Clinical and genetic analysis of a case of O'Donnell-Luria-Rodan syndrome manifesting as growth retardation. / 以生长发育迟缓为表现的1例O'Donnell-Luria-Rodanç»¼åˆå¾ä¸´åºŠä¸Žé—ä¼ å­¦ç‰¹å¾åˆ†æž.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant genetic disorder caused by mutations in the KMT2E (lysine methyltransferase 2E) gene. The Third Xiangya Hospital of Central South University admitted a 12-year and 9-month-old male patient who presented with growth retardation, intellectual disability, and distinctive facial features. Peripheral blood was collected from the patient, and DNA was extracted for genetic testing. Chromosome karyotyping showed 46XY. Whole-exome sequencing and low-coverage massively parallel copy number variation sequencing (CNV-seq) revealed a 506 kb heterozygous deletion in the 7q22.3 region, which includes 6 genes, including KMT2E. The patient was diagnosed with ODLURO syndrome. Both the patient's parents and younger brother had normal clinical phenotypes and genetic test results, indicating that this deletion was a de novo mutation. The clinical and genetic characteristics of this case can help increase clinicians' awareness of ODLURO syndrome.

Methods for two nonstandard problems arising from the Luria-Delbrück experiment.

The fluctuation experiment, devised by Luria and Delbrück in 1943, remains the method of choice for measuring microbial mutation rates in the laboratory. While most inference problems commonly encountered in a fluctuation experiment can be tackled by existing standard algorithms, investigators from time to time run into nonstandard problems not amenable to any existing algorithms. A major obstacle to solving these nonstandard problems is the construction of confidence intervals for mutation rates. This note describes methods for two important categories of nonstandard problems, namely, pooling data from separate experiments and analyzing grouped mutant count data, focusing on the construction of likelihood ratio confidence intervals. In addition to illustrative examples using real-world data, simulation results are presented to help assess the proposed methods.

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies.

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Neurofeedback Training Based on Motor Imagery Strategies Increases EEG Complexity in Elderly Population.

Neurofeedback training (NFT) has shown promising results in recent years as a tool to address the effects of age-related cognitive decline in the elderly. Since previous studies have linked reduced complexity of electroencephalography (EEG) signal to the process of cognitive decline, we propose the use of non-linear methods to characterise changes in EEG complexity induced by NFT. In this study, we analyse the pre- and post-training EEG from 11 elderly subjects who performed an NFT based on motor imagery (MI-NFT). Spectral changes were studied using relative power (RP) from classical frequency bands (delta, theta, alpha, and beta), whilst multiscale entropy (MSE) was applied to assess EEG-induced complexity changes. Furthermore, we analysed the subject's scores from Luria tests performed before and after MI-NFT. We found that MI-NFT induced a power shift towards rapid frequencies, as well as an increase of EEG complexity in all channels, except for C3. These improvements were most evident in frontal channels. Moreover, results from cognitive tests showed significant enhancement in intellectual and memory functions. Therefore, our findings suggest the usefulness of MI-NFT to improve cognitive functions in the elderly and encourage future studies to use MSE as a metric to characterise EEG changes induced by MI-NFT.

Modality-general and modality-specific processes in hallucinations.

There is a growing recognition in psychosis research of the importance of hallucinations in modalities other than the auditory. This has focused attention on cognitive and neural processes that might be shared by, and which might contribute distinctly to, hallucinations in different modalities. In this article, I address some issues around the modality-generality of cognitive and neural processes in hallucinations, including the role of perceptual and reality-monitoring systems, top-down and bottom-up processes in relation to the psychological and neural substrates of hallucinations, and the phenomenon of simultaneous multimodal hallucinations of the same entity. I suggest that a functional systems approach, inspired by some neglected aspects of the writings of A. R. Luria, can help us to understand patterns of hallucinatory experience across modalities and across clinical and non-clinical groups. Understanding the interplay between modality-general and modality-specific processes may bear fruit for improved diagnosis and therapeutic approaches to dealing with distressing hallucinations.

The "Ice Age" in Cardiac Surgery: Evolution of the "Siberian" Method of Brain Protection During Deep Hypothermic Perfusionless Circulatory Arrest.

Deep hypothermic perfusionless circulatory arrest was the first practical neuroprotective technique used for open-heart surgery. It was refined at the Novosibirsk Medical Research Center in Siberia and was actively used from the mid-1950s until 2001.This review describes the development of this technique and its contribution to our understanding of the dynamic changes in human physiology during induced hypothermia for circulatory arrest without extracorporeal perfusion. Deep hypothermic perfusionless circulatory arrest was an important stepping stone in the development of modern approaches in neuroprotection and monitoring during cardiac surgery.

Development and Utilization of VHH Antibodies Derived from Camelus Dromedarius Against Foot-and-Mouth Disease Virus.

Foot-and-mouth disease (FMD) is an acute, highly contagious, and economically devastating viral disease of domestic and wildlife species. For effective implementation of FMD control program, there is an imperative need for developing a rapid, sensitive, and specific diagnostics which help in the identification of serotypes involved in the outbreaks. The humoral immune response of the Camelidae is unique since in these animals 75% of circulating antibodies are constituted by heavy-chain antibodies and 25% are conventional immunoglobulin with two identical heavy chains. In the present study, we developed and characterized FMD virus-specific single-domain heavy-chain antibodies (VHHs) against inactivated whole-virus antigens of FMDV serotypes O (INDR2/1975), A (IND40/2000), and Asia 1 (IND63/1972) vaccine strains. After six rounds of panning and enrichment, these VHHs were stably expressed in Escherichia coli cells. The VHHs directed against outer capsid proteins of FMD virus were successfully utilized as the capture antibody in liquid-phase blocking ELISA (LPBE) thus replacing rabbit coating antibodies. Our study demonstrated the utility of FMD virus-specific VHHs as potential candidates in FMD research and diagnostic application.

CpdA is involved in amino acid metabolism in Shewanella oneidensis MR-1.

Cyclic 3',5'-adenosine monophosphate (cAMP) phosphodiesterase (CPD) is an enzyme that catalyzes the hydrolysis of cAMP, a signaling molecule affecting diverse cellular and metabolic processes in bacteria. Some CPDs are also known to function in cAMP-independent manners, while their physiological roles remain largely unknown. Here, we investigated physiological roles of CPD in Shewanella oneidensis MR-1, a model environmental bacterium, and report that CPD is involved in amino-acid metabolism. We found that a CPD-deficient mutant of MR-1 (ΔcpdA) showed decreased expression of genes for the synthesis of methionine, S-adenosylmethionine, and histidine and required these three compounds to grow in minimal media. Interestingly, deletion of adenylate cyclases in ΔcpdA did not restore the ability to grow in minimal media, indicating that the amino acid requirements were not due to the accumulation of cAMP. These results suggest that CPD is involved in the regulation of amino acid metabolism in MR-1 in a cAMP-independent manner.

Identification and characterization of chitinolytic bacteria isolated from a freshwater lake.

To develop a novel type of biocontrol agent, we focus on bacteria that are characterized by both chitinase activity and biofilm development. Chitinolytic bacteria were isolated from sediments and chitin flakes immersed in the water of a sand dune lake, Sakata, in Niigata, Japan. Thirty-one isolates from more than 5100 isolated strains were examined chitinase activity and biofilm formation. Phylogenetic analysis of these isolates based on the 16S rRNA gene sequences revealed that most isolates belonged to the family Aeromonadaceae, followed by Paenibacillaceae, Enterobacteriaceae, and Neisseriaceae. The specific activity of chitinase of four selected strains was higher than that of a reference strain. The molecular size of one chitinase produced by Andreprevotia was greater than that of typical bacterial chitinases. The dialyzed culture supernatant containing chitinases of the four strains suppressed hyphal growth of Trichoderma reesei. These results indicate that these four strains are good candidates for biocontrol agents.

Toward a Unique Definition of the Mutation Rate.

In around 1943, while writing a classic paper with Luria, Delbrück envisioned two kinds of mutation rates: One was expressed as mutations per bacterium per unit time, the other as mutations per bacterium per division cycle. Due to minor mathematical errors, the precise connection between the two concepts remained elusive for Delbrück. As a result, researchers and educators alike are still grappling with the definition of the mutation rate. Within the context of microbial mutation, the current author proposes an idealized model to bring new clarity to the distinction between the two forms of the mutation rate that Delbrück once attempted to define and characterize. The paper also critiques two incorrect estimators of mutation rates and brings to light two important yet unexplored "invariance" hypotheses about mutation rates.

Time Inhomogeneous Mutation Models with Birth Date Dependence.

The classic Luria-Delbrück model for fluctuation analysis is extended to the case where the split instant distributions of cells are not i.i.d.: the lifetime of each cell is assumed to depend on its birth date. This model takes also into account cell deaths and non-exponentially distributed lifetimes. In particular, it is possible to consider subprobability distributions and to model non-exponential growth. The extended model leads to a family of probability distributions which depend on the expected number of mutations, the death probability of mutant cells, and the split instant distributions of normal and mutant cells. This is deduced from the Bellman-Harris integral equation, written for the birth date inhomogeneous case. A new theorem of convergence for the final mutant counts is proved, using an analytic method. Particular examples like the Haldane model or the case where hazard functions of the split-instant distributions are proportional are studied. The Luria-Delbrück distribution with cell deaths is recovered. A computation algorithm for the probabilities is provided.

Obtention and characterization of the recombinant simian Interleukin-15 in Escherichia coli for the preclinical assessment of an IL-15-based therapeutic vaccine.

Recombinant simian IL-15 (siIL-15) was obtained for the preclinical assessment of an anti-human IL-15 vaccine. For this purpose, the cDNA from peripheral blood mononuclear cells of a Macaca fascicularis monkey was cloned into a pIL-2 vector. The siIL-15 was expressed in Escherichia coli strain W3110 as an insoluble protein which accounted for 13% of the total cellular proteins. Inclusion bodies were solubilized in an 8 M urea solution, which was purified by ion exchange and reverse phase chromatography up to 92% purity. The protein identity was validated by electrospray ionization-mass spectrometry, confirming the presence of the amino acids which distinguish the siIL-15 from human IL-15. The purified siIL-15 stimulates the proliferation of cytotoxic T-lymphocytes line (CTLL)-2 and Kit 225 cells with EC50 values of 3.1 and 32.5 ng/mL, respectively. Antisera from modified human IL-15-immunized macaques were reactive to human and simian IL-15 in enzyme-linked immunosorbent assays. Moreover, the anti-human IL-15 antibodies from immune sera inhibited siIL-15 activity in CTLL-2 and Kit 225 cells, supporting the activity and purity of recombinant siIL-15. These results indicate that the recombinant siIL-15 is biologically active in two IL-15-dependent cell lines, and it is also suitable for the preclinical evaluation of an IL-15-based therapeutic vaccine.

Universal Asymptotic Clone Size Distribution for General Population Growth.

Deterministically growing (wild-type) populations which seed stochastically developing mutant clones have found an expanding number of applications from microbial populations to cancer. The special case of exponential wild-type population growth, usually termed the Luria-Delbrück or Lea-Coulson model, is often assumed but seldom realistic. In this article, we generalise this model to different types of wild-type population growth, with mutants evolving as a birth-death branching process. Our focus is on the size distribution of clones-that is the number of progeny of a founder mutant-which can be mapped to the total number of mutants. Exact expressions are derived for exponential, power-law and logistic population growth. Additionally, for a large class of population growth, we prove that the long-time limit of the clone size distribution has a general two-parameter form, whose tail decays as a power-law. Considering metastases in cancer as the mutant clones, upon analysing a data-set of their size distribution, we indeed find that a power-law tail is more likely than an exponential one.

Antarctic bacterial haemoglobin and its role in the protection against nitrogen reactive species.

In a cold and oxygen-rich environment such as Antarctica, mechanisms for the defence against reactive oxygen and nitrogen species are needed and represent important components in the evolutionary adaptations. In the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125, the presence of multiple genes encoding 2/2 haemoglobins and a flavohaemoglobin strongly suggests that these proteins fulfil important physiological roles, perhaps associated to the peculiar features of the Antarctic habitat. In this work, the putative role of Ph-2/2HbO, encoded by the PSHAa0030 gene, was investigated by in vivo and in vitro experiments in order to highlight its involvement in NO detoxification mechanisms. The PSHAa0030 gene was cloned and then over-expressed in a flavohaemoglobin-deficient mutant of Escherichia coli, unable to metabolise NO, and the resulting strain was studied analysing its growth properties and oxygen uptake in the presence of NO. We here demonstrate that Ph-2/2HbO protects growth and cellular respiration of the heterologous host from the toxic effect of NO-donors. Unlike in Mycobacterium tuberculosis 2/2 HbN, the deletion of the N-terminal extension of Ph-2/2HbO does not seem to reduce the NO scavenging activity, showing that the N-terminal extension is not a requirement for efficient NO detoxification. Moreover, the ferric form of Ph-2/2HbO was shown to catalyse peroxynitrite isomerisation in vitro, confirming its potential role in the scavenging of reactive nitrogen species. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.

Cytochrome bd-I in Escherichia coli is less sensitive than cytochromes bd-II or bo'' to inhibition by the carbon monoxide-releasing molecule, CORM-3: N-acetylcysteine reduces CO-RM uptake and inhibition of respiration.

BACKGROUND: CO-releasing molecules (CO-RMs) are potential therapeutic agents, able to deliver CO - a critical gasotransmitter - in biological environments. CO-RMs are also effective antimicrobial agents; although the mechanisms of action are poorly defined, haem-containing terminal oxidases are primary targets. Nevertheless, it is clear from several studies that the effects of CO-RMs on biological systems are frequently not adequately explained by the release of CO: CO-RMs are generally more potent inhibitors than is CO gas and other effects of the molecules are evident. METHODS: Because sensitivity to CO-RMs cannot be predicted by sensitivity to CO gas, we assess the differential susceptibilities of strains, each expressing only one of the three terminal oxidases of E. coli - cytochrome bd-I, cytochrome bd-II and cytochrome bo', to inhibition by CORM-3. We present the first sensitive measurement of the oxygen affinity of cytochrome bd-II (Km 0.24µM) employing globin deoxygenation. Finally, we investigate the way(s) in which thiol compounds abolish the inhibitory effects of CORM-2 and CORM-3 on respiration, growth and viability, a phenomenon that is well documented, but poorly understood. RESULTS: We show that a strain expressing cytochrome bd-I as the sole oxidase is least susceptible to inhibition by CORM-3 in its growth and respiration of both intact cells and membranes. Growth studies show that cytochrome bd-II has similar CORM-3 sensitivity to cytochrome bo'. Cytochromes bo' and bd-II also have considerably lower affinities for oxygen than bd-I. We show that the ability of N-acetylcysteine to abrogate the toxic effects of CO-RMs is not attributable to its antioxidant effects, or prevention of CO targeting to the oxidases, but may be largely due to the inhibition of CO-RM uptake by bacterial cells. CONCLUSIONS: A strain expressing cytochrome bd-I as the sole terminal oxidase is least susceptible to inhibition by CORM-3. N-acetylcysteine is a potent inhibitor of CO-RM uptake by E. coli. GENERAL SIGNIFICANCE: Rational design and exploitation of CO-RMs require a fundamental understanding of their activity. CO and CO-RMs have multifaceted effects on mammalian and microbial cells; here we show that the quinol oxidases of E. coli are differentially sensitive to CORM-3. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.

Analysis of human invasive cytotrophoblasts using multicolor fluorescence in situ hybridization.

Multicolor fluorescence in situ hybridization, or FISH, is a widely used method to assess fixed tissues or isolated cells for numerical and structural chromosome aberrations. Unlike other screening procedures which provide average chromosome numbers for heterogeneous samples, FISH is a sensitive cell-by-cell method to analyze the distribution of abnormal cells in complex tissues. Here, we applied FISH to characterize chromosomal composition of a rare, but very important class of human cells that stabilize the fetal-maternal interface connecting the placenta to the uterine wall during early pregnancy, called invasive cytotrophoblasts (iCTBs). Combining differently-labeled, chromosome-specific DNA probes, we were able to unambiguously determine the number of up to six different autosomes and gonosomes in individual cell nuclei from iCTBs selected on the basis of their invasive behavior. In this manuscript, we describe a method for generation of iCTBs from placental villi, and provide the complete workflow of our FISH experiments including a detailed description of reagents and a trouble-shooting guide. We also include an in-depth discussion of the various types and sources of DNA probes which have evolved considerably in the last two decades. Thus, this communication represents both a complete guide as well as a valuable resource, intended to allow an average laboratory to reproduce the experiments and minimize the amount of specialized, and often costly, equipment.

A novel abbreviated version of the Luria neuropsychological diagnosis battery: reliability and convergent validity in Spanish older adults.

OBJECTIVE: To estimate the test-retest and inter-rater reliability of the new Spanish abbreviated version of the Luria Neuropsychological Diagnosis (DNA-2) battery for older adults. METHOD: A total of thirty cognitively healthy volunteers were examined in this study. The participants completed a comprehensive standardized assessment, encompassing cognitive and functional performance. Intraclass correlation coefficients (ICC) were used to examine test-retest and inter-rater reliability. One month was allowed between administrations. Furthermore, correlations between Luria DNA-2 (total and domain subscores) and other classical cognitive measures were explored. RESULTS: The test-retest reliability on the overall Luria DNA-2 score was high (ICC= .834, 95% CI [.680, .917], p < .001). Furthermore, the inter-rater reliability for the total score demonstrated an excellent concordance between administrators (ICC= .990, 95% CI [.979, .995], p < .001). Positive and significant correlations were observed between Luria DNA-2 (both total and domain subscores) and the Addenbrooke's Cognitive Examination (ACE-III; ρ = .857, p < .001). CONCLUSIONS: This study supports the adequate reliability of the Luria DNA-2, as an abbreviated neuropsychological battery, for assessing cognitive performance in Spaniards aged 55 years and older. Future studies should continue to explore the psychometric properties of the Luria DNA-2, particularly those related to its diagnostic validity for early detection of cognitive impairment.

Separated at birth: Rediscovering the lost emotions in Luria's Working Brain.

Aleksandr Luria repeatedly emphasised the importance of emotions and the right hemisphere in his neuropsychological writings. It is surprising, therefore, that Luria's most influential book, The Working Brain, appears to lack an explicit section on these topics. This is especially notable because of a comment in the book's English-language Introduction, by Karl Pribram, referencing Luria's thoughts about precisely this material. Remarkably, it seems that Luria did write such an explicit chapter, in the original Russian edition. However, in the English-language version, the relevant sections were separated, embedded elsewhere without chapter headings, and altered, presumably following an explicit translation decision. The present paper tracks the nature of these changes and, 50 years later, presents the material for the first time translated and reunited in English, as Luria intended. After the translation, we offer a brief commentary, on the ways in which Luria's ideas were in some respects prescient, and in other respects less well-informed about the brain basis of emotions and the right hemisphere. This reunification offers an interesting time capsule on the opinions of one of neuropsychology's greatest minds, on a topic which Luria admits had, at the time, only a modest empirical foundation.

The Pavlovian interpretation of speech and aphasia: Alexander Luria and Wilder Penfield.

This paper discusses a neglected aspect of the historiography of aphasia, the role that Pavlovian conditioning played in Alexander Luria's and Wilder Penfield's understanding of the acquisition, expression, and loss of spoken and written speech. Luria was born into a bourgeois family in Tzarist Russia and pursued his research on speech and aphasia under the Soviet regime. Luria's work was condemned in the last years of Stalin's rule, but it received international acclaim in the West after Stalin's death. Penfield was conversant with Pavlov's writing having had a working relationship with one of Pavlov's foremost students, Boris Babkin, who came to McGill University and later to the Montreal Neurological Institute after being jailed and exiled from the Soviet Union for lack of revolutionary fervor. Both Luria and Penfield, the latter as early as 1935, saw in Pavlovian conditioning mediated by specific areas of the human cerebral cortex the basic neurophysiological mechanism underlying speech and thought, and in Penfield's' case, memory, perception, self-awareness, and purposeful behavior. It is concluded that Luria and Penfield independently arrived at a general hypothesis, based on Pavlovian conditioning, that united the localization of speech, the syndromes caused by damage to speech-competent regions, and the putative neurophysiological mechanisms that they believed to underlie speech and higher cortical functions.

Updating functional brain units: Insights far beyond Luria.

This paper reviews Luria's model of the three functional units of the brain. To meet this objective, several issues were reviewed: the theory of functional systems and the contributions of phylogenesis and embryogenesis to the brain's functional organization. This review revealed several facts. In the first place, the relationship/integration of basic homeostatic needs with complex forms of behavior. Secondly, the multi-scale hierarchical and distributed organization of the brain and interactions between cells and systems. Thirdly, the phylogenetic role of exaptation, especially in basal ganglia and cerebellum expansion. Finally, the tripartite embryogenetic organization of the brain: rhinic, limbic/paralimbic, and supralimbic zones. Obviously, these principles of brain organization are in contradiction with attempts to establish separate functional brain units. The proposed new model is made up of two large integrated complexes: a primordial-limbic complex (Luria's Unit I) and a telencephalic-cortical complex (Luria's Units II and III). As a result, five functional units were delineated: Unit I. Primordial or preferential (brainstem), for life-support, behavioral modulation, and waking regulation; Unit II. Limbic and paralimbic systems, for emotions and hedonic evaluation (danger and relevance detection and contribution to reward/motivational processing) and the creation of cognitive maps (contextual memory, navigation, and generativity [imagination]); Unit III. Telencephalic-cortical, for sensorimotor and cognitive processing (gnosis, praxis, language, calculation, etc.), semantic and episodic (contextual) memory processing, and multimodal conscious agency; Unit IV. Basal ganglia systems, for behavior selection and reinforcement (reward-oriented behavior); Unit V. Cerebellar systems, for the prediction/anticipation (orthometric supervision) of the outcome of an action. The proposed brain units are nothing more than abstractions within the brain's simultaneous and distributed physiological processes. As function transcends anatomy, the model necessarily involves transition and overlap between structures. Beyond the classic approaches, this review includes information on recent systemic perspectives on functional brain organization. The limitations of this review are discussed.