Biomedical subjects

Patrick May

Publications and source records attributed to Patrick May.

11 recordsLinked to original sources

PubMed2025

Genome-wide association study of copy number variations in Parkinson's disease.

OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

Journal Article↗

PubMed2006

Connectivity independent protein-structure alignment: a hierarchical approach.

BACKGROUND: Protein-structure alignment is a fundamental tool to study protein function, evolution and model building. In the last decade several methods for structure alignment were introduced, but most of them ignore that structurally similar proteins can share the same spatial arrangement of secondary structure elements (SSE) but differ in the underlying polypeptide chain connectivity (non-sequential SSE connectivity). RESULTS: We perform protein-structure alignment using a two-level hierarchical approach implemented in the program GANGSTA. On the first level, pair contacts and relative orientations between SSEs (i.e. alpha-helices and beta-strands) are maximized with a genetic algorithm (GA). On the second level residue pair contacts from the best SSE alignments are optimized. We have tested the method on visually optimized structure alignments of protein pairs (pairwise mode) and for database scans. For a given protein structure, our method is able to detect significant structural similarity of functionally important folds with non-sequential SSE connectivity. The performance for structure alignments with strictly sequential SSE connectivity is comparable to that of other structure alignment methods. CONCLUSION: As demonstrated for several applications, GANGSTA finds meaningful protein-structure alignments independent of the SSE connectivity. GANGSTA is able to detect structural similarity of protein folds that are assigned to different superfamilies but nevertheless possess similar structures and perform related functions, even if these proteins differ in SSE connectivity.

Algorithms↗

PubMed2004

Auditory event-related responses are generated independently of ongoing brain activity.

For researchers and clinical practitioners alike, evoked and event-related responses measured with MEG and EEG provide the means for studying human brain function and dysfunction. However, the generation mechanism of event-related responses remains unclear, hindering our ability to formulate viable theories of neural information processing. Event-related responses are assumed to be generated either (1) separately of ongoing, oscillatory brain activity or (2) through stimulus-induced reorganization of ongoing activity. Here, we approached this issue through examining single-trial auditory MEG data in humans. We demonstrate that phase coherence over trials observed with commonly used signal decomposition methods (e.g., wavelets) can result from both a phase-coherent state of ongoing oscillations and from the presence of a phase-coherent event-related response which is additive to ongoing oscillations. To avoid this problem, we introduce a method based on amplitude variance to establish the relationship between ongoing oscillations and event-related responses. We found that auditory stimuli do not give rise to phase reorganization of ongoing activity. Further, increases in spectral power accompany the emergence of event-related responses, and the relationship between spectral power and the amplitude of these responses can be accounted for by a linear summation of the event-related response and ongoing oscillation with a stochastically distributed phase. Thus, on the basis of our observations, auditory event-related responses are unique descriptors of neural information processing in humans, generated by processes separate from and additive to ongoing brain activity.

Acoustic Stimulation↗

PubMed2004

PTGL--a web-based database application for protein topologies.

Protein Topology Graph Library (PTGL) is a database application for the representation and retrieval of protein topologies. Protein topologies are based on a graph-theoretical protein model at secondary structure level. Different views on protein topology are given by four linear notations for their characterization. Protein topologies can be derived at different description levels considering alpha- and beta-structures. The on-line search tool is based on an object-relational database and provides a query browser for data interrogation by string patterns, keyword queries and sequence similarity. Protein topologies are represented both as schematic diagrams and as three-dimensional images.

Computer Graphics↗

PubMed2004

Human posterior auditory cortex gates novel sounds to consciousness.

Life or death in hostile environments depends crucially on one's ability to detect and gate novel sounds to awareness, such as that of a twig cracking under the paw of a stalking predator in a noisy jungle. Two distinct auditory cortex processes have been thought to underlie this phenomenon: (i) attenuation of the so-called N1 response with repeated stimulation and (ii) elicitation of a mismatch negativity response (MMN) by changes in repetitive aspects of auditory stimulation. This division has been based on previous studies suggesting that, unlike for the N1, repetitive "standard" stimuli preceding a physically different "novel" stimulus constitute a prerequisite to MMN elicitation, and that the source loci of MMN and N1 are different. Contradicting these findings, our combined electromagnetic, hemodynamic, and psychophysical data indicate that the MMN is generated as a result of differential adaptation of anterior and posterior auditory cortex N1 sources by preceding auditory stimulation. Early ( approximately 85 ms) neural activity within posterior auditory cortex is adapted as sound novelty decreases. This alters the center of gravity of electromagnetic N1 source activity, creating an illusory difference between N1 and MMN source loci when estimated by using equivalent current dipole fits. Further, our electroencephalography data show a robust MMN after a single standard event when the interval between two consecutive novel sounds is kept invariant. Our converging findings suggest that transient adaptation of feature-specific neurons within human posterior auditory cortex filters superfluous sounds from entering one's awareness.

Adult↗

PubMed2004

Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR.

We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).

Amyloid Precursor Protein Secretases↗

PubMed2004

P3 cap modified Phe*-Ala series BACE inhibitors.

With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).

Amyloid Precursor Protein Secretases↗

PubMed2004

Transient brain responses predict the temporal dynamics of sound detection in humans.

The neural events leading up to the conscious experience of stimulus events have remained elusive. Here we describe stimulation conditions under which activation in human auditory cortex can be used to predict the temporal dynamics of behavioral sound detection. Subjects were presented with auditory stimuli whose energy smoothly increased from a silent to a clearly audible level over either 1, 1.5, or 2 s. Magnetoencephalographic (MEG) recordings were carried out in the passive and active recording conditions. In the active condition, the subjects were instructed to attend to the auditory stimuli and to press a response key when these became audible. In both conditions, the stimuli elicited a prominent transient response whose emergence is unexplainable by changes in stimulus intensity alone. This transient response was larger in amplitude over the right hemisphere and in the active condition. Importantly, behavioral sound detection followed this brain activation with a constant delay of 180 ms, and further the latency variations of the brain response were directly carried over to behavioral reaction times. Thus, noninvasively measured transient events in the human auditory cortex can be used to predict accurately the temporal course of sound detection and may therefore turn out to be useful in clinical settings.

Adult↗

PubMed2003

Visual short-term memory load affects sensory processing of irrelevant sounds in human auditory cortex.

We used whole-head magnetoencephalography (MEG) to investigate neural activity in human auditory cortex elicited by irrelevant tones while the subjects were engaged in a short-term memory task presented in the visual modality. As compared to a no-memory-task condition, memory load enhanced the amplitude of the auditory N1m response. In addition, the N1m amplitude depended on the phase of the memory task, with larger response amplitudes observed during encoding than retention. Further, these amplitude modulations were accompanied by anterior-posterior shifts in N1m source locations. The results show that a memory task for visually presented stimuli alters sensory processing in human auditory cortex, even when subjects are explicitly instructed to ignore any auditory stimuli. Thus, it appears that task demands requiring attentional allocation and short-term memory result in interaction across visual and auditory brain areas carrying out the processing of stimulus features.

Acoustic Stimulation↗

PubMed2002

Human cortical dynamics determined by speech fundamental frequency.

Evidence for speech-specific brain processes has been searched for through the manipulation of formant frequencies which mediate phonetic content and which are, in evolutionary terms, relatively "new" aspects of speech. Here we used whole-head magnetoencephalography and advanced stimulus reproduction methodology to examine the contribution of the fundamental frequency F0 and its harmonic integer multiples in cortical processing. The subjects were presented with a vowel, a frequency-matched counterpart of the vowel lacking in phonetic contents, and a pure tone. The F0 of the stimuli was set at that of a typical male (i.e., 100 Hz), female (200 Hz), or infant (270 Hz) speaker. We found that speech sounds, both with and without phonetic content, elicited the N1m response in human auditory cortex at a constant latency of 120 ms, whereas pure tones matching the speech sounds in frequency, intensity, and duration gave rise to N1m responses whose latency varied between 120 and 160 ms. Thus, it seems that the fundamental frequency F0 and its harmonics determine the temporal dynamics of speech processing in human auditory cortex and that speech specificity arises out of cortical sensitivity to the complex acoustic structure determined by the human sound production apparatus.

Adult↗

PubMed2002

Cortical processing of speech sounds and their analogues in a spatial auditory environment.

We used magnetoencephalographic (MEG) measurements to study how speech sounds presented in a realistic spatial sound environment are processed in human cortex. A spatial sound environment was created by utilizing head-related transfer functions (HRTFs), and using a vowel, a pseudo-vowel, and a wide-band noise burst as stimuli. The behaviour of the most prominent auditory response, the cortically generated N1m, was investigated above the left and right hemisphere. We found that the N1m responses elicited by the vowel and by the pseudo-vowel were much larger in amplitude than those evoked by the noise burst. Corroborating previous observations, we also found that cortical activity reflecting the processing of spatial sound was more pronounced in the right than in the left hemisphere for all of the stimulus types and that both hemispheres exhibited contralateral tuning to sound direction.

Acoustic Stimulation↗