Biology subjects

Halpern, D.

Publications and source records attributed to Halpern, D..

8 recordsLinked to original sources

bioRxiv2026

Identifying Phelan-McDermid-Like Electrophysiological Subtypes in Autism Using EEG and Machine Learning

BackgroundPhelan McDermid syndrome (PMS), caused by SHANK3 haploinsufficiency, is a genetic form of autism spectrum disorder (ASD) that provides a genetically defined model for studying ASD-related circuit dysfunction. SHANK3 mutations disrupt synaptic organization and cortical synchrony, leading to attenuated gamma-band auditory steady-state responses (ASSRs). We investigated whether PMS-related electrophysiological signatures could be identified using machine learning and whether similar patterns are present in a subset of individuals with idiopathic ASD (iASD). MethodsEEG recorded during a 40-Hz ASSR paradigm was collected from 123 participants (42 TD aged 2-30, 56 iASD aged 3-31, 25 PMS aged 2-26). We extracted time-series, ERSP, FOOOF-derived spectral, and intertrial phase coherence (ITPC) features. XGBoost models with leave-one-out cross-validation classified PMS versus TD; the best age/sex-adjusted ITPC model was then applied to iASD participants to derive a Synchrony Atypicality Index (SAI). Unsupervised clustering of high-dimensional ITPC features was also performed. ResultsITPC-based models showed the strongest discrimination between TD and PMS participants (AUROC = 0.83). When applied to iASD participants, 35.7% exhibited elevated SAI, indicating a PMS-like gamma-band phase-locking profile. Classification of iASD versus PMS performed poorly in the full sample but improved markedly after excluding high-SAI iASD individuals, consistent with substantial heterogeneity within iASD. Unsupervised clustering of ITPC features identified PMS-enriched clusters that also captured high-SAI iASD participants. Results were consistent after controlling for age in sensitivity analyses. ConclusionsReduced 40-Hz ITPC is a mechanistically interpretable electrophysiological signature of PMS and identifies a biologically meaningful PMS-like subgroup within iASD, supporting biomarker-guided stratification.

neuroscience↗

bioRxiv2024

Metabolic rerouting by gain-of-function mutations overcomes plsX essentiality in Staphylococcus aureus

Phospholipids are essential components of most cell membranes. In Staphylococcus aureus, PlsX acyltransferase is considered indispensable for initiating phospholipid synthesis, unless exogenous fatty acids (FAs) are available to bypass this requirement. We report that S. aureus can capture internal FA sources to overcome PlsX essentiality in a {Delta}plsX mutant via point mutations in either of two genes: fabF, which encodes the FA synthesis enzyme 3-oxoacyl-(acyl-carrier-protein) synthase II, or fadM, which encodes an understudied bifunctional acyl-CoA thioesterase and ACP binding protein. Despite growth rescue, both {Delta}plsX suppressors differ from the parental strain by producing phospholipids with shortened FA lengths suggesting that both suppressors lead to premature FA release during synthesis. Additionally, both suppressors display increased sensitivity to {beta}-lactam antibiotics. The similar behavior of both suppressors led us to show that fabF suppressors require the presence of fadM, indicative of FabF-FadM cooperation. We propose that reduced processivity of FabF suppressor variants, or greater availability of FadM for ACP binding in FadM variants, facilitates FA release from FabF-acyl-ACP intermediates. A FabF-FadM relay leading to FA release may contribute to homeostasis between FASII and phospholipid synthesis pathways. SignificancePhospholipids are vital cell membrane components. The essential Staphylococcus aureus phospholipid synthesis enzyme PlsX uses acyl-ACP, the end-product of fatty acid (FA) synthesis (FASII), to initiate phospholipid production. Despite its central role, PlsX can be substituted by exogenous FAs whose phosphorylation yields the same product. We discovered that without FA supplementation, mutants arise that rescue growth, indicating that internal FAs are released. Mutations occurred in either FabF, a FASII enzyme, or in FadM, an incompletely characterized protein. Our analyses give evidence that FabF and FadM proteins cooperate, and facilitate FA availability when either protein is mutated. We propose that in normal conditions, FadM might act as an "overflow valve" by releasing FAs from the FabF intermediate, which prevents buildup of FASII intermediates, and ensures FA-phospholipid balance. Remarkably, while this pathway rescues S. aureus growth, it sensitizes the MRSA strain to {beta}-lactam antibiotics.

microbiology↗

bioRxiv2023

Study-Phase Reinstatement: Encoding Spontaneous Thoughts as Memories

Can the brain improve the retrievability of an experience after it has occurred? Systems consolidation theory proposes that item-specific cortical reactivation during post-encoding rest periods facilitates the formation of stable memory representations, a prediction supported by neural evidence in humans and animals. Such reactivation may also occur on shorter time scales, offering a potential account of classic list memory phenomena but lacking in support from neural data. Leveraging the high-temporal specificity of intracranial electroencephalography (iEEG), we investigate spontaneous reactivation of previously experienced items during brief intervals between individual encoding events. Across two large-scale free recall experiments, we show that reactivation during these periods, measured by spectral iEEG similarity, predicts subsequent recall. In a third experiment, we show that the same methodology can identify post-encoding reactivation that correlates with subsequent memory, consistent with previous results. Thus, spontaneous study-phase reinstatement reliably predicts memory behavior, linking psychological accounts to neural mechanisms and providing evidence for rapid consolidation processes during encoding.

neuroscience↗

bioRxiv2023

Optimizing learning via real-time neural decoding

BackgroundSpectral features of human electroencephalographic (EEG) recordings during learning predict subsequent recall variability. New methodCapitalizing on these fluctuating neural features, we develop a non-invasive closed-loop (NICL) system for real-time optimization of human learning. Participants play a virtual navigation and memory game; recording multi-session data across days allowed us to build participant-specific classification models of recall success. In subsequent closed-loop sessions, our platform manipulated the timing of memory encoding, selectively presenting items during periods of predicted good or poor memory function based on EEG features decoded in real time. ResultsWe observed greater memory modulation (difference between recall rates when presenting items during predicted good vs. poor learning periods) for participants with higher out-of-sample classification accuracy. Comparison with Existing MethodsThis study demonstrates greater-than-chance memory decoding from EEG recordings in a naturalistic virtual navigation task with greater real-world validity than basic word-list recall paradigms. Here we modulate memory by timing stimulus presentation based on noninvasive scalp EEG recordings, whereas prior closed-loop studies for memory improvement involved intracranial recordings and direct electrical stimulation. Other noninvasive studies have investigated the use of neurofeedback or remedial study for memory improvement. ConclusionsThese findings present a proof-of-concept for using non-invasive closed-loop technology to optimize human learning and memory through principled stimulus timing, but only in those participants for whom classifiers reliably predict out-of-sample memory function.

neuroscience↗

bioRxiv2022

Searching memory in time and space

We investigated memory encoding and retrieval during a quasi-naturalistic spatial-episodic memory task in which subjects delivered items to landmarks in a desktop virtual environment and later recalled the delivered items. Transition probabilities and latencies revealed the spatial and temporal organization of memory. As subjects gained experience with the town, their improved spatial knowledge led to more efficient navigation and increased spatial organization during recall. Subjects who exhibited stronger spatial organization exhibited weaker temporal organization. Scalp-recorded electroencephalographic (EEG) signals revealed spectral correlates of successful encoding and retrieval. Increased theta power (T +) and decreased alpha/beta power (A-) accompanied successful encoding, with the addition of increased gamma (G+) accompanying successful retrieval. Logistic-regression classifiers trained on spectral features reliably predicted mnemonic success in held-out sessions. Univariate and multivariate EEG analyses revealed a similar spectral T +A-G+ of successful memory. These findings extend behavioral and neural signatures of successful encoding and retrieval to a naturalistic task in which learning occurs within a spatiotemporal context.

neuroscience↗

bioRxiv2022

Inverse correlation between stress response and virulence factor expression in FASII antibiotic-adapted Staphylococcus aureus and consequences for infection

Antibiotics inhibiting the fatty acid synthesis (FASII) pathway of the major pathogen Staphylococcus aureus reach their enzyme targets, but bacteria continue growth by using environmental fatty acids (eFAs) to produce phospholipids. We assessed how extreme changes in membrane phospholipids provoked by FASII-antibiotics affect global S. aureus physiology. Anti-FASII provoked massive lasting expression changes without genomic rearrangements. Several regulators, rather than one master switch, contributed to the timing of anti-FASII adaptation. Numerous virulence and adhesion factors showed decreased levels and/or activity. Conversely, stress response protein levels increased, and correlated with greater tolerance to peroxides. Notably, peroxide priming stimulated eFA incorporation efficiency and facilitated adaptation to FASII inhibition. These findings establish a link between oxidative stress and FA incorporation. Consistent with major shift in protein expression, anti-FASII-adapted S. aureus killed an insect host more slowly but continued multiplying. Thus, while anti-FASII-adapted populations are less equipped to damage the host, they may be better fit for long term survival, and could constitute a reservoir for re-infection.

microbiology↗

bioRxiv2020

(p)ppGpp and malonyl-CoA set the pace for Staphylococcus aureus adaptation to FASII antibiotics and provide a basis for bi-therapy inhibition

Fatty acid biosynthesis (FASII) enzymes are considered valid targets for antimicrobial drug development against the human pathogen Staphylococcus aureus. However, incorporation of host fatty acids confers FASII antibiotic adaptation that compromises prospective treatments. S. aureus adapts to FASII inhibitors by a first non-replicative latency period followed by outgrowth. Here we used transcriptional fusions and direct metabolite measurements to investigate the factors that dictate the duration of latency prior to outgrowth. We show that stringent response induction leads to repression of FASII and phospholipid synthesis genes. (p)ppGpp induction inhibits synthesis of malonyl-CoA, a molecule that derepresses FapR, a key regulator of FASII and phospholipid synthesis. Anti-FASII treatment also triggers transient expression of (p)ppGpp-regulated genes during the anti-FASII latency phase, with concomitant repression of FapR regulon expression. These effects are reversed upon outgrowth. GTP depletion, a known consequence of stringent response, also occurs during FASII latency, and is proposed as the common signal linking these responses. We next show that anti-FASII treatment shifts malonyl-CoA distribution between its interactants FapR and FabD, towards FapR, increasing expression of phospholipid synthesis genes plsX and plsC during outgrowth. We conclude that components of the stringent response dictate malonyl-CoA availability in S. aureus FASII regulation, and contribute to latency prior to anti-FASII-adapted outgrowth. A combinatory approach, coupling a (p)ppGpp inducer and an anti-FASII, blocks S. aureus outgrowth, opening perspectives for bi-therapy treatment. ImportanceStaphylococcus aureus is a major human bacterial pathogen for which new inhibitors are urgently needed. Antibiotic development has centered on the fatty acid synthesis (FASII) pathway, which provides the building blocks for bacterial membrane phospholipids. However, S. aureus overcomes FASII inhibition and adapts to anti-FASII by using exogenous fatty acids that are abundant in host environments. This adaptation mechanism comprises a transient latency period, followed by bacterial outgrowth. Here we use metabolite sensors and promoter reporters to show that responses to stringent conditions and to FASII inhibition intersect: both involve GTP and malonyl-CoA. These two signaling molecules contribute to modulating the duration of latency prior to S. aureus adaptation outgrowth. We exploit these novel findings to propose a bi-therapy treatment against staphylococcal infections.

microbiology↗

bioRxiv2019

Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

Development of fatty acid synthesis pathway (FASII) inhibitors against the major human pathogen Staphylococcus aureus hinges on the accepted but unproven postulate that an endogenously synthesized branched chain fatty acid is required to complete membrane phospholipids. Evidence for anti-FASII efficacy in animal models supported this view. However, restricted test conditions used previously to show FASII antibiotic efficacy led us to investigate these questions in a broader, host-relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations when exposed to host environments. Treatment with a lead FASII antibiotic upon signs of infection, rather than just after inoculation as commonly practiced, failed to eliminate S. aureus from infected organs in a septicemia model. In vitro, addition of serum facilitated rapid S. aureus FASII bypass by environmental fatty acid (eFA) replacement in phospholipids. Serum lowers membrane stress, leading to increased retention of the two substrates required for exogenous fatty acid (eFA) utilization. In these conditions, eFA occupy both phospholipid positions 1 and 2, regardless of anti-FASII selection. This study revises conclusions on S. aureus fatty acid requirements by disproving the postulate of fatty acid stringency, and reveals an Achilles heel for using FASII antibiotics to treat infection in monotherapy.\n\nSignificance statementAntibiotic discovery to overcome treatment failure has huge socio-medical and economic stakes. The fatty acid synthesis (FASII) pathway is considered an ideal druggable target against the human pathogen Staphylococcus aureus, based on evidence of anti-FASII efficacy in infection models, and the postulate that S. aureus synthesizes an irreplaceable fatty acid. We report that S. aureus alters its behavior in host-relevant conditions. Administering FASII antibiotics upon signs of infection, rather than just after inoculation as frequently practiced, failed to clear septicemic infections. In serum, S. aureus rapidly overcomes FASII antibiotics by incorporating alternative fatty acids. We conclude that previously, premature antibiotic treatments and experimental constraints masked S. aureus antibiotic adaptation capacity. These findings should help streamline future drug development programs.

microbiology↗