Engineering oxidoreductases: maquette proteins designed from scratch.

The study of natural enzymes is complicated by the fact that only the most recent evolutionary progression can be observed. In particular, natural oxidoreductases stand out as profoundly complex proteins in which the molecular roots of function, structure and biological integration are collectively intertwined and individually obscured. In the present paper, we describe our experimental approach that removes many of these often bewildering complexities to identify in simple terms the necessary and sufficient requirements for oxidoreductase function.

Low maternal hemoglobin during pregnancy and diminished neuromotor and neurocognitive performance in offspring with schizophrenia.

Objective: Previous research has linked maternal anemia during pregnancy with increased risk for schizophrenia in offspring. However, no study has sought to determine whether this early insult leads to a more severe form of the disorder, characterized by worsened motor and neurocognitive functioning.

Method: Subjects were 24 cases diagnosed with schizophrenia and 22 controls from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study.

Cancer stem cells and drug resistance: the potential of nanomedicine.

Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs.

Generation of phosphorescent triplet states via photoinduced electron transfer: energy and electron transfer dynamics in Pt porphyrin-Rhodamine B dyads.

Control over generation and dynamics of excited electronic states is fundamental to their utilization in all areas of technology. We present the first example of multichromophoric systems in which emissive triplet states are generated via a pathway involving photoinduced electron transfer (ET), as opposed to local intrachromophoric processes. In model dyads, PtP-Ph(n)-pRhB(+) (1-3, n = 1-3), comprising platinum(II) meso-tetraarylporphyrin (PtP) and Rhodamine B piperazine derivative (pRhB(+)), linked by oligo-p-phenylene bridges (Ph(n)), upon selective excitation of pRhB(+) at a frequency below that of the lowest allowed transition of PtP, room-temperature T(1)→S(0) phosphorescence of PtP was observed.

A phylogenetic analysis of the globins in fungi.

Background: All globins belong to one of three families: the F (flavohemoglobin) and S (sensor) families that exhibit the canonical 3/3 α-helical fold, and the T (truncated 3/3 fold) globins characterized by a shortened 2/2 α-helical fold. All eukaryote 3/3 hemoglobins are related to the bacterial single domain F globins. It is known that Fungi contain flavohemoglobins and single domain S globins.

Birth weight and neurocognition in schizophrenia spectrum disorders.

Low birth weight is associated with both schizophrenia and neurocognitive impairment. Yet, to our knowledge, no previous study has examined the relationship between lower birth weight and neurocognitive deficits in schizophrenia spectrum disorders (SSD). In this preliminary study, we investigated the relationship using a broad neuropsychological battery in cases with SSD and matched control subjects.

Computerized cognitive training restores neural activity within the reality monitoring network in schizophrenia.

Schizophrenia patients suffer from severe cognitive deficits, such as impaired reality monitoring. Reality monitoring is the ability to distinguish the source of internal experiences from outside reality. During reality monitoring tasks, schizophrenia patients make errors identifying "I made it up" items, and even during accurate performance, they show abnormally low activation of the medial prefrontal cortex (mPFC), a region that supports self-referential cognition.

Evolution of the globin gene family in deuterostomes: lineage-specific patterns of diversification and attrition.

In the Metazoa, globin proteins display an underlying unity in tertiary structure that belies an extraordinary diversity in primary structures, biochemical properties, and physiological functions. Phylogenetic reconstructions can reveal which of these functions represent novel, lineage-specific innovations, and which represent ancestral functions that are shared with homologous globin proteins in other eukaryotes and even prokaryotes. To date, our understanding of globin diversity in deuterostomes has been hindered by a dearth of genomic sequence data from the Ambulacraria (echinoderms + hemichordates), the sister group of chordates, and the phylum Xenacoelomorpha, which includes xenoturbellids, acoelomorphs, and nemertodermatids.

Monitoring cardiopulmonary function and progression toward shock: oxygen micro-sensor for peripheral tissue.

We are developing a robust, minimally invasive device for detecting progression toward hemorrhagic shock in trauma patients. To accomplish this, oxygen micro-sensors are being developed that contain a solution of oxygen sensitive phosphorescent probes within gas permeable tubing attached to optical fibers. These micro-sensors can be inserted into peripheral tissue to accurately measure tissue oxygenation.

Frontiers in optical imaging of cerebral blood flow and metabolism.

In vivo optical imaging of cerebral blood flow (CBF) and metabolism did not exist 50 years ago. While point optical fluorescence and absorption measurements of cellular metabolism and hemoglobin concentrations had already been introduced by then, point blood flow measurements appeared only 40 years ago. The advent of digital cameras has significantly advanced two-dimensional optical imaging of neuronal, metabolic, vascular, and hemodynamic signals.

Androglobin: a chimeric globin in metazoans that is preferentially expressed in Mammalian testes.

Comparative genomic studies have led to the recent identification of several novel globin types in the Metazoa. They have revealed a surprising evolutionary diversity of functions beyond the familiar O(2) supply roles of hemoglobin and myoglobin. Here we report the discovery of a hitherto unrecognized family of proteins with a unique modular architecture, possessing an N-terminal calpain-like domain, an internal, circular permuted globin domain, and an IQ calmodulin-binding motif.

Error monitoring dysfunction across the illness course of schizophrenia.

Response monitoring abnormalities have been reported in chronic schizophrenia patients, but it is unknown whether they predate the onset of psychosis, are present in early stages of illness, or are late-developing abnormalities associated with illness progression. Response-synchronized event-related potentials (ERP) recorded during a picture-word matching task yielded error-related negativity (ERN), correct-response negativity (CRN), and error positivity (Pe) from 84 schizophrenia patients (SZ), 48 clinical high risk patients (CHR), and their age-matched healthy controls (HC; n = 110 and 88, respectively). A sub-sample of 35 early illness schizophrenia patients (ESZ) was compared to 93 age-matched HC and the CHR patients (after statistically removing the effects of normal aging).

Cognitive training for impaired neural systems in neuropsychiatric illness.

Neuropsychiatric illnesses are associated with dysfunction in distributed prefrontal neural systems that underlie perception, cognition, social interactions, emotion regulation, and motivation. The high degree of learning-dependent plasticity in these networks-combined with the availability of advanced computerized technology-suggests that we should be able to engineer very specific training programs that drive meaningful and enduring improvements in impaired neural systems relevant to neuropsychiatric illness. However, cognitive training approaches for mental and addictive disorders must take into account possible inherent limitations in the underlying brain 'learning machinery' due to pathophysiology, must grapple with the presence of complex overlearned maladaptive patterns of neural functioning, and must find a way to ally with developmental and psychosocial factors that influence response to illness and to treatment.

Auditory cortex responsiveness during talking and listening: early illness schizophrenia and patients at clinical high-risk for psychosis.

Objective: The corollary discharge mechanism is theorized to dampen sensations resulting from our own actions and distinguish them from environmental events. Deficits in this mechanism in schizophrenia may contribute to misperceptions of self-generated sensations as originating from external stimuli. We previously found attenuated speech-related suppression of auditory cortex in chronic patients, consistent with such deficits.

Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.

Background: We report on copy number variants (CNVs) found in Palauan subjects ascertained for schizophrenia and related psychotic disorders in extended pedigrees in Palau. We compare CNVs found in this Oceanic population with those seen in other samples, typically of European ancestry. Assessing CNVs in Palauan extended pedigrees yields insight into the evolution of risk CNVs, such as how they arise, are transmitted, and are lost from populations by stochastic or selective processes, none of which are easily measured from case-control samples.

What are the origins and phylogeny of plant hemoglobins?

Land plants and algae are now represented by about 40 genomes. Although most are incomplete, putative globins appear to be present in all the ca. 30 land plant genomes and in all except one algal genomes.

Two new "protected" oxyphors for biological oximetry: properties and application in tumor imaging.

We report the synthesis, calibration, and examples of application of two new phosphorescent probes, Oxyphor R4 and Oxyphor G4, optimized specifically for in vivo oxygen imaging by phosphorescence quenching. These "protected" dendritic probes can operate in either albumin-rich (blood plasma) or albumin-free (interstitial space) environments at all physiological oxygen concentrations, from normoxic to deep hypoxic conditions. Oxyphors R4 and G4 are derived from phosphorescent Pd-meso-tetra-(3,5-dicarboxyphenyl)-porphyrin (PdP) or Pd-meso-tetra-(3,5-dicarboxyphenyl)-tetrabenzoporphyrin (PdTBP), respectively, and possess features common for protected dendritic probes, i.

"Overshoot" of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels.

In vivo imaging of cerebral tissue oxygenation is important in defining healthy physiology and pathological departures associated with cerebral disease. We used a recently developed two-photon microscopy method, based on a novel phosphorescent nanoprobe, to image tissue oxygenation in the rat primary sensory cortex in response to sensory stimulation. Our measurements showed that a stimulus-evoked increase in tissue pO₂ depended on the baseline pO₂ level.

Theory of mind skills are related to gray matter volume in the ventromedial prefrontal cortex in schizophrenia.

Background: Among individuals with schizophrenia, deficits in theory of mind (ToM) skills predict poor social functioning. Therefore, identifying the neural basis of ToM may assist the development of treatments that improve social outcomes. Despite growing evidence that the ventromedial prefrontal cortex (VMPFC) facilitates ToM skills among healthy individuals, methodological challenges, such as the influence of general cognitive deficits, have made it difficult to identify the relationship between ToM processing and VMPFC function in schizophrenia.

Novel anticancer polymeric conjugates of activated nucleoside analogues.

Inherent or therapy-induced drug resistance is a major clinical setback in cancer treatment. The extensive usage of cytotoxic nucleobases and nucleoside analogues in chemotherapy also results in the development of specific mechanisms of drug resistance, such as nucleoside transport or activation deficiencies. These drugs are prodrugs; and being converted into the active mono-, di-, and triphosphates inside cancer cells following administration, they affect nucleic acid synthesis, nucleotide metabolism, or sensitivity to apoptosis.

Clinical symptoms and alpha band resting-state functional connectivity imaging in patients with schizophrenia: implications for novel approaches to treatment.

Background: Schizophrenia (SZ) is associated with functional decoupling between cortical regions, but we do not know whether and where this occurs in low-frequency electromagnetic oscillations. The goal of this study was to use magnetoencephalography (MEG) to identify brain regions that exhibit abnormal resting-state connectivity in the alpha frequency range in patients with schizophrenia and investigate associations between functional connectivity and clinical symptoms in stable outpatient participants.

Methods: Thirty patients with SZ and 15 healthy comparison participants were scanned in resting-state MEG (eyes closed).

Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin.

The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated.

Single cell responses to spatially controlled photosensitized production of extracellular singlet oxygen.

The response of individual HeLa cells to extracellularly produced singlet oxygen was examined. The spatial domain of singlet oxygen production was controlled using the combination of a membrane-impermeable Pd porphyrin-dendrimer, which served as a photosensitizer, and a focused laser, which served to localize the sensitized production of singlet oxygen. Cells in close proximity to the domain of singlet oxygen production showed morphological changes commonly associated with necrotic cell death.

Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels.

Uncovering principles that regulate energy metabolism in the brain requires mapping of partial pressure of oxygen (PO(2)) and blood flow with high spatial and temporal resolution. Using two-photon phosphorescence lifetime microscopy (2PLM) and the oxygen probe PtP-C343, we show that PO(2) can be accurately measured in the brain at depths up to 300 μm with micron-scale resolution. In addition, 2PLM allowed simultaneous measurements of blood flow and of PO(2) in capillaries with less than one-second temporal resolution.

Association of maternal genital and reproductive infections with verbal memory and motor deficits in adult schizophrenia.

Maternal exposure to genital and reproductive infections has been associated with schizophrenia in previous studies. Impairments in several neuropsychological functions, including verbal memory, working memory, executive function, and fine-motor coordination occur prominently in patients with schizophrenia. The etiologies of these deficits, however, remain largely unknown.