Response to Comment on "Following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion" and "Molecular Diffusivity of Click Reaction Components: The Diffusion Enhancement Question".

In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our groups (J. Am. Chem. Soc. 2021, 143, 20884-20890; DOI: 10.1021/jacs.1c09455) and another (J. Am. Chem. Soc. 2022, 144, 1380-1388; DOI: 10.1021/jacs.1c11754), Huang and Granick discuss the diffusion NMR measurements of molecules during a copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. Here we respond to these comments and maintain that no diffusion enhancement was observed for any species during the reaction. We show that the relaxation agent does not interfere with the CuAAC reaction kinetics nor the diffusion of the molecules involved. Similarly, the gradient pulse length and diffusion time do not affect the diffusion coefficients. Peak overlap was completely removed in our study with the use of hydrazine as the reducing agent. The steady-state assumption does not hold for these diffusion measurements that take several minutes, which is the reason monotonic gradient orders are not suitable. Finally, we discuss the other reactions where similar changes in diffusion have been claimed. Our conclusions are fully supported by the results represented in our original JACS Article and the corresponding Supporting Information.

Nonlinear functional network connectivity in resting functional magnetic resonance imaging data.

In this work, we focus on explicitly nonlinear relationships in functional networks. We introduce a technique using normalized mutual information (NMI) that calculates the nonlinear relationship between different brain regions. We demonstrate our proposed approach using simulated data and then apply it to a dataset previously studied by Damaraju et al. This resting-state fMRI data included 151 schizophrenia patients and 163 age- and gender-matched healthy controls. We first decomposed these data using group independent component analysis (ICA) and yielded 47 functionally relevant intrinsic connectivity networks. Our analysis showed a modularized nonlinear relationship among brain functional networks that was particularly noticeable in the sensory and visual cortex. Interestingly, the modularity appears both meaningful and distinct from that revealed by the linear approach. Group analysis identified significant differences in explicitly nonlinear functional network connectivity (FNC) between schizophrenia patients and healthy controls, particularly in the visual cortex, with controls showing more nonlinearity (i.e., higher normalized mutual information between time courses with linear relationships removed) in most cases. Certain domains, including subcortical and auditory, showed relatively less nonlinear FNC (i.e., lower normalized mutual information), whereas links between the visual and other domains showed evidence of substantial nonlinear and modular properties. Overall, these results suggest that quantifying nonlinear dependencies of functional connectivity may provide a complementary and potentially important tool for studying brain function by exposing relevant variation that is typically ignored. Beyond this, we propose a method that captures both linear and nonlinear effects in a "boosted" approach. This method increases the sensitivity to group differences compared to the standard linear approach, at the cost of being unable to separate linear and nonlinear effects.

1H NMR Studies of Intramolecular OH/OH Hydrogen Bonds via Titratable Isotope Shifts.

Methanol titrations of partially deuterated 1,4- and 1,3-diols dissolved in nonpolar solvents such as CD2Cl2 and benzene-d6 have provided 1H NMR measurements of OH/OD isotope shifts, diagnostic for intact intramolecular hydrogen bonds, under conditions of increasing protic solvent concentration. 1,4- and 1,3-diols with conformationally favored intramolecular OH/OH hydrogen bonds can be titrated to constant isotope shift values, albeit with variable sign, in the presence of excess methanol equivalents, providing evidence for intact intramolecular hydrogen bonds under these conditions. Conversely, the isotope shift in a 1,3-diol with a conformationally labile intramolecular hydrogen bond titrated to zero when in the presence of excess equivalents methanol, consistent with intramolecular hydrogen bond rupture under these conditions. Additionally, the titration behavior of hydroxyl chemical shifts in diols and protected derivatives has revealed significant OH/OD isotope shifts in the absence of chemical shift differences (δOHin = δOHout) that are necessary for an equilibrium isotope effect, lending evidence for an intrinsic contribution to the isotope effect. OH/OD isotope shift titration thus provides a means for understanding the origins of these isotope effects and for probing the intact or nonintact nature of intramolecular OH/OH hydrogen bonds in response to intermolecular hydrogen bonds provided by a protic solvent.

A flow electrochemistry-enabled synthesis of 2-substituted N-(methyl-d)piperidines.

A synthesis of N-monodeuteriomethyl-2-substituted piperidines is described. An efficient and readily scalable anodic methoxylation of N-formylpiperidine in an undivided microfluidic electrolysis cell delivers methoxylated piperidine 3, which is a precursor to a N-formyliminium ion and enables C-nucleophiles to be introduced at the 2-position. The isotopically labelled N-deuteriomethyl group is installed using the Eschweiler-Clarke reaction with formic acid-d2 and unlabelled formaldehyde. Monodeuterated N-methyl groups in these molecular systems possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long-lived nuclear spin states in solution nuclear magnetic resonance.

Following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion.

The reported changes in self-diffusion of small molecules during reactions have been attributed to "boosted mobility". We demonstrate the critical role of changing concentrations of paramagnetic ions on nuclear magnetic resonance (NMR) signal intensities, which led to erroneous measurements of diffusion coefficients. We present simple methods to overcome this problem. The use of shuffled gradient amplitudes allows accurate diffusion NMR measurements, even with time-dependent relaxation rates caused by changing concentrations of paramagnetic ions. The addition of a paramagnetic relaxation agent allows accurate determination of both diffusion coefficients and reaction kinetics during a single experiment. We analyze a copper-catalyzed azide-alkyne cycloaddition "click" reaction, for which boosted mobility has been claimed. With our methods, we accurately measure the diffusive behavior of the solvent, starting materials, and product and find no global increase in diffusion coefficients during the reaction. We overcome NMR signal overlap using an alternative reducing agent to improve the accuracy of the diffusion measurements. The alkyne reactant diffuses slower as the reaction proceeds due to binding to the copper catalyst during the catalytic cycle. The formation of this intermediate was confirmed by complementary NMR techniques and density functional theory calculations. Our work calls into question recent claims that molecules actively propel or swim during reactions and establishes that time-resolved diffusion NMR measurements can provide valuable insight into reaction mechanisms.

Sparse deep neural networks on imaging genetics for schizophrenia case-control classification.

Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case-control classification. An L0 -norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi-study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools.

Cutaneous T-cell lymphoma is associated with increased risk of lymphoma, melanoma, lung cancer, and bladder cancer.

BACKGROUND: Patients with cutaneous T-cell lymphoma (CTCL) are at a higher risk of developing second malignancies. However, rates of incidence vary significantly across studies. METHODS: A systematic review and meta-analysis of articles published between 1950 and 2019 was performed to evaluate the risk of second malignancies in patients with CTCL. RESULTS: We identified 10 eligible studies, including 12 patient cohorts, with 5.9% to 16.8% of patients developing second malignancies. All studies showed a male predominance for patients developing second malignancies. The mean age across the studies ranged from 44.6 to 68.0 years. The time between the diagnosis of CTCL and second malignancy ranged from 2.1 to 5.4 years (mean, 3.29 y; 95% confidence interval [CI], 2.69-5.15). Meta-analysis showed a standardized incidence ratio of 2.18 (95% CI, 1.43-2.93) for all malignancies. The standardized incidence ratios were 15.25 (95% CI, 7.70-22.79) for Hodgkin lymphoma, 4.96 (95% CI, 3.58-6.33) for non-Hodgkin lymphoma, 1.69 (95% CI, 1.18-2.21) for lung cancer, 1.72 (95% CI, 1.18-2.21) for bladder cancer, and 3.09 (95% CI, 1.77-6.43) for melanoma. CONCLUSIONS: We find that patients with CTCL are at increased risk of second malignancies, especially Hodgkin and non-Hodgkin lymphoma, lung cancer, bladder cancer, and melanoma. These findings provide evidence of a population at increased risk of malignancy. Early detection may decrease the morbidity burden of second malignancies, thus providing a strong rationale for prospective screening studies.

The significance of epidermal involvement in primary cutaneous gamma/delta (γδ) T-cell lymphoma: A systematic review and meta-analysis.

BACKGROUND: Primary cutaneous gamma/delta (γδ) T-cell lymphoma (PCGDTCL) is a rare, aggressive peripheral T-cell lymphoma. There is evidence that patients with epidermotropic PCGDTCL may have an improved prognosis compared with those with only dermal and/or subcutaneous involvement. METHODS: Systematic review of the literature and application of inclusion criteria yielded 48 manuscripts detailing the cases of 104 patients. RESULTS: Of the 104 patients, 57 were male (51.4%) and 47 were female (48.5%) Based on provided histopathologic descriptions, 57 cases (54.8%) had no epidermotropism, 47 cases (45.2%) patients demonstrated any degree of epidermotropism, and 25 cases were predominantly epidermotropic (25/104, 24%). Five-year overall survivals for patients with no epidermotropism, any epidermotropism, and predominantly epidermotropic presentation were 32.8%, 28.9%, and 40.0%, respectively (p = 0.40). The most commonly performed immunohistochemical markers were CD3, CD4, CD8, CD5, CD7, CD30, CD56, TCR beta, TCR γ, and TCR δ. There was no statistically significant difference in immunophenotype between groups. Lesion morphology was described in the majority of cases (85/104, 80.9%); most cases presented as a combination of nodules, plaques, and tumors (77.4%). Several cases had more atypical presentations, including "mycosis-fungoides-like" and ulcerated. CONCLUSION: In PCGDTCL, neither epidermotropism nor predominantly epidermotropic phenotype predict a better prognosis. In addition, the case report literature in dermatology and dermatopathology is rich and highly valuable.

Dentate gyrus volume deficit in schizophrenia.

BACKGROUND: Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined. METHODS: Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed. RESULTS: This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (ß = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume. CONCLUSIONS: This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.

Increased risk of second primary hematologic and solid malignancies in patients with mycosis fungoides: A Surveillance, Epidemiology, and End Results analysis.

BACKGROUND: Mycosis fungoides (MF) is associated with increased risk of second primary hematologic malignancies, but its association with second primary solid tumors is less well characterized. OBJECTIVE: This retrospective analysis seeks to assess the risk of being diagnosed with a second primary hematologic or solid malignancy in patients with MF. DESIGN: We performed an analysis of patients diagnosed with MF from 2000 through 2015 in the United States cancer registries of SEER-18 (N = 6742). RESULTS: Relative risks were estimated by using standardized incidence ratios (SIRs). Among 6742 patients, there were 511 (7.5%) second cancer events (SIR, 10.15; 95% confidence interval [CI], 9.29-11.07). These included 184 (36.0%) hematologic malignancies (SIR, 39.71; 95% CI, 34.05-46.05) and 327 (64.0%) solid tumor malignancies (SIR, 7.33; 95% CI, 6.56-8.17). Patients with MF were at increased risk for non-Hodgkin lymphoma; Hodgkin lymphoma; melanoma; and lung, female breast, prostate, colon, and renal cancers. Females were at higher risk than males (P < .05). All ethnic groups showed a statistically significant elevation in SIRs. Elevation of SIRs was observed across all stages of MF. CONCLUSIONS AND RELEVANCE: Patients with MF are at increased risk for diagnosis of second primary malignancies and should be carefully screened for discernable signs and symptoms of second malignancies.

A Social Blow: The Role of Interpersonal Relationships in Mild Traumatic Brain Injury.

BACKGROUND: Mild traumatic brain injury (mTBI; concussion) is a common and costly public health concern that exhibits diverse patterns of recovery, making ascertainment of prognosis difficult. Interpersonal factors are critical determinants of health and linked to both adjustment to injury and illness and may critically impact mTBI outcomes. However, their potential role remains largely unexplored at present. OBJECTIVES: To provide a framework for incorporating interpersonal factors into the study and treatment of mTBI. METHODS: We provide a narrative summary of the existing literature on adjustment to mTBI and present an overview of interpersonal biopsychosocial frameworks for adjustment to injury and illness. RESULTS: We discuss ways of applying interpersonal framework models to the study of mTBI. In addition, we identified several factors or themes shared across frameworks that mTBI researchers and clinicians can integrate into their work. Finally, we discuss gaps in the literature and suggest directions for future research. CONCLUSIONS: Adding an interpersonal framework to established biopsychosocial models in mTBI would allow for novel opportunities for prediction of symptom course and for the development of novel interventions.

Hand-foot skin reaction with primarily dorsal involvement in a patient with metastatic renal cell carcinoma on cabozantinib.

A 61-year-old man with metastatic renal cell carcinoma on cabozantinib developed hand-foot skin reaction with predominantly dorsal involvement including painful violaceous plaques over the joints and keratotic yellow plaques on the palmar fingers. The medication was discontinued with resolution of the plaques and later reinitiated at a lower dose uneventfully.

Associations of edge-detected and manual-traced common carotid artery intima-media thickness with incident peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis.

Common carotid artery (CCA) intima-media thickness (IMT) is associated with coronary heart disease and can be measured on ultrasound images either by hand or with an automated edge detector. The association of CCA IMT with incident peripheral artery disease (PAD) is poorly studied. We studied 5467 participants of the Multi-Ethnic Study of Atherosclerosis composed of non-Hispanic white, Chinese, Hispanic, and African American participants with a mean age of 61.9 years (47.8% men). Framingham Risk Factors, manual-traced IMT (mt-IMT), and edge-detected IMT (ed-IMT) were entered into multivariable Cox proportional hazards models with incident PAD as the outcome. There were 87 events during a median follow-up of 12.2 years. In fully adjusted models and expressing the hazard ratios (HR) as an increment in SD values, both mt-IMT and ed-IMT were significantly associated with incident PAD: HR 1.36 (95% CI: 1.15, 1.61) and 1.29 (95% CI: 1.04, 1.60), respectively. We conclude that ed- and mt-CCA IMT measurements are associated with incident PAD. ClinicalTrials.gov Identifier: NCT00063440.

Personality traits and negative consequences associated with binge drinking and marijuana use in college students.

Background: Binge drinking is common in college students, and many drink in quantities greater than the standard definition of bingeing. Combined use of additional substances, particularly marijuana, is also common. Objectives: Increased impulsivity and sensation seeking are risk factors for bingeing, and this study was designed to characterize their association with extreme compared to standard bingeing, as well as with combined bingeing and marijuana use. Negative consequences of alcohol use were also investigated. Methods: Self-report personality measures and a measure of the negative consequences of alcohol use were given to a sample of 221 college students (109 females) sorted into a control and 4 binge groups based upon their patterns of bingeing and marijuana use. Narrowly defined, non-overlapping measures of impulsivity and sensation seeking were analyzed to assess the association of these personality measures with substance-use patterns and negative consequences of bingeing. Results: Standard bingers did not differ from non-bingeing controls on either impulsivity or sensation seeking, whereas extreme bingers had significantly higher impulsivity and sensation seeking scores than controls and also significantly higher sensation seeking than standard bingers. Exploratory analyses of a broader set of personality scales showed that a disinhibition scale was also significant predictor of substance use group. A number of personality traits significantly predicted substance use patterns as well as specific negative consequences of bingeing. Conclusions: Impulsivity, sensation seeking and disinhibition are significant associates of substance use patterns and the negative consequences of use in college students.

Cortical Thickness in Adolescents with a Family History of Alcohol Use Disorder.

BACKGROUND: Individuals with a family history (FH+) of alcohol use disorder (AUD) have a higher risk for developing an AUD than those with no family history (FH-) of AUD. In addition, FH+ individuals tend to perform worse on neuropsychological measures and show heightened impulsivity, which may be due to underlying differences in brain structure such as cortical thickness. The primary aim of this study was to investigate differences in cortical thickness in FH+ compared to FH- adolescents. Secondary aims were to (i) investigate differences in executive functioning and impulsivity, and (ii) examine associations between brain structure and behavior. METHODS: Brain scans of 95 FH- and 93 FH+ subjects aged 13 to 18 were obtained using magnetic resonance imaging. FH+ subjects were required to have at least 1 biological parent with a history of an AUD. FH+ and FH- individuals had limited or no past alcohol use, thereby minimizing potential effects of alcohol. Subjects were evaluated on impulsivity and executive functioning tasks. Thicknesses of cortical lobes and subregions were analyzed using FreeSurfer. Regions showing group differences were examined for group-by-age interactions and correlations with neuropsychological and personality measures. RESULTS: FH+ adolescents had thinner cortices in frontal and parietal lobes, notably in the medial orbitofrontal, lateral orbitofrontal, and superior parietal cortices. The difference in cortical thickness between family history groups was strongest among the youngest subjects. FH+ subjects were also more impulsive and had poorer performance on a spatial memory task. CONCLUSIONS: These findings demonstrate frontal and parietal structural differences in FH+ adolescents that might underlie cognitive and behavioral characteristics associated with AUD risk.

Origins of Small Proton Chemical Shift Differences in Monodeuterated Methyl Groups.

We have recently shown that the small proton chemical shift difference in 2-methyl-1-(methyl-d)piperidine supports a long-lived nuclear spin state. To identify additional candidate molecules with CH2D groups exhibiting accessible long-lived states, and to investigate the factors governing the magnitude of the shift differences, we report a computational and experimental investigation of methyl rotational equilibria and proton chemical shifts in a variety of 2-substituted 1-(methyl-d)piperidines. The polarity and size of the 2-substituent affect the 1,2-stereoisomeric relationship, and consequently, the strength of the rotational asymmetry within the CH2D group. Nonpolar and large 2-substituents prefer the equatorial position, and relatively large shift differences (i.e., > 13 ppb) are observed. Polar and small substituents, however, increasingly prefer the axial position, and medium to small shift differences (i.e., 0 to 9 ppb) are observed. In addition, the diastereotopic CH2D proton chemical shift difference for tricarbonyl(1-chloro-2-deuteriomethylbenzene) chromium(0) was computed, showing that reasonable predictions of these small shift differences can be extended to more complex, organometallic species.

Association between depression and fruit and vegetable consumption among adults in South Asia.

BACKGROUND: In recent years there has been a growing research interest regarding the impact of dietary behaviour on mental health outcomes. The present study aimed to investigate the association between fruit and vegetable (F&V) consumption and depression in three south Asian countries- Bangladesh, India and Nepal. METHODS: Cross-sectional data were obtained from World Health Survey of WHO conducted during 2002-04. In total 14,133 adult subjects (Bangladesh 3262, India 7594, Nepal 3277) aged 18 years and above were included in the study. Outcome variables were Self-Reported Depression (SRD) during last 30 days and 12 months. Multivariable regression methods were used to explore the association between F&V consumption and depression. RESULTS: Prevalence of Self-Reported Depression during past 12 months were respectively 39%, 17.7%, and 49.9% for Bangladesh, India and Nepal. In India, those who consumed less than five servings of vegetables were respectively 41% [AOR = 1.41; 95%CI = 0.60-3.33] and 57% [AOR = 1.57; 95%CI = 0.93-2.64] more likely to report severe-extreme and mild-moderate depression during past 30 days compared to those who consumed five servings a day. Regarding fruit consumption, compared to those who consumed five servings a day, the odds of severe-extreme and mild-moderate SRD were respectively 3.5 times [AOR = 3.48; 95%CI = 1.216-10.01] and 45% [AOR = 1.44; 95%CI = 0.89-2.32] higher in Bangladesh, and 2.9 times [AOR = 2.92; 95%CI = 1.12-7.64] and 42% higher [AOR = 1.41; 95%CI = 0.89-2.24] in Nepal compared to those who consumed less than five servings a day during last 30 days. CONCLUSION: Daily intake of less than five servings of F&V was associated with higher odds of depression. Nutrition programs aimed at promoting F&V consumption might prove beneficial to reduce the prevalence of depression in south Asian population. Further studies are required to understand the factors limiting the adequate consumption of F&V.

Physical inactivity and self-reported depression among middle- and older-aged population in South Asia: World health survey.

BACKGROUND: With the increase in the understanding of the influence of various lifestyle factors such as sedentary behaviour and level of physical activity (PA) on physical and mental health, there has been a growing research interest on how physical inactivity correlates with depressive outcomes across countries. The present study aimed to examine 1) the pattern of engaging in PA among middle- and older-aged population in four South Asian countries, and 2) whether PA is associated with higher prevalence of depression. METHODS: This cross-sectional study is based on country-representative data obtained from WHO's World Health Survey (WHS). Subjects were 7204 men and women aged above 50 years from Bangladesh, India, Nepal and Sri Lanka, all of which are classified as Low-and-middle-income countries (LMICs) in World Bank reports. Outcome variables were self-ported depression (SRD) and ever being diagnosed with depression. Association between frequency of moderate (MPA) and vigorous physical activity (VPA) and depression was analysed by multivariable regression methods. RESULT: Prevalence of self-reported depression was respectively 47.7%, 40.3%, 40.4% and 11.4% in Bangladesh, India, Nepal and Sri Lanka. Prevalence of being ever diagnosed with depression was highest in Nepal (38.7%), followed by India (17.7%), Bangladesh (2.5%) and Sri Lanka (2%). Multivariable analysis shown statistically significant association between PA and diagnosed depression in Bangladesh and India, but not with SRD. In Bangladesh, compared to those who reported engaging in MPA on daily basis, the odds of reporting diagnosed depression were more than five times higher [AOR = 5.512; 95% CI = 1.159-26.21] for those who never took MPA. In India, those never took VPA had 44% higher [AOR = 1.442; 95% CI = 1.046-1.987] odds of being diagnosed with depression compared those who never engaged in VPA. CONCLUSION: Lower frequency of vigorous physical activity were significantly associated with higher rates of depression diagnosed. Based on the findings, it is recommendable that health programs targeting mental health among middle- and older-aged population take steps to promote the level of PA within a multi-dimensional depression prevention framework. Longitudinal studies are needed to understand the role of vigorous and moderate physical activity on the onset and intervention of depression among elderly population in the region.