Aperiodic neural activity is a biomarker for depression severity.

A reliable physiological biomarker for Major Depressive Disorder (MDD) is necessary to improve treatment success rates by shoring up variability in outcome measures. In this study, we establish a passive biomarker that tracks with changes in mood on the order of minutes to hours. We record from intracranial electrodes implanted deep in the brain - a surgical setting providing exquisite temporal and spatial sensitivity to detect this relationship in a difficult-to-measure brain area, the ventromedial prefrontal cortex (VMPFC). The aperiodic slope of the power spectral density captures the balance of activity across all frequency bands and is construed as a putative proxy for excitatory/inhibitory balance in the brain. This study demonstrates how shifts in aperiodic slope correlate with depression severity in a clinical trial of deep brain stimulation for treatment-resistant depression (TRD). The correlation between depression severity scores and aperiodic slope is significant in N=5 subjects, indicating that flatter (less negative) slopes correspond to reduced depression severity, especially in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient response to MDD treatment, facilitating individualized therapies in both intracranial and non-invasive monitoring scenarios.

Electronic properties and structure of single crystal perylene.

The transport properties of electronic devices made from single crystalline molecular semiconductors typically outperform those composed of thin-films of the same material. To further understand the superiority of these extrinsic device properties, an understanding of the intrinsic electronic structure and properties of the organic semiconductor is necessary. An investigation of the electronic structure and properties of single crystal α-phase perylene (C20H12), a five-ringed aromatic molecule, is presented using angle-resolved ultraviolet photoemission, x-ray photoelectron spectroscopy (XPS), and field-effect transistor measurements. Key aspects of the electronic structure of single crystal α-perylene critical to charge transport are determined, including the energetic location of the highest occupied molecular orbital (HOMO), the HOMO bandwidth, and surface work function. In addition, using high resolution XPS, we can distinguish between inequivalent carbon atoms within the perylene crystal and, from the shake-up satellite structure in XPS, gain insight into the intramolecular properties in α-perylene. From the device measurements, the charge carrier mobility of α-perylene is found to depend on the device structure and the choice of dielectric, with values in the range of 10-3 cm2 V-1 s-1.

Interface Engineering for Nanoelectronics.

Innovation in the electronics industry is tied to interface engineering as devices increasingly incorporate new materials and shrink. Molecular layers offer a versatile means of tuning interfacial electronic, chemical, physical, and magnetic properties enabled by a wide variety of molecules available. This paper will describe three instances where we manipulate molecular interfaces with a specific focus on the nanometer scale characterization and the impact on the resulting performance. The three primary themes include, 1-designer interfaces, 2-electronic junction formation, and 3-advancing metrology for nanoelectronics. We show the ability to engineer interfaces through a variety of techniques and demonstrate the impact on technologies such as molecular memory and spin injection for organic electronics. Underpinning the successful modification of interfaces is the ability to accurately characterize the chemical and electronic properties and we will highlight some measurement advances key to our understanding of the interface engineering for nanoelectronics.

Non-volatile memory devices with redox-active diruthenium molecular compound.

Reduction-oxidation (redox) active molecules hold potential for memory devices due to their many unique properties. We report the use of a novel diruthenium-based redox molecule incorporated into a non-volatile Flash-based memory device architecture. The memory capacitor device structure consists of a Pd/Al2O3/molecule/SiO2/Si structure. The bulky ruthenium redox molecule is attached to the surface by using a 'click' reaction and the monolayer structure is characterized by x-ray photoelectron spectroscopy to verify the Ru attachment and molecular density. The 'click' reaction is particularly advantageous for memory applications because of (1) ease of chemical design and synthesis, and (2) provides an additional spatial barrier between the oxide/silicon to the diruthenium molecule. Ultraviolet photoelectron spectroscopy data identified the energy of the electronic levels of the surface before and after surface modification. The molecular memory devices display an unsaturated charge storage window attributed to the intrinsic properties of the redox-active molecule. Our findings demonstrate the strengths and challenges with integrating molecular layers within solid-state devices, which will influence the future design of molecular memory devices.

The circuitry of abulia: insights from functional connectivity MRI.

BACKGROUND: Functional imaging and lesion studies have associated willed behavior with the anterior cingulate cortex (ACC). Abulia is a syndrome characterized by apathy and deficiency of motivated behavior. Abulia is most frequently associated with ACC damage, but also occurs following damage to subcortical nuclei (striatum, globus pallidus, thalamic nuclei). We present resting state functional connectivity MRI (fcMRI) data from an individual who suffered a stroke leading to abulia. We hypothesized that, although structural imaging revealed no damage to the patient's ACC, fcMRI would uncover aberrant function in this region and in the relevant cortical networks. METHODS: Resting state correlations in the patient's gray matter were compared to those of age-matched controls. Using a novel method to identify abnormal patterns of functional connectivity in single subjects, we identified areas and networks with aberrant connectivity. RESULTS: Networks associated with memory (default mode network) and executive function (cingulo-opercular network) were abnormal. The patient's anterior cingulate was among the areas showing aberrant functional connectivity. In a rescan 3 years later, deficits remained stable and fcMRI findings were replicated. CONCLUSIONS: These findings suggest that the aberrant functional connectivity mapping approach described may be useful for linking stroke symptoms to disrupted network connectivity.

Lag structure in resting-state fMRI.

The discovery that spontaneous fluctuations in blood oxygen level-dependent (BOLD) signals contain information about the functional organization of the brain has caused a paradigm shift in neuroimaging. It is now well established that intrinsic brain activity is organized into spatially segregated resting-state networks (RSNs). Less is known regarding how spatially segregated networks are integrated by the propagation of intrinsic activity over time. To explore this question, we examined the latency structure of spontaneous fluctuations in the fMRI BOLD signal. Our data reveal that intrinsic activity propagates through and across networks on a timescale of ∼1 s. Variations in the latency structure of this activity resulting from sensory state manipulation (eyes open vs. closed), antecedent motor task (button press) performance, and time of day (morning vs. evening) suggest that BOLD signal lags reflect neuronal processes rather than hemodynamic delay. Our results emphasize the importance of the temporal structure of the brain's spontaneous activity.

Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors.

Dietary casein promotes a progressive decline in the glomerular filtration rate (GFR) of remnant kidneys associated with metabolic acidosis and an endothelin-mediated increase in renal acidification. We tested whether diets that affect the acid-base status contributes to the decline of GFR through endothelin receptors in rats with a remnant kidney. Rats on a casein diet had metabolic acidosis at baseline and developed a progressive decline in GFR after renal mass reduction. Dietary sodium bicarbonate but not sodium chloride ameliorated metabolic acidosis and prevented the decrease in GFR but only after the sodium bicarbonate-induced increase in blood pressure was treated. Dietary soy protein did not induce baseline metabolic acidosis and rats with remnant kidney on a soy diet had no decrease in their GFR. By contrast, rats with a remnant kidney on soy protein given dietary acid developed metabolic acidosis and a decreased GFR. This decline in GFR was prevented in either case by endothelin A but not endothelin A/B receptor antagonism. Our study suggests that the casein-induced decline in GFR of the remnant kidney is mediated by metabolic acidosis through endothelin A receptors.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: study of errors in dosimetry.

To provide direct estimates of cancer risk after low-dose protracted exposure to ionizing radiation, a large-scale epidemiological study of nuclear industry workers was conducted in 15 countries. As part of this study, identification and quantification of errors in historical recorded doses was conducted based on a review of dosimetric practices and technologies in participating facilities. The main sources of errors on doses from "high-energy" photons (100-3000 keV) were identified as the response of dosimeters in workplace exposure conditions and historical calibration practices. Errors related to dosimetry technology and radiation fields were quantified to derive period- and facility-specific estimates of bias and uncertainties in recorded doses. This was based on (1) an evaluation of predominant workplace radiation from measurement studies and dosimetry expert assessment and (2) an estimation of the energy and geometry response of dosimeters used historically in study facilities. Coefficients were derived to convert recorded doses to H(p) (10) and organ dose, taking into account different aspects of the calibration procedures. A parametric, lognormal error structure model was developed to describe errors in doses as a function of facility and time period. Doses from other radiation types, particularly neutrons and radionuclide intake, could not be adequately reconstructed in the framework of the 15-Country Study. Workers with substantial doses from these radiation types were therefore identified and excluded from analyses. Doses from "lower-energy" photons (<100 keV) and from "higher-energy" photons (>3 MeV) were estimated to be small.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.

A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI -0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries.

OBJECTIVES: To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. DESIGN: Multinational retrospective cohort study of cancer mortality. SETTING: Cohorts of workers in the nuclear industry in 15 countries. PARTICIPANTS: 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. MAIN OUTCOME MEASUREMENTS: Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. RESULTS: The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. CONCLUSIONS: These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21.

Global patterns of human DNA sequence variation (haplotypes) defined by common single nucleotide polymorphisms (SNPs) have important implications for identifying disease associations and human traits. We have used high-density oligonucleotide arrays, in combination with somatic cell genetics, to identify a large fraction of all common human chromosome 21 SNPs and to directly observe the haplotype structure defined by these SNPs. This structure reveals blocks of limited haplotype diversity in which more than 80% of a global human sample can typically be characterized by only three common haplotypes.

Thyroid hormone regulates the obesity gene tub.

Thyroid hormone T3/T4 is a major regulator of energy metabolism in vertebrates, and defects in thyroid status are frequently associated with changes in body weight. It is demonstrated here that thyroid hormone regulates in vivo and in vitro the tub gene, which when mutated in tubby mice causes obesity, insulin resistance and sensory deficits. Hypothyroidism in rats altered tub mRNA and protein in discrete brain areas. These changes could be attributed to thyroid hormone deficiency since T3/T4 treatment restored normal tub expression. T3 also upregulated tub mRNA within 4-6 h in neuronal cells in culture, suggesting that T3 is a positive regulator of tub gene expression. Thus, these results establish a novel pathway of T3 action and provide an important molecular link between thyroid status and the tubby-associated syndrome.

Mutational analysis of the N-methyltransferase domain of the multifunctional enzyme enniatin synthetase.

N-Methylcyclopeptides like cyclosporins and enniatins are synthesized by multifunctional enzymes representing hybrid systems of peptide synthetases and S-adenosyl-l-methionine (AdoMet)-dependent N-methyltransferases. The latter constitute a new family of N-methyltransferases sharing high homology within procaryotes and eucaryotes. Here we describe the mutational analysis of the N-methyltransferase domain of enniatin synthetase from Fusarium scirpi to gain insight into the assembly of the AdoMet-binding site. The role of four conserved motifs (I, (2085)VLEIGTGSGMIL; II/Y, (2105)SYVGLDPS; IV, (2152)DLVVFNSVVQYFTPPEYL; and V, (2194)ATNGHFLAARA) in cofactor binding as measured by photolabeling was studied. Deletion of the first 21 N-terminal amino acid residues of the N-methyltransferase domain did not affect AdoMet binding. Further shortening close to motif I resulted in loss of binding activity. Truncation of 38 amino acids from the C terminus and also internal deletions containing motif V led to complete loss of AdoMet-binding activity. Point mutations converting the conserved Tyr(223) (corresponding to position 2106 in enniatin synthetase) in motif II/Y (close to motif I) into Val, Ala, and Ser, respectively, strongly diminished AdoMet binding, whereas conversion of this residue to Phe restored AdoMet-binding activity to approximately 70%, indicating that Tyr(223) is important for AdoMet binding and that the aromatic Tyr(223) may be crucial for AdoMet binding in N-methylpeptide synthetases.

Potent, orally absorbed glucagon receptor antagonists.

The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrr ole 49 (L-168,049), a potent (Kb = 25 nM), selective antagonist of glucagon.

Characterization of a novel, non-peptidyl antagonist of the human glucagon receptor.

We have identified a series of potent, orally bioavailable, non-peptidyl, triarylimidazole and triarylpyrrole glucagon receptor antagonists. 2-(4-Pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)p yrr ole (L-168,049), a prototypical member of this series, inhibits binding of labeled glucagon to the human glucagon receptor with an IC50 = 3. 7 +/- 3.4 nM (n = 7) but does not inhibit binding of labeled glucagon-like peptide to the highly homologous human glucagon-like peptide receptor at concentrations up to 10 microM. The binding affinity of L-168,049 for the human glucagon receptor is decreased 24-fold by the inclusion of divalent cations (5 mM). L-168,049 increases the apparent EC50 for glucagon stimulation of adenylyl cyclase in Chinese hamster ovary cells expressing the human glucagon receptor and decreases the maximal glucagon stimulation observed, with a Kb (concentration of antagonist that shifts the agonist dose-response 2-fold) of 25 nM. These data suggest that L-168,049 is a noncompetitive antagonist of glucagon action. Inclusion of L-168, 049 increases the rate of dissociation of labeled glucagon from the receptor 4-fold, confirming that the compound is a noncompetitive glucagon antagonist. In addition, we have identified two putative transmembrane domain residues, phenylalanine 184 in transmembrane domain 2 and tyrosine 239 in transmembrane domain 3, for which substitution by alanine reduces the affinity of L-168,049 46- and 4. 5-fold, respectively. These mutations do not alter the binding of labeled glucagon, suggesting that the binding sites for glucagon and L-168,049 are distinct.

Differential expression of putative transbilayer amphipath transporters.

The aminophospholipid translocase transports phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to another. Cloning of the gene encoding the enzyme identified a new subfamily of P-type ATPases, proposed to be amphipath transporters. As reported here, mammals express as many as 17 different genes from this subfamily. Phylogenetic analysis reveals the genes to be grouped into several distinct classes and subclasses. To gain information on the functions represented by these groups, Northern analysis and in situ hybridization were used to examine the pattern of expression of a panel of subfamily members in the mouse. The genes are differentially expressed in the respiratory, digestive, and urogenital systems, endocrine organs, the eye, teeth, and thymus. With one exception, all of the genes are highly expressed in the central nervous system (CNS); however, the pattern of expression within the CNS differs substantially from gene to gene. These results suggest that the genes are expressed in a tissue-specific manner, are not simply redundant, and may represent isoforms that transport a variety of different amphipaths.

Policy incongruence and public health professionals' dissonance: the case of immigrants and welfare policy.

The steady increase in immigrants to the United States has fueled a critical analysis of the process of allocation of health and social benefits to these newcomers. The myriad of interests and values surrounding this issue precipitated the formulation and adoption of the Personal Responsibility and Work Opportunity (Welfare Reform) Act of 1996. This dramatic welfare reform impacts federal, state, and local agencies that are required to determine the eligibility of benefits and manage the attendant consequences to the public as well as members of this vulnerable group. Especially challenging are the decisions confronting public health professionals who struggle to reconcile the resulting policy, programmatic mandates, and compliance imperatives with prevailing public health principles and practice norms. This paper proposes a framework for understanding the incongruence between the provisions of the law as it pertains to legal and illegal immigrants and public health values. The impact of policy incongruence and professionals' dissonance on public health practice norms is explored with an explicit focus on public health outcomes and legal implications. The examination of tuberculosis as a health example reveals the policy conflicts and public health dilemmas. Finally, the paper elicits a range of options available to public professionals for responding to these legal mandates.

Molecular basis for p38 protein kinase inhibitor specificity.

p38 is a member of the mitogen-activated protein (MAP) kinase family and is a critical enzyme in the proinflammatory cytokine pathway. Other MAP kinase group members that share both structural and functional homology to p38 include the c-Jun NH2-terminal kinases (JNKs or SAPKs) and the extracellular-regulated protein kinases (ERKs). In this study, we determined the molecular basis for p38alpha inhibitor specificity exhibited by five compounds in the diarylimidazole, triarylimidazole, and triarylpyrrole classes of protein kinase inhibitors. These compounds are significantly more potent inhibitors of p38 compared to the JNKs and ERKs. Three active site ATP-binding domain residues in p38, T106, M109, and A157, selected based on primary sequence alignment, molecular modeling, and X-ray crystal structure data, were mutated to assess their role in inhibitor binding and enzymatic catalysis. All mutants, with the exception of T106M, had kinase activity within 3-fold of wild-type p38. Mutation of T106 to glutamine, the residue present at the corresponding position in ERK-2, or methionine, the corresponding residue in p38gamma, p38delta, and the JNKs, rendered all five inhibitors ineffective. The diarylimidazoles had approximately a 6-fold decrease in potency toward M109A p38. For the mutant A157V, all diarylimidazoles and triarylimidazoles tested were 5-10-fold more potent compared with wild-type p38. In contrast, two triarylpyrroles were 15-40-fold less potent versus A157V p38. These results showed that the molecular basis for the specificity of the p38 inhibitors was attributed largely to threonine 106 in p38 and that methionine 109 contributes to increased binding affinity for imidazole based inhibitors.