Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity across viruses.

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.

Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project.

BACKGROUND: A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting. METHODS: We utilized genome sequencing (GS) data from families sequenced in the Rare Genomes Project (RGP), a direct-to-participant research study on the utility of GS for rare disease diagnosis and gene discovery. Challenge predictors were provided with a dataset of variant calls and phenotype terms from 175 RGP individuals (65 families), including 35 solved training set families with causal variants specified, and 30 unlabeled test set families (14 solved, 16 unsolved). We tasked teams to identify causal variants in as many families as possible. Predictors submitted variant predictions with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on the rank position of causal variants, and the maximum F-measure, based on precision and recall of causal variants across all EPCR values. RESULTS: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performers recalled causal variants in up to 13 of 14 solved families within the top 5 ranked variants. Newly discovered diagnostic variants were returned to two previously unsolved families following confirmatory RNA sequencing, and two novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant in an unsolved proband with phenotypes consistent with asparagine synthetase deficiency. CONCLUSIONS: Model methodology and performance was highly variable. Models weighing call quality, allele frequency, predicted deleteriousness, segregation, and phenotype were effective in identifying causal variants, and models open to phenotype expansion and non-coding variants were able to capture more difficult diagnoses and discover new diagnoses. Overall, computational models can significantly aid variant prioritization. For use in diagnostics, detailed review and conservative assessment of prioritized variants against established criteria is needed.

Host protease activity classifies pneumonia etiology.

Community-acquired pneumonia (CAP) has been brought to the forefront of global health priorities due to the COVID-19 pandemic. However, classification of viral versus bacterial pneumonia etiology remains a significant clinical challenge. To this end, we have engineered a panel of activity-based nanosensors that detect the dysregulated activity of pulmonary host proteases implicated in the response to pneumonia-causing pathogens and produce a urinary readout of disease. The nanosensor targets were selected based on a human protease transcriptomic signature for pneumonia etiology generated from 33 unique publicly available study cohorts. Five mouse models of bacterial or viral CAP were developed to assess the ability of the nanosensors to produce etiology-specific urinary signatures. Machine learning algorithms were used to train diagnostic classifiers that could distinguish infected mice from healthy controls and differentiate those with bacterial versus viral pneumonia with high accuracy. This proof-of-concept diagnostic approach demonstrates a way to distinguish pneumonia etiology based solely on the host proteolytic response to infection.

Transient 2D IR Spectroscopy and Multiscale Simulations Reveal Vibrational Couplings in the Cyanobacteriochrome Slr1393-g3.

Cyanobacteriochromes are bistable photoreceptor proteins with desirable photochemical properties for biotechnological applications, such as optogenetics or fluorescence microscopy. Here, we investigate Slr1393-g3, a cyanobacteriochrome that reversibly photoswitches between a red-absorbing (Pr) and green-absorbing (Pg) form. We applied advanced IR spectroscopic methods to track the sequence of intermediates during the photocycle over many orders of magnitude in time. In the conversion from Pg to Pr, we have revealed a new intermediate with distinct spectroscopic features in the IR, which precedes Pr formation using transient IR spectroscopy. In addition, stationary and transient 2D IR experiments measured the vibrational couplings between different groups of the chromophore and the protein in these intermediate states, as well as their structural disorder. Anharmonic QM/MM calculations predict spectra in good agreement with experimental 2D IR spectra of the initial and final states of the photocycle. They facilitate the assignment of the IR spectra that serve as a basis for the interpretation of the spectroscopic results and suggest structural changes of the intermediates along the photocycle.

The interplay between chromophore and protein determines the extended excited state dynamics in a single-domain phytochrome.

Phytochromes are a diverse family of bilin-binding photoreceptors that regulate a wide range of physiological processes. Their photochemical properties make them attractive for applications in optogenetics and superresolution microscopy. Phytochromes undergo reversible photoconversion triggered by the Z ⇄ E photoisomerization about the double bond in the bilin chromophore. However, it is not fully understood at the molecular level how the protein framework facilitates the complex photoisomerization dynamics. We have studied a single-domain bilin-binding photoreceptor All2699g1 (Nostoc sp. PCC 7120) that exhibits photoconversion between the red light-absorbing (Pr) and far red-absorbing (Pfr) states just like canonical phytochromes. We present the crystal structure and examine the photoisomerization mechanism of the Pr form as well as the formation of the primary photoproduct Lumi-R using time-resolved spectroscopy and hybrid quantum mechanics/molecular mechanics simulations. We show that the unusually long excited state lifetime (broad lifetime distribution centered at ∼300 picoseconds) is due to the interactions between the isomerizing pyrrole ring D and an adjacent conserved Tyr142. The decay kinetics shows a strongly distributed character which is imposed by the nonexponential protein dynamics. Our findings offer a mechanistic insight into how the quantum efficiency of the bilin photoisomerization is tuned by the protein environment, thereby providing a structural framework for engineering bilin-based optical agents for imaging and optogenetics applications.

Photoisomerization of phytochrome chromophore models: an XMS-CASPT2 study.

Phytochromes are a superfamily of photoreceptors that harbor linear tetrapyrroles as chromophores. Upon light illumination, the linear tetrapyrrole chromophore undergoes a double bond isomerization which starts a photocycle. In this work, we studied the photoisomerization of chromophore models designed based on the C- and D-rings of the phycocyanobilin (PCB) chromophore. In total, five different models with varying substitutions were investigated. Firstly, the vertical excitation energies were benchmarked using different computational methods to establish the relative order of the excited states. Based on these calculations, we computed the photoisomerization profiles using the extended multi-state (XMS) version of the CASPT2 method. The profiles were obtained for both the clockwise and counterclockwise rotations of the C15C16 bond in the Z and E isomers using a linear interpolation of internal coordinates between the Franck-Condon and MECI geometries. In the minimal chromophore model that lacks the substitutions at the pyrrole rings, the isomerization involves both C14-C15 and C15C16 bonds of the methine bridge between the C- and D-rings, resembling the hula-twist motion. The MECIs are characterized by a partial charge transfer between the two pyrrole rings pointing towards a twisted intramolecular charge transfer. Systematic introduction of substituents leads to an increase in the steric repulsion between the two pyrrole rings causing a pretwist of the dihedral around the C15C16 bond, which creates a preference for the counterclockwise isomerization. An introduction of the carbonyl group at the D-ring increases the extent of charge transfer which changes the isomerization mechanism from hula-twist to one-bond flip.

Outcomes Analysis of Textured Versus Smooth Tissue Expanders in Breast Reconstruction.

INTRODUCTION: Because of concerns related to the correlation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and textured implants, the use of smooth devices in breast reconstruction has been increasing. Currently, there is a paucity of literature evaluating the safety of smooth tissue expanders (STEs), which are now being used more frequently in first-stage breast reconstruction. This study sought to compare the safety and outcomes associated with STEs compared with textured tissue expanders in prosthesis-based breast reconstruction. METHODS: A single-institution retrospective review of 394 patients undergoing tissue expander-based breast reconstruction (147 smooth and 247 textured) between 2015 and 2019 was conducted. Patient demographics, comorbidities, treatment characteristics, complications, and surgical outcomes were evaluated. Data analysis was performed using Fisher exact and t tests. RESULTS: No significant difference in demographics or complication rates were identified, including rates of hematoma, seroma, wound dehiscence, delayed wound healing, infection, tissue expander malposition, nipple necrosis, mastectomy flap necrosis, reoperation, readmission, and explantation. Average follow-up was 19 and 22 months for the smooth and textured groups, respectively. No cases of BIA-ALCL were identified in either group. CONCLUSIONS: With equivocal safety profiles and no demonstrated risk in BIA-ALCL associated with STEs, this study supports the safety of using STEs compared with textured tissue expanders in prosthesis-based breast reconstruction with the advantage in preventing BIA-ALCL and concludes that there is no role for textured breast expanders.

Fast automatic segmentation of thalamic nuclei from MP2RAGE acquisition at 7 Tesla.

PURPOSE: Thalamic nuclei are largely invisible in conventional MRI due to poor contrast. Thalamus Optimized Multi-Atlas Segmentation (THOMAS) provides automatic segmentation of 12 thalamic nuclei using white-matter-nulled (WMn) Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence at 7T, but increases overall scan duration. Routinely acquired, bias-corrected Magnetization Prepared 2 Rapid Gradient Echo (MP2RAGE) sequence yields superior tissue contrast and quantitative T1 maps. Application of THOMAS to MP2RAGE has been investigated in this study. METHODS: Eight healthy volunteers and five pediatric-onset multiple sclerosis patients were recruited at Children's Hospital of Philadelphia and scanned at Siemens 7T with WMn-MPRAGE and multi-echo-MP2RAGE (ME-MP2RAGE) sequences. White-matter-nulled contrast was synthesized (MP2-SYN) from T1 maps from ME-MP2RAGE sequence. Thalamic nuclei were segmented using THOMAS joint label fusion algorithm from WMn-MPRAGE and MP2-SYN datasets. THOMAS pipeline was modified to use majority voting to segment bias corrected T1-weighted uniform (MP2-UNI) images. Thalamic nuclei from MP2-SYN and MP2-UNI images were evaluated against corresponding nuclei obtained from WMn-MPRAGE images using dice coefficients, volume similarity indices (VSIs) and distance between centroids. RESULTS: For MP2-SYN, dice > 0.85 and VSI > 0.95 was achieved for five larger nuclei and dice > 0.6 and VSI > 0.7 was achieved for seven smaller nuclei. The dice and VSI were slightly higher, whereas the distance between centroids were smaller for MP2-SYN compared to MP2-UNI, indicating improved performance using the MP2-SYN image. CONCLUSIONS: THOMAS algorithm can successfully segment thalamic nuclei in MP2RAGE images with essentially equivalent quality as WMn-MPRAGE, widening its applicability in studies focused on thalamic involvement in aging and disease.

Investigation of long interspersed element-1 retrotransposons as potential risk factors for idiopathic temporal lobe epilepsy.

OBJECTIVE: To determine if long interspersed element-1 (L1) retrotransposons convey risk for idiopathic temporal lobe epilepsy (TLE). METHODS: Surgically resected temporal cortex from individuals with TLE (N = 33) and postmortem temporal cortex from individuals with no known neurological disease (N = 33) were analyzed for L1 content by Restriction Enzyme Based Enriched L1Hs sequencing (REBELseq). Expression of three KCNIP4 splice variants was assessed by droplet digital PCR (ddPCR). Protein ANalysis THrough Evolutionary Relationships (PANTHER) was used to determine ontologies and pathways for lists of genes harboring L1 insertions. RESULTS: We identified novel L1 insertions specific to individuals with TLE, and others specific to controls. Although there were no statistically significant differences between cases and controls in the numbers of known and novel L1 insertions, PANTHER analyses of intragenic L1 insertions showed statistically significant enrichments for epilepsy-relevant gene ontologies in both cases and controls. Gene ontologies "neuron projection development" and "calcium ion transmembrane transport" were among those found only in individuals with TLE. We confirmed novel L1 insertions in several genes associated with seizures/epilepsy, including a de novo somatic L1 retrotransposition in KCNIP4 that occurred after neural crest formation in one patient. However, ddPCR results suggest this de novo L1 did not alter KCNIP4 mRNA expression. SIGNIFICANCE: Given current data from this small cohort, we conclude that L1 elements, either rare heritable germline insertions or de novo somatic retrotranspositions, may contribute only minimally to overall genetic risk for idiopathic TLE. We suggest that further studies in additional patients and additional brain regions are warranted.

Correction: Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2.

Correction for 'Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2' by Aditya G. Rao et al., Phys. Chem. Chem. Phys., 2021, DOI: 10.1039/d0cp05314g.

Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2.

Cyanobacteriochromes are compact and spectrally diverse photoreceptor proteins that bind a linear tetrapyrrole as a chromophore. They show photochromicity by having two stable states that can be interconverted by the photoisomerization of the chromophore. These photochemical properties make them an attractive target for biotechnological applications. However, their application is impeded by structural heterogeneity that reduces the yield of the photoconversion. The heterogeneity can originate either from the chromophore structure or the protein environment. Here, we study the origin of the heterogeneity in AnPixJg2, a representative member of the red/green cyanobacteriochrome family, that has a red absorbing parental state and a green absorbing photoproduct state. Using molecular dynamics simulations and umbrella sampling we have identified the protonation state of a conserved histidine residue as a trigger for structural heterogeneity. When the histidine is in a neutral form, the chromophore structure is homogenous, while in a positively charged form, the chromophore is heterogeneous with two different conformations. We have identified a correlation between the protonation of the histidine and the structural heterogeneity of the chromophore by detailed characterization of the interactions in the protein binding site. Our findings reconcile seemingly contradicting spectroscopic studies that attribute the heterogeneity to different sources. Furthermore, we predict that circular dichroism can be used as a diagnostic tool to distinguish different substates.

Current concepts of spondylosis and posterior spinal motion preservation for radiologists.

Spinal fusion is performed to eliminate motion at a degenerated or unstable segment. However, this is associated with loss of motion at the fused levels and increased stress on adjacent levels. Motion-preserving implants have been designed in effort to mitigate the limitations of fusion. This review will focus on posterior spinal motion-preserving technologies. In the cervical spine, laminoplasty is a posterior motion-preserving procedure used in the management of myelopathy/cord compression. In the lumbar spine, motion-sparing systems include interspinous process devices (also referred to as interspinous process spacers or distraction devices), posterior dynamic stabilization devices (also referred to as pedicle screw/rod fixation-based systems), and posterior element replacement systems (also referred to as total facet replacement devices). Knowledge of the intended physiologic purpose, hardware utilized, and complications is important in the assessment of imaging in those who have undergone posterior motion preservation procedures.

From CT to 3D Printed Models, Serious Gaming, and Virtual Reality: Framework for Educational 3D Visualization of Complex Anatomical Spaces From Within-the Pterygopalatine Fossa.

We describe the framework for capturing the internal view of complex anatomical spaces via multiple media and haptic platforms, exemplified by realistic and conceptual representations of the pterygopalatine fossa (PPF). A realistic three-dimensional (3D) mesh of the PPF was developed by segmenting the osseous anatomy on computed tomography (CT) using Materialize InPrint. Subsequently in Autodesk 3D Studio Max, the realistic mesh was enhanced with graphically designed neurovascular anatomy and additionally a conceptual representation of the PPF with its connections and contents was created. An interactive web-compatible Adobe Flash tutorial using ActionScript was developed, allowing users to advance through a series of educational slides that contained interactive rotatable interior camera views and scrollable CT cross-sectional content, incorporating both the realistic and conceptual models. Both models were also 3D printed using polyamide material. In the realistic model, the neurovasculature was colored with water-based acrylic paint. A 3-piece modular design with embedded magnets allows for internal visualization and seamless assembly. A serious gaming environment of the conceptual PPF was also developed using Truevision3D application programming interface, where users can freely move around rooms and hallways that represent various spaces. Lastly, the realistic model was incorporated into a headset-based virtual reality environment, Surgical Theater, allowing visualization and fly-through inside and outside the model. Multiple 3D techniques for visualization of complex 3D anatomical spaces from within were described, with the necessary software and skills detailed. A rough estimate of the time and cost needed to develop these tools as well as multiple supplementary source and end result files are also made available. Educators could utilize multiple advanced delivery methods to incorporate custom digital 3D models of complex anatomical spaces understood from inside.

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases.

Whole-genome sequencing (WGS) holds great potential as a diagnostic test. However, the majority of patients currently undergoing WGS lack a molecular diagnosis, largely due to the vast number of undiscovered disease genes and our inability to assess the pathogenicity of most genomic variants. The CAGI SickKids challenges attempted to address this knowledge gap by assessing state-of-the-art methods for clinical phenotype prediction from genomes. CAGI4 and CAGI5 participants were provided with WGS data and clinical descriptions of 25 and 24 undiagnosed patients from the SickKids Genome Clinic Project, respectively. Predictors were asked to identify primary and secondary causal variants. In addition, for CAGI5, groups had to match each genome to one of three disorder categories (neurologic, ophthalmologic, and connective), and separately to each patient. The performance of matching genomes to categories was no better than random but two groups performed significantly better than chance in matching genomes to patients. Two of the ten variants proposed by two groups in CAGI4 were deemed to be diagnostic, and several proposed pathogenic variants in CAGI5 are good candidates for phenotype expansion. We discuss implications for improving in silico assessment of genomic variants and identifying new disease genes.

The Effective Conjugation Length Is Responsible for the Red/Green Spectral Tuning in the Cyanobacteriochrome Slr1393g3.

The origin of the spectral shift from a red- to a green-absorbing form in a cyanobacteriochrome, Slr1393g3, was identified by combined quantum mechanics/molecular mechanics simulations. This protein, related to classical phytochromes, carries the open-chain tetrapyrrole chromophore phycocyanobilin. Our calculations reveal that the effective conjugation length in the chromophore becomes shorter upon conversion from the red to the green form. This is related to the planarity of the entire chromophore. A large distortion was found for the terminal pyrrole rings A and D; however, the D ring contributes more strongly to the photoproduct tuning, despite a larger change in the twist of the A ring. Our findings implicate that the D ring twist can be exploited to regulate the absorption of the photoproduct. Hence, mutations that affect the D ring twist can lead to rational tuning of the photoproduct absorption, allowing the tailoring of cyanobacteriochromes for biotechnological applications such as optogenetics and bioimaging.

Single-cell epigenetics - Chromatin modification atlas unveiled by mass cytometry.

Modifications of histone proteins are fundamental to the regulation of epigenetic phenotypes. Dysregulations of histone modifications have been linked to the pathogenesis of diverse human diseases. However, identifying differential histone modifications in patients with immune-mediated diseases has been challenging, in part due to the lack of a powerful analytic platform to study histone modifications in the complex human immune system. We recently developed a highly multiplexed platform, Epigenetic landscape profiling using cytometry by Time-Of-Flight (EpiTOF), to analyze the global levels of a broad array of histone modifications in single cells using mass cytometry. In this review, we summarize the development of EpiTOF and discuss its potential applications in biomedical research. We anticipate that this platform will provide new insights into the roles of epigenetic regulation in hematopoiesis, immune cell functions, and immune system aging, and reveal aberrant epigenetic patterns associated with immune-mediated diseases.

A pipeline to extract drug-adverse event pairs from multiple data sources.

BACKGROUND: Pharmacovigilance aims to uncover and understand harmful side-effects of drugs, termed adverse events (AEs). Although the current process of pharmacovigilance is very systematic, the increasing amount of information available in specialized health-related websites as well as the exponential growth in medical literature presents a unique opportunity to supplement traditional adverse event gathering mechanisms with new-age ones. METHOD: We present a semi-automated pipeline to extract associations between drugs and side effects from traditional structured adverse event databases, enhanced by potential drug-adverse event pairs mined from user-comments from health-related websites and MEDLINE abstracts. The pipeline was tested using a set of 12 drugs representative of two previous studies of adverse event extraction from health-related websites and MEDLINE abstracts. RESULTS: Testing the pipeline shows that mining non-traditional sources helps substantiate the adverse event databases. The non-traditional sources not only contain the known AEs, but also suggest some unreported AEs for drugs which can then be analyzed further. CONCLUSION: A semi-automated pipeline to extract the AE pairs from adverse event databases as well as potential AE pairs from non-traditional sources such as text from MEDLINE abstracts and user-comments from health-related websites is presented.

Comparative Analysis of Hemostasis and Staple-Line Integrity between Medtronic Tri-StapleTM with Preloaded Buttress Material and the AEONTM Stapler in Bariatric Surgery.

Background and Objectives: Haemostasis-related complications associated with Medtronic Tri-stapleTM with preloaded buttress material and the novel, naked AEONTM gastrointestinal staplers have not been extensively studied in bariatric surgery. The study aimed to assess and compare the 30-day haemostasis-related complications between Medtronic Tri-stapleTM and AEONTM GIA staplers. Methods: A retrospective analysis was performed on data from patients who underwent primary or revision sleeve gastrectomy (SG) or the sleeve component of single anastomosis duodeno-ileal bypass with SG (SADI-S) in a private hospital in Australia between November 2021 and December 2022. The surgeries were performed by a single surgeon, using either Medtronic Tri-stapleTM or AEONTM staplers. Results: The analysis included 250 patients, with the first 125 consecutive patients receiving staple line using the Medtronic Tri-stapleTM GIA stapler and the subsequent 125 patients receiving staple line using the AEONTM GIA stapler. Statistical analysis revealed no significant differences in the distribution of surgical procedures between the Medtronic and AEON groups. In the AEON group, there were statistically higher numbers of diabetics and former tobacco users, while other preoperative characteristics did not significantly differ between the two groups. The AEON group had a significantly longer mean operative time, while the length of hospital stay was significantly shorter. No intraoperative or 30-day complications, deaths, emergency room visits, readmissions, or reoperations were observed in either group. Conclusion: The novel, naked AEONTM stapler demonstrated non-inferiority to the established Medtronic Tri-StapleTM with preloaded buttress material in achieving hemostasis and maintaining staple-line integrity in bariatric surgery.

The Role of Natriuretic Peptides in Predicting Adverse Outcomes After Cardiac Surgery: An Updated Systematic Review.

The increasing global burden of cardiovascular disease, particularly, in the aging population, has led to an increase in high-risk cardiac surgical procedures. The current preoperative risk stratification scores, such as the European System for Cardiac Operative Risk Evaluation and the Society for Thoracic Surgeons score, have limitations in their predictive accuracy and tend to underestimate the mortality risk in higher-risk populations. This systematic review aimed to evaluate the utility of natriuretic peptides, brain natriuretic peptide (BNP) and its precursor prohormone (N-terminal prohormone BNP), as predictive biomarkers for adverse outcomes after cardiac surgery. A comprehensive search strategy was performed, and 63 studies involving 40,667 patients who underwent major cardiac operations were included for data extraction. Preoperative levels of BNP and N-terminal prohormone BNP seemed to be associated with an increased risk of short- and long-term mortality, postoperative heart failure, kidney injury, and length of intensive care unit stay. However, their predictive value for postoperative arrhythmias and myocardial infarction was less established. Our findings suggest that natriuretic peptides may play an important role in risk prediction in patients who underwent cardiac surgery. The addition of these biomarkers to the existing clinical risk stratification strategies may enhance their predictive accuracy. However, this needs to be endorsed by data derived from wide-scale clinical trials.

MTL neurons phase-lock to human hippocampal theta.

Memory formation depends on neural activity across a network of regions, including the hippocampus and broader medial temporal lobe (MTL). Interactions between these regions have been studied indirectly using functional MRI, but the bases for interregional communication at a cellular level remain poorly understood. Here, we evaluate the hypothesis that oscillatory currents in the hippocampus synchronize the firing of neurons both within and outside the hippocampus. We recorded extracellular spikes from 1854 single- and multi-units simultaneously with hippocampal local field potentials (LFPs) in 28 neurosurgical patients who completed virtual navigation experiments. A majority of hippocampal neurons phase-locked to oscillations in the slow (2-4 Hz) or fast (6-10 Hz) theta bands, with a significant subset exhibiting nested slow theta × beta frequency (13-20 Hz) phase-locking. Outside of the hippocampus, phase-locking to hippocampal oscillations occurred only at theta frequencies and primarily among neurons in the entorhinal cortex and amygdala. Moreover, extrahippocampal neurons phase-locked to hippocampal theta even when theta did not appear locally. These results indicate that spike-time synchronization with hippocampal theta is a defining feature of neuronal activity in the hippocampus and structurally connected MTL regions. Theta phase-locking could mediate flexible communication with the hippocampus to influence the content and quality of memories.