independently associated with intraabdominal infectious complications in trauma patients. The goal of this study was to evaluate the impact of concomitant pancreatic injury on outcomes in patients with traumatic colon injuries. METHODS: Consecutive patients over a 3-year period who underwent operative management of colon injuries were identified. Patient characteristics, severity of injury and shock, presence and grade of pancreatic injury, and intraoperative packed red blood cell (PRBC) transfusions were recorded. Outcomes including intraabdominal abscess formation and suture line failure were collected and compared. Multivariable logistic regression analysis was then performed to determine the impact of concomitant pancreatic injury on intraabdominal abscess formation. RESULTS: 243 patients with traumatic colon injuries were identified. 17 of these also had pancreatic injuries. Patients with combined colon and pancreatic injuries were clinically similar to those with isolated colon injuries with respect to age, gender, penetrating mechanism of injury, admission lactate, ISS, suture line failure, and admission systolic blood pressure. Both intraabdominal abscess rates (88.2% vs 29.6%, P < .001) and intraoperative PRBC transfusions (8 vs 1 units, P = .004) were higher in the combined pancreatic and colon injury group. Multivariable logistic regression identified both intraoperative PRBC transfusions (odds ratio, 1.09; 95% confidence interval, 1.04-1.15; P < .001) and concomitant pancreatic injury (odds ratio, 14.8; 95% confidence interval, 3.92-96.87; P < .001) as independent predictors of intraabdominal abscess formation. DISCUSSION: Both intraoperative PRBC transfusions and presence of concomitant pancreatic injury are independent predictors of intraabdominal abscess formation in patients with traumatic colon injuries.

Case Report: Sudden very late-onset near fatal PD1 inhibitor-associated myocarditis with out-of-hospital cardiac arrest after >2.5 years of pembrolizumab treatment.

Introduction: Immune checkpoint inhibitors have advanced the outcomes of many different types of cancer. A rare but extraordinarily severe complication of these agents resembles immune checkpoint inhibitor-related myocarditis, which typically occurs within the first few weeks after treatment initiation with a mortality of 25%-50%. Case report: A 57-year-old woman had uneventfully received pembrolizumab for metastatic non-small cell lung cancer for over 2.5 years and was admitted after an out-of-hospital cardiac arrest due to ventricular fibrillation. After successful cardiopulmonary resuscitation, the initial diagnostic work-up showed elevated cardiac enzymes and a limited left-ventricular ejection fraction, while coronary angiography did not show relevant stenosis. Despite cardiac MRI being unsuggestive of myocarditis, myocardial biopsies were obtained and histologically confirmed anti-PD-1 antibody-associated myocarditis. After the initiation of prednisone at 1 mg/kg body weight, the patient gradually recovered and was discharged three weeks later with markedly improved cardiac function. Conclusion: This case resembles the first description of a very late onset irMyocarditis, occurring over 2.5 years after the start of treatment. It demonstrates the importance of contemplating that severe immune-related toxicities with a sudden onset clinical presentation may occur even after long uneventful periods of anti-PD-1 immune checkpoint inhibitor treatment. Furthermore, it underlines the critical importance of myocardial biopsies in this setting, especially when cardiac MRI remains inconclusive. Moreover, it demonstrates the necessity and benefits of early immunosuppressive treatment if immune-related myocarditis is considered a differential diagnosis.

Comparative utility of vestibular function tests in patients with peripheral and central vestibular dysfunction.

Background: Bithermal caloric irrigation, video head impulse test (vHIT), and rotational testing are commonly used to assess peripheral vestibular function, but the relative clinical utility of each test in differentiating patients with peripheral vestibulopathy is debated. Objectives: To determine whether (1) the combination of two or more vestibular tests enhances diagnostic utility over a single test; (2) abnormal test results on vestibular tests correlate with one another. Methods: Retrospective analysis of data collected from multidisciplinary vestibular clinics at two academic medical centers from 2016 to 2022. Results: 150 patients (54.10 ± 15.09 years, 88 females) were included. No individual test was significantly better at predicting the presence of peripheral vestibular damage (p > 0.05). vHIT test results improved significantly when combined with either the caloric test (p = 0.007) or rotary chair test (p = 0.039). Caloric and rotational testing had high sensitivity (74.65% and 76.06%, respectively) and specificity (83.54% and 78.48%, respectively). vHIT demonstrated excellent specificity (89.87%) but poor sensitivity (47.89%). Caloric, vHIT, and rotary chair tests results did not correlate with one another (p > 0.05). Conclusions: Vestibular function tests have comparable diagnostic utility, yet each offers unique advantages. Caloric and rotational testing may be best suited for screening peripheral damage and vHIT may function ideally as a confirmatory test.

Inhibition of N-type calcium channels by phenoxyaniline and sulfonamide analogues.

Building on previous investigations, structural modifications to the neuronal calcium ion channel blocker MONIRO-1 and related compounds were conducted that included replacement of the amide linker with an aniline and isosteric sulfonamide moiety, and the previously used strategy of substitution of the guanidinium group with less hydrophilic amine functionalities. A comprehensive SAR study revealed a number of phenoxyaniline and sulfonamide compounds that were more potent or had similar potency for the CaV2.2 and CaV3.2 channel compared to MONIRO-1 when evaluated in a FLIPR-based intracellular calcium response assay. Cytotoxicity investigations indicated that the sulfonamide analogues were well tolerated by Cos-7 cells at dosages required to inhibit both calcium ion channels. The sulfonamide derivatives were the most promising CaV2.2 inhibitors developed by us to date due, possessing high stability in plasma, low toxicity (estimated therapeutic index > 10), favourable CNS MPO scores (4.0-4.4) and high potency and selectivity, thereby, making this class of compounds suitable candidates for future in vivo studies.

Novel hemizygous single-nucleotide duplication in RPGR in a patient with retinal dystrophy and sensorineural hearing loss.

BACKGROUND: The RPGR gene has been associated with X-linked cone-rod dystrophy. This report describes a variant in RPGR detected with exome sequencing (ES). Genes like RPGR have not always been included in panel-based testing and thus genome-wide tests such as ES may be required for accurate diagnosis. METHODS: The Texome Project is studying the impact of ES in medically underserved patients who are in need of genomic testing to guide diagnosis and medical management. The hypothesis is that ES could uncover diagnoses not made by standard medical care. RESULTS: A 58-year-old male presented with retinitis pigmentosa, sensorineural hearing loss, and a family history of retinal diseases. A previous targeted gene panel for retinal disorders had not identified a molecular cause. ES through the Texome Project identified a novel, hemizygous variant in RPGR (NM_000328.3: c.1302dup, p.L435Sfs*18) that explained the ocular phenotype. CONCLUSIONS: Continued genetics evaluation can help to end diagnostic odysseys of patients. Careful consideration of genes represented when utilizing gene panels is crucial to ensure an accurate diagnosis. Medically underserved populations are less likely to receive comprehensive genetic testing in their diagnostic workup. Our report is an example of the medical impact of genomic medicine implementation.

N-Sulfonylphenoxazines as neuronal calcium ion channel blockers.

Neuropathic pain is a type of chronic pain, usually caused by nerve damage, that responds poorly to traditional pain therapies. The N-type calcium channel (CaV2.2) is a well-validated pharmacological target to treat this condition. In order to further improve the inhibition of the N-type calcium channel relative to previously described inhibitors, and also address their problematic instability in blood plasma, the development of N-sulfonylphenoxazines as new calcium channel inhibitors was pursued. A series of N-sulfonylphenoxazines bearing ammonium side chains were synthesised and tested for their ability to inhibit both CaV2.2 and CaV3.2 (T-type) neuronal ion channels. Compounds with low micromolar activity in CaV2.2 were identified, equivalent to the most effective reported for this class of bioactive, and calculations based on their physical and chemical characteristics suggest that the best performing compounds have a high likelihood of being able to penetrate the blood-brain barrier. Representative N-sulfonylphenoxazines were tested for their stability in rat plasma and were found to be much more resilient than the previously reported N-acyl analogues. These compounds were also found to be relatively stable in an in vitro liver microsome metabolism model, the first time that this has been investigated for this class of compound. Finally, molecular modelling of the CaV2.2 channel was used to gain an understanding of the mode of action of these inhibitors at a molecular level. They appear to bind in a part of the channel, in and above its selectivity filter, in a way that hinders its ability to undergo the conformational changes required to open and allow calcium ions to pass through.

Age-Related Changes in Temporal Binding Involving Auditory and Vestibular Inputs.

Maintaining balance involves the combination of sensory signals from the visual, vestibular, proprioceptive, and auditory systems. However, physical and biological constraints ensure that these signals are perceived slightly asynchronously. The brain only recognizes them as simultaneous when they occur within a period of time called the temporal binding window (TBW). Aging can prolong the TBW, leading to temporal uncertainty during multisensory integration. This effect might contribute to imbalance in the elderly but has not been examined with respect to vestibular inputs. Here, we compared the vestibular-related TBW in 13 younger and 12 older subjects undergoing 0.5 Hz sinusoidal rotations about the earth-vertical axis. An alternating dichotic auditory stimulus was presented at the same frequency but with the phase varied to determine the temporal range over which the two stimuli were perceived as simultaneous at least 75% of the time, defined as the TBW. The mean TBW among younger subjects was 286 ms (SEM ± 56 ms) and among older subjects was 560 ms (SEM ± 52 ms). TBW was related to vestibular sensitivity among younger but not older subjects, suggesting that a prolonged TBW could be a mechanism for imbalance in the elderly person independent of changes in peripheral vestibular function.

Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Rα. Guided by the first X-ray crystal structure of a small peptide binding to TSLP and the identification of key metabolites, we were able to improve the proteolytic stability of this series in lung S9 fractions without sacrificing binding affinity. This resulted in the potent Bicycle 46 with nanomolar affinity to TSLP (KD = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats.

Vestibular damage affects the precision and accuracy of navigation in a virtual visual environment.

Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed, which either activated dynamic idiothetic cues ('dynamic task', navigate by turning, walking in place) or eliminated them ('static task', navigate with key presses, head stationary). For both protocols, we employed a standard 'triangle completion task' in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear 'accuracy' (derived from response error) and 'precision' (derived from response variability) were calculated. Comparing performance 'within tasks', navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm, vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance 'between tasks', normal men performed better on the dynamic than the static paradigm while vestibular-deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage, they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage.