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PubMed1977

Structural basis of heme reactivity in myoglobin and leghemoglobin: thermal difference spectra.

Thermal pertubation difference spectra of sperm whale myoglobin (Mb) and soybean leghemoglobin a (Lb a) in the near-ultraviolet reveal similarities in the tryptophan environment of the two proteins. Of the two tryptophans in each protein, one has its indolyl NH group fully exposed to aqueous solvent, while the other behaves as if it were surrounded by motile but nonpolar residues with little access to water. These environments are not significantly altered by removal of the heme group. Assuming conformational homology, the helix-spacing role of Trp-A12 in Mb (Kendrew, J.C. (1962), Brookhaven Symp. Biol. 15, 216-228) may be taken over, in Lb a, by Trp-H8 which, though remote in linear sequence, would occupy a suitable spatial location. Thermal difference spectra in the Soret and visible regions of pure high-spin (fluoroferric) and pure low-spin (cyanoferric) complexes showed a red shift on cooling Mb complexes, reflecting a predominantly nonpolar environment around the heme, but a blue shift on cooling Lb complexes, reflecting a more solvent-exposed environment. Thermal difference spectra using rose bengal as a probe of the heme pockets in the two apoproteins supported these conclusions. Thermal difference spectra for the high-spin complexes of both Mb and Lb are slightly larger in magnitude than in the low-spin complexes. This may reflect a more flexible heme pocket in the high-spin state, as suggested by recent circular dichroic results. A structural basis for the high oxygen affinity of Lb compared with Mb is proposed, based upon the observed differences in polarity and flexibility of the heme pocket and in amino acid substitutions.

Animals↗

PubMed1997

Post-translational processing and renal expression of mouse Indian hedgehog.

The full-length mouse Indian hedgehog (Ihh) cDNA was cloned from an embryonic 17.5-day kidney library and was used to study the post-translational processing of the peptide and temporal and spatial expression of the transcript. Sequence analysis predicted two putative translation initiation sites. Ihh translation was initiated at both initiation sites when expressed in an in vitro transcription/translation system. Expression of an Ihh mutant demonstrated that the internal translation initiation site was sufficient to produce the mature forms of Ihh. Ihh post-translational processing proceeded in a fashion similar to Sonic and Drosophila hedgehog; the unprocessed form underwent signal peptide cleavage as well as internal proteolytic processing to form a 19-kDa amino-terminal peptide and a 26-kDa carboxyl-terminal peptide. This processing required His313 present in a conserved serine protease motif. Ihh transcript was detected by in situ RNA hybridization as early as 10 days postcoitum (dpc) in developing gut, as early as 14.5 dpc in the cartilage primordium, and in the developing urogenital sinus. In semiquantitative reverse transcription-polymerase chain reaction experiments, Indian hedgehog transcript was first detected in the mouse metanephros at 14.5 dpc; transcript abundance increased with gestational age, becoming maximal in adulthood. In adult kidney, Ihh transcript was detected only in the proximal convoluted tubule and proximal straight tubule.

Amino Acid Sequence↗

PubMed2026

Mechanotransduction in musculoskeletal mesenchymal tissues: implications for bone, tendon, and cartilage regenerative engineering-a narrative review.

PURPOSE/AIM OF THE STUDY: To integrate evidence on how mechanical signals regulate musculoskeletal connective-tissue biology and how cellular context and loading history shape mechanotransduction and mechanical memory. MATERIALS AND METHODS: This narrative review synthesized PubMed-indexed evidence on extracellular matrix mechanics, adhesion complexes, the cytoskeleton, nucleus, primary cilia, mechanosensitive ion channels, cell state, and loading history in bone, tendon, ligament, and cartilage. RESULTS: Mechanotransduction is best understood as a coupled extracellular matrix-integrin-cytoskeleton-nucleus continuum rather than as independent cytoskeletal or nuclear drivers. Responses are conditioned by lineage stage, anatomic niche, inflammation, cellular subpopulation, and prior mechanical exposure. Mechanical memory may be encoded through persistent YAP/TAZ activity, microRNA programs, DNA methylation, histone modifications, chromatin architecture, and metabolic remodeling. Evidence is strongest for bone, including Piezo-dependent osteogenesis, TRPV4-mediated shear sensing, viscoelastic compression, osteocyte-stromal extracellular-vesicle signaling, and osteogenesis-angiogenesis coupling. Tendon and ligament require anisotropic architecture and strain-window control, whereas cartilage shows a narrow distinction between physiologic TRPV4-associated anabolism and high-strain or inflammation-sensitized Piezo/YAP-mediated maladaptation. CONCLUSIONS: Translational implications include mechanically defined cell expansion, biomaterial preconditioning, stage-specific rehabilitation, and potency assays incorporating loading history. Direct clinical validation of stable perioperative cellular mechanical memory remains limited. Future studies should combine controlled mechanical perturbation with bulk and single-cell RNA sequencing, chromatin-accessibility profiling, spatial methods, and perturbational genomics.

Mechanotransduction↗

PubMed2026

Cognitive impairment as a manifestation of SPG7: case report.

Hereditary spastic paraplegia (HSP) is a group of genetic disorders caused by >80 genes that can be described as either pure or complex forms.We report a case of a patient with a complex form of SPG7 with significant cognitive impairment.A 42-year-old man presented with a 10-year history of dysarthria, 5 years of gait difficulties, and 3 years of cognitive symptoms. Neuropsychological analysis showed deficits involving speed of information processing, mental flexibility, ideational fluency, verbal concept formation, visual working memory, and visual-spatial perception. Next-generation sequencing on whole blood revealed 2 heterozygous pathogenic variants in SPG7 (c. 1049_1077del, p. Pro350Glnfs*36 and c. 1529C>T, p. Ala510Val).There are emerging reports of complex forms of SPG7 presenting with impairments in memory, executive dysfunction, language, visuospatial processing, social functioning, and emotional communication. In this report, we describe a complex SPG7 patient who underwent formal neuropsychological testing to assess cognitive status in depth. This revealed deficits in speed of processing, visuospatial working memory and perception, impaired non-verbal intellect, and overall lack of insight, which have not yet been described in the literature.

Cognitive impairment↗

PubMedDate not supplied

4D bioinformatics: a new look at the ribosome as an example.

We have adapted the Java Molecular Viewer (JMV) to virtual reality display environments, through a number of extensions to the Java 3D code. Phylogenetic information derived from multiple alignments (temporal information) can be overlaid onto molecule structures (spatial information). The number of sequences included in the underlying multiple alignment can be changed instantaneously, resulting in dynamical updates of the displayed information. JMV was also extended to handle an infinite number of objects (molecules) in the same display. The objects can be manipulated in six degrees of freedom simultaneously or independently. We have used the small subunit ribosomal RNA to demonstrate the system (http:// cave.ucalgary.ca), which can be used for any molecule with a resolved structure.

Animals↗

PubMed2000

Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population.

Acquired cerebellar lesions in adults have been shown to produce impairments in higher function as exemplified by the cerebellar cognitive affective syndrome. It is not yet known whether similar findings occur in children with acquired cerebellar lesions, and whether developmental factors influence their presentation. In studies to date, survivors of childhood cerebellar tumours who demonstrate long-term deficits in cognitive functions have undergone surgery as well as cranial irradiation or methotrexate treatment. Investigation of the effects of the cerebellar lesion independent of the known deleterious effects of these agents is important for understanding the role of the cerebellum in cognitive and affective development and for informing treatment and rehabilitation strategies. If the cerebellar contribution to cognition and affect is significant, then damage in childhood may influence a wide range of psychological processes, both as an immediate consequence and as these processes fail to develop normally later on. In this study we evaluated neuropsychological data in 19 children who underwent resection of cerebellar tumours but who received neither cranial irradiation nor methotrexate chemotherapy. Impairments were noted in executive function, including planning and sequencing, and in visual-spatial function, expressive language, verbal memory and modulation of affect. These deficits were common and in some cases could be dissociated from motor deficits. Lesions of the vermis in particular were associated with dysregulation of affect. Behavioural deficits were more apparent in older than younger children. These results reveal that clinically relevant neuropsychological changes may occur following cerebellar tumour resection in children. Age at the time of surgery and the site of the cerebellar lesion influence the neurobehavioural outcome. The results of the present study indicate that the cerebellar cognitive affective syndrome is evident in children as well as in adults, and they provide further clinical evidence that the cerebellum is an essential node in the distributed neural circuitry subserving higher-order behaviours.

Adolescent↗

PubMed1989

Factorial analysis of dynamic lymphoscintigraphy in lower limb lymphoedema.

The purpose of this work is to assess the contribution of factor analysis to the interpretation of dynamic lymphoscintigraphy. Twenty six adult patients with a lower limb lymphoedema and five control patients were studied. The technique involved a 3 mCi lymphovectoscint* 99Tcm-labelled ammonium sulphur colloid, bilateral pedal subcutaneous injection. Recording consisted of 40 consecutive 1-min frames of both legs followed by static pictures of each leg and pelvis at 40 min and 4 h after injection. The analysis of static pictures allowed a classification of patients into three groups: enhanced pattern, hypoplasia and dermic reflux. To evaluate better the different kinetic components of the sequential pictures, a factorial analysis (FA) software package was used. FA processing enabled the extraction from the dynamic series of different dynamic components, factorial curves and their associated factorial images which represent the anatomic structures with the same temporal behaviour. In each pattern the results of dynamic recording and of three FA factors were compared. FA provides an analytical temporal and spatial description of the dynamic sequence by extracting the different kinetic components; it yields a better differentiation of vessel and interstitium activity. It also provides some clues towards the understanding of oedema physiopathology and is of potential interest for the management of lymphoedema.

Adolescent↗

PubMed1998

In vivo human cervical spinal cord deformation and displacement in flexion.

STUDY DESIGN: In vivo, quasi-static distortion of the human cervical spinal cord was measured in five volunteers during flexion of the neck using a motion-tracking magnetic resonance imaging technique. OBJECTIVES: To measure cord distortion and movement in living subjects. SUMMARY OF BACKGROUND DATA: In situ spinal cord measurements in human and rhesus monkey cadavers taken at full flexion demonstrate that the entire cervical cord elongates approximately 10% of its length at a neutral position, but no data are available at other angles of flexion, or in living subjects. METHODS: The spatial modulation of magnetization pulse sequence created a series of parallel lines in the image that deform with the tissue. A custom-designed device was built to guide the flexion of the neck and enhance motion reproducibility. Midsagittal plane images were acquired before and after flexion. The tagged line pattern in each pair of magnetic resonance images was compared to compute distortion and movement of the cervical spinal cord at varying degrees of flexion. RESULTS: Between a neutral posture and full flexion, the entire cord (C2-C7) elongated linearly with head flexion, increasing 10% and 6% of its initial length along the posterior and anterior surfaces, respectively. Average displacement was on the order of 1-3 mm, and varied with region. Specifically, the upper cord showed caudad movement in the spinal canal, and the lower cord moved cephalad, again with larger movements on the posterior surface. CONCLUSIONS: The cervical cord elongates and displaces significantly during head flexion in human volunteers, offering valuable information regarding the normal milieu of the cord.

Adult↗

PubMed2003

A functional magnetic resonance imaging study in patients with benign essential blepharospasm.

OBJECTIVE To identify blinking-induced functional magnetic resonance imaging (fMRI) activation patterns in five benign essential blepharospasm (BEB) patients and five age-matched control subjects. METHODS fMRI brain activation maps were obtained during repeated conditions of spontaneous and voluntary blinking in BEB and control groups. Blood oxygen level-dependent intensity images were collected from two separate runs as 16 axial and 16 coronal, 8 mm thick slices using a T2-star weighted gradient echo EPI sequence, coregistered with anatomic images. Spatially normalized and isotropically blurred activation maps for each subject were combined within groups of BEB patients and control subjects to generate maps of the intersubject mean fractional signal change.RESULTS Substantially greater activation during spontaneous and voluntary blinking was seen in BEB patients compared with control subjects in the anterior visual cortex, anterior cingulate cortex, primary motor cortex, central region of the thalamus, and superior cerebellum. In both groups, activations were generally greater for voluntary than for spontaneous blinking. CONCLUSIONS The activations observed might represent a hyperactive cortical circuit linking visual cortex, limbic system, supplementary motor cortex, cerebellum, and supranuclear motor pathways innervating the periorbital muscles.

Blepharospasm↗

PubMed2026

From genotype to phenotype: understanding the genetic basis of autism.

PURPOSE OF REVIEW: This paper covers some of the key findings on the topic of genetic influences in autism over the last 12-18 months, which consist of significant conceptual shifts and new insights from recent technological advances. RECENT FINDINGS: Autism is a highly heritable condition, with significant heterogeneity of the genes that influence the development of this condition. The heterogeneity of autism, and multiple pathways contributing to the development of an autistic phenotype, create challenges in our understanding, diagnosis, and management of this condition.Recent studies of common genetic variation and polygenic risk scores have focussed on resolving phenotypic heterogeneity and identifying meaningful autism subtypes. Rare-variant discovery has expanded across ancestries, the X chromosome, noncoding loci, structural variants, and tandem repeats, aided by long-read and pangenome-informed sequencing. Single-cell multiomics, spatial perturbation methods and human organoid models have connected genetic variation to cell-type-specific and developmental phenotypes, while also revealing substantial mutation-specific effects and methodological sensitivity. Genetic testing increasingly provides aetiological diagnoses and informs medical surveillance. Recent developments also illustrate the therapeutic potential of gene-first approaches for selected monogenic neurodevelopmental disorders. SUMMARY: Recent developments have expanded our understanding of the way the genetic basis of autism manifests phenotypically.

autism↗

PubMed1990

Different Temporal and Spatial Gene Expression Patterns Occur during Anther Development.

We studied the temporal and spatial regulation of three mRNA sequence sets that are present exclusively, or at elevated levels, in the tobacco anther. One mRNA set accumulates in the tapetum and decays as the tapetum degenerates later in anther development. The second mRNA set accumulates after the tapetal-specific mRNAs, is localized within the stomium and connective, and also decays as these cell types degenerate during anther maturation. The third mRNA sequence set persists throughout anther development and is localized within most anther tissues. A tapetal-specific gene, designated as TA29, was isolated from a tobacco genome library. Runoff transcription studies and experiments with chimeric [beta]-glucuronidase and diphtheria toxin A-chain genes showed that the TA29 gene is regulated primarily at the transcriptional level and that a 122-base pair 5[prime] region can program the tapetal-specific expression pattern. Destruction of the tapetum by the cytotoxic gene had no effect on the differentiation and/or function of surrounding sporophytic tissues but led to the production of male-sterile plants. Together, our studies show that several independent gene expression programs occur during anther development and that these programs correlate with the differentiated state of specific anther cell types.

Journal Article↗

PubMed2004

Registration of real-time 3-D ultrasound images of the heart for novel 3-D stress echocardiography.

Stress echocardiography is a routinely used clinical procedure to diagnose cardiac dysfunction by comparing wall motion information in prestress and poststress ultrasound images. Incomplete data, complicated imaging protocols and misaligned prestress and poststress views, however, are known limitations of conventional stress echocardiography. We discuss how the first two limitations are overcome via the use of real-time three-dimensional (3-D) ultrasound imaging, an emerging modality, and have called the new procedure "3-D stress echocardiography." We also show that the problem of misaligned views can be solved by registration of prestress and poststress 3-D image sequences. Such images are misaligned because of variations in placing the ultrasound transducer and stress-induced anatomical changes. We have developed a technique to temporally align 3-D images of the two sequences first and then to spatially register them to rectify probe placement error while preserving the stress-induced changes. The 3-D spatial registration is mutual information-based. Image registration used in conjunction with 3-D stress echocardiography can potentially improve the diagnostic accuracy of stress testing.

Algorithms↗

PubMed2007

Spatio-temporal context for robust multitarget tracking.

In multitarget tracking, the main challenge is to maintain the correct identity of targets even under occlusions or when differences between the targets are small. The paper proposes a new approach to this problem by incorporating the context information. The context of a target in an image sequence has two components: the spatial context including the local background and nearby targets and the temporal context including all appearances of the targets that have been seen previously. The paper considers both aspects. We propose a new model for multitarget tracking based on the classification of each target against its spatial context. The tracker searches a region similar to the target while avoiding nearby targets. The temporal context is included by integrating the entire history of target appearance based on probabilistic principal component analysis (PPCA). We have developed a new incremental scheme that can learn the full set of PPCA parameters accurately online. The experiments show robust tracking performance under the condition of severe clutter, occlusions, and pose changes.

Algorithms↗

PubMed2005

Age, phylogeography and population structure of the microendemic banded spring snail, Mexipyrgus churinceanus.

Recent theoretical and empirical studies of phylogeography and population structure indicate that many processes influence intraspecific evolutionary history. The present study represents the first examination of various forces influencing the spatial and temporal patterns of sequence variation in the freshwater Mexican banded spring snail, Mexipyrgus churinceanus. This snail occurs in one of the most critically endangered centres of freshwater endemism, the desert ecosystem of Cuatro Ciénegas. From cytochrome b mtDNA sequence variation, there is strong evidence of long-term isolation of three regions, suggesting that these regions represent evolutionarily distinct lineages. Molecular clock estimates of clade age indicate a time to most recent common ancestor of approximately 2.5 million years ago (Ma). The three regions differ considerably in the historical and demographic forces affecting population structure. The western populations have extremely low mtDNA diversity consistent with a severe bottleneck dating to 50,000 years before present (bp). The nearby Rio Mesquites drainage is characterized by fragmentation events, restricted gene flow with isolation by distance, and higher levels of mtDNA polymorphism. These patterns are consistent with the long-term stability of this drainage along with habitat heterogeneity and brooding contributing to population isolation and restricted gene flow. Southeastern populations show evidence of range expansion and a strong influence of genetic drift. Migration rates between drainages indicate very little gene flow between drainages except for asymmetric migration from the Rio Mesquites into both western and southeastern drainages.

Animals↗

PubMed1992

Use of magnetic resonance imaging to analyze the performance of hollow-fiber bioreactors.

Preliminary experiments were described that demonstrate that MRI is an effective tool for the noninvasive study of hollow-fiber bioreactors. Flow-compensated velocity-encoding pulse sequences were successively applied to analyze the velocity patterns in a module operated without cells, with an artificially induced flow field perturbation. Diffusion damping pulse sequences were also used to spatially resolve regions of cell growth in a bioreactor. These experiments provide the necessary basis from which future flow and spectroscopic studies can be conducted.

Animals↗

PubMed1998

Serial report and item recognition of novel visual patterns.

Previous studies of memory for novel visual patterns have reported how item recognition varies across serial positions, but have neglected serial order memory. In Expts 1 and 2 participants reported the order in which short series of novel patterns had been presented. The results showed markedly bowed serial position curves similar to those reported for sequences of verbal items or spatial locations. Concurrent articulation reduced performance in the serial report task relative to the memory task alone (Expt 2) or concurrent tapping (Expt 3) suggesting that a verbal component was involved. When two-alternative forced choice tests were used to test memory for the configuration of each pattern in the series, no primacy or recency was found (Expt 4). In Expt 5 the presentation of a series of five items was followed at random by either a serial report or the two-choice item recognition task. The serial position curves for the two tasks remained different, suggesting that encoding strategies were not responsible. The results show that bowed serial position curves are found when judgments of serial order are required, even when phonological coding is discouraged, whereas memory for item descriptions is independent of serial position. The implications for current conceptualizations of short-term memory are discussed.

Analysis of Variance↗

PubMed2025

The auxin gatekeepers: Evolution and diversification of the YUCCA family.

The critically important YUCCA (YUC) gene family is highly conserved and specific to the plant kingdom, primarily responsible for the final and rate-limiting step for indole-3-acetic acid (IAA) biosynthesis. IAA is an essential phytohormone, involved in virtually all aspects of plant growth and development. In addition, IAA is involved in fine-tuning plant responses to biotic and abiotic interactions and stresses. While the YUC gene family has significantly expanded throughout the plant kingdom, a detailed analysis of the evolutionary patterns driving this diversification has not been performed. Here, we present a comprehensive phylogenetic analysis of the YUC family, combining YUCs from species representing key evolutionary plant lineages. The evolutionary history of YUCs is complex and suggests multiple recruitment events via horizontal gene transfer from bacteria. We identify and hierarchically classify the YUC family into an early diverging grade, five distinct classes and 41 subclasses. Angiosperm YUC diversity and expansion are explained in the context of protein sequence conservation, as well as spatial and gene expression patterns. The presented YUC gene landscape offers new perspectives on the distribution and evolutionary trends of this crucial family, which facilitates further YUC characterization within plant development and response to environmental change.

Indoleacetic Acids↗

PubMed2026

Spatiotemporal mapping of tertiary lymphoid structure heterogeneity shapes immune niches and clinical outcomes in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified intratumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based tumor microenvironment classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS+ tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13+ CD4+ T cells colocalize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudotemporal maturation continuum: aggregated, activated, and postactivated. Intraniche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12+ macrophages, evolved dynamically with maturation. Single-nucleus RNA sequencing combined with Tangram-based spatial mapping revealed CXCL12+ macrophages and iCAFs forming a peripheral band in aggregated TLSs, whereas ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy.

Cholangiocarcinoma↗