Faculty Bibliography

Ammonium is a major urinary buffer that is necessary for the normal excretion of the daily acid load. Its urinary rate of excretion (UNH₄) may be increased several fold in the presence of extrarenal metabolic acidosis. Therefore, measurement of UNH₄ can provide important clues about causes of metabolic acidosis. Because UNH₄ is not commonly measured in clinical laboratories, the urinary anion gap (UAG) was proposed as its surrogate about four decades ago and it is still frequently used for that purpose. Several published studies strongly suggest that UAG is not a good index of UNH₄ and support the concept that direct measurement of UNH₄ is an important parameter to define in clinical nephrology. Low UNH₄ levels have recently been found to be associated with a higher risk of metabolic acidosis, loss of kidney function, and death in persons with chronic kidney disease, while surrogates like the UAG do not recapitulate this risk. In order to advance the field it is necessary for the medical community to become more familiar with UNH₄ levels in a variety of clinical settings. Herein, we have reviewed the literature, searching for available data on UNH₄ under normal and various pathological conditions, in an attempt to establish reference values to interpret UNH₄ results if and when UNH₄ measurements become available as a routine clinical test. In addition, we present original data in two large populations which provide further evidence that the UAG is not a good predictor of UNH₄. Measurement of urine NH₄ holds promise to aid clinicians in the care of patients and we encourage further research to determine its best diagnostic usage.

OBJECTIVE:Abnormal cerebellar development has been implicated in Attention-Deficit/Hyperactivity Disorder (ADHD), although cerebro-cerebellar functional connectivity (FC) has yet to be examined in ADHD. Our objective is to investigate the disturbed cerebro-cerebellar FC in children and adolescents with ADHD. METHOD/METHODS:We analyzed the dataset of 106 individuals with ADHD (68 children, 38 adolescents) and 62 healthy comparisons (34 children, 28 adolescents) from the publicly available ADHD-200 dataset. We identified seven cerebellar sub-regions based on cerebro-cerebellar FC and subsequently obtained the FC maps of cerebro-cerebellar networks. Main effects of ADHD and age and their interaction were examined using two-way analysis of variance. RESULTS:Compared to comparisons, ADHD showed higher cerebro-cerebellar FC in superior temporal gyrus within the somatomotor network. Interactions of diagnosis and age were identified in the supplementary motor area and postcentral gyrus within the somatomotor network and middle temporal gyrus within the ventral attention network. Follow-up Pearson correlation analysis revealed decreased cerebro-cerebellar FC in these regions with increasing age in comparisons, while the opposite pattern of increased cerebro-cerebellar FC occurred in ADHD. CONCLUSION/CONCLUSIONS:Increased cerebro-cerebellar FC in superior temporal gyrus within the somatomotor network could underlie impairments in cognitive control and somatic motor function in ADHD. In addition, increasing cerebro-cerebellar FC in older participants with ADHD suggests that enhanced cerebellar involvement may compensate for dysfunctions of the cerebral cortex in ADHD.

PURPOSE/UNASSIGNED:To explore the limits of deep learning-based brain MRI reconstruction and identify useful acceleration ranges for general-purpose imaging and potential screening. MATERIALS AND METHODS/UNASSIGNED:potential use in a screening protocol. A Monte Carlo procedure was developed to estimate reconstruction error with only undersampled data. The model was evaluated on both in-domain and out-of-domain data. The 95% CIs were calculated using the percentile bootstrap method. RESULTS/UNASSIGNED:Radiologists rated 100% of 69 volumes as having sufficient image quality for general-purpose imaging at up to 4× acceleration and 65 of 69 volumes (94%) as having sufficient image quality for screening at up to 14× acceleration. The Monte Carlo procedure estimated ground truth peak signal-to-noise ratio and mean squared error with coefficients of determination greater than 0.5 at 2× to 20× acceleration levels. Out-of-distribution experiments demonstrated the model's ability to produce images substantially distinct from the training set, even at 100× acceleration. CONCLUSION/UNASSIGNED:© RSNA, 2022.

BACKGROUND:Male sex, elevated troponin levels, and elevated D-dimer levels are associated with more complicated COVID-19 illness and greater mortality; however, while there are known sex differences in the prognostic value of troponin and D-dimer in other disease states, it is unknown whether they exist in the setting of COVID-19. OBJECTIVE:We assessed whether sex modified the relationship between troponin, D-dimer, and severe COVID-19 illness (defined as mechanical ventilation, ICU admission or transfer, discharge to hospice, or death). METHODS:We conducted a retrospective cohort study of patients hospitalized with COVID-19 at a large, academic health system. We used multivariable regression to assess associations between sex, troponin, D-dimer, and severe COVID-19 illness, adjusting for demographic, clinical, and laboratory covariates. To test whether sex modified the relationship between severe COVID-19 illness and troponin or D-dimer, models with interaction terms were utilized. RESULTS:Among 4,574 patients hospitalized with COVID-19, male sex was associated with higher levels of troponin and greater odds of severe COVID-19 illness, but lower levels of initial D-dimer when compared with female sex. While sex did not modify the relationship between troponin level and severe COVID-19 illness, peak D-dimer level was more strongly associated with severe COVID-19 illness in male patients compared to female patients (males: OR=2.91, 95%CI=2.63-2.34, p<0.001; females: OR=2.31, 95%CI=2.04-2.63, p<0.001; p-interaction=0.005). CONCLUSION/CONCLUSIONS:Sex did not modify the association between troponin level and severe COVID-19 illness, but did modify the association between peak D-dimer and severe COVID-19 illness, suggesting greater prognostic value for D-dimer in males with COVID-19.

The little skate Leucoraja erinacea, a cartilaginous fish, displays pelvic fin driven walking-like behavior using genetic programs and neuronal subtypes similar to those of land vertebrates. However, mechanistic studies on little skate motor circuit development have been limited, due to a lack of high-quality reference genome. Here, we generated an assembly of the little skate genome, with precise gene annotation and structures, which allowed post-genome analysis of spinal motor neurons (MNs) essential for locomotion. Through interspecies comparison of mouse, skate and chicken MN transcriptomes, shared and divergent gene expression profiles were identified. Comparison of accessible chromatin regions between mouse and skate MNs predicted shared transcription factor (TF) motifs with divergent ones, which could be used for achieving differential regulation of MN-expressed genes. A greater number of TF motif predictions were observed in MN-expressed genes in mouse than in little skate. These findings suggest conserved and divergent molecular mechanisms controlling MN development of vertebrates during evolution, which might contribute to intricate gene regulatory networks in the emergence of a more sophisticated motor system in tetrapods.

A body of work spanning neuroscience, economics, and psychology indicates that decision-making is context-dependent, which means that the value of an option depends not only on the option in question, but also on the other options in the choice set-or the 'context'. While context effects have been observed primarily in small-scale laboratory studies with tightly constrained, artificially constructed choice sets, it remains to be determined whether these context effects take hold in real-world choice problems, where choice sets are large and decisions driven by rich histories of direct experience. Here, we investigate whether valuations are context-dependent in real-world choice by analyzing a massive restaurant rating dataset as well as two independent replication datasets which provide complementary operationalizations of restaurant choice. We find that users make fewer ratings-maximizing choices in choice sets with higher-rated options-a hallmark of context-dependent choice-and that post-choice restaurant ratings also varied systematically with the ratings of unchosen restaurants. Furthermore, in a follow-up laboratory experiment using hypothetical choice sets matched to the real-world data, we find further support for the idea that subjective valuations of restaurants are scaled in accordance with the choice context, providing corroborating evidence for a general mechanistic-level account of these effects. Taken together, our results provide a potent demonstration of context-dependent choice in real-world choice settings, manifesting both in decisions and subjective valuation of options.

Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels (I _Kir) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current mediated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels (I _h), providing a hyperpolarizing drive. The combined reduction in both I _Kir and I _h synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resistant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhythmic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain circuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states.SIGNIFICANCE STATEMENT Oxytocin (OXT) plays key roles in reproduction, parenting and social and emotional behavior, and deficiency in OXT receptor (OXTR) signaling may contribute to neuropsychiatric disorders. We identified a novel array of OXTR-modulated ion channels that operate in close coordination to retune hippocampal CA2 pyramidal neurons, enhancing responsiveness to synaptic inputs and sculpting output. OXTR signaling inhibits both potassium conductance (I _Kir) and mixed cation conductance (I _h), engaging opposing influences on membrane potential, stabilizing it while synergistically elevating membrane resistance and electrotonic spread. OXT signaling also facilitates a tetrodotoxin-resistant (TTX-R) Na⁺ current, not previously described in hippocampus (HP), engaged on further depolarization. This TTX-R current lowers the spike threshold and supports rhythmic depolarization and burst firing, a potent driver of downstream circuitry.

The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions, and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the "natural product lipidome". According to this analysis, lipidated natural products predominantly contain saturated medium-chain lipids (MCLs), which are significantly shorter than the long-chain lipids (LCLs) found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that MCL conjugation can render molecules cell-permeable and modulate their bioactivity. With all explored chemotypes, MCL-conjugates consistently exhibited superior uptake or bioactivity compared to LCL-conjugates and either comparable or superior uptake or bioactivity to short-chain lipid (SCL)-conjugates. Together, our findings suggest that conjugation of small molecules with MCLs could be a powerful strategy for the design of probes and drugs.