Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75 th percentile), mid- (75 th -90 th percentile) and high-risk (>90 th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers. Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.
INTRODUCTION: Ovarian Sertoli cell tumors represent a subset of sex cord-stromal tumors and are exceedingly rare in prepubertal children. Here we report a girl with vaginal bleeding due to a Sertoli cell tumor who was originally thought to have McCune-Albright syndrome (MAS). CASE PRESENTATION: A previously healthy girl presented at age two years six months with breast development and vaginal bleeding. On exam, she had Tanner 4 breasts, Tanner 1 pubic hair, estrogenized vaginal mucosa, and a café-au-lait macule. Laboratory studies revealed an elevated estradiol with suppressed gonadotropins and negative tumor markers. Her bone age was advanced by more than three years. Pelvic ultrasound (US) revealed an enlarged uterus and a slightly larger left compared to right ovary. She was started on tamoxifen for presumed MAS. A repeat pelvic US one month later showed a heterogenous mass in the left ovary which was subsequently resected. Pathology revealed a Sertoli cell tumor, lipid-rich variant. Germline sequencing revealed a pathogenic STK11 variant, diagnostic for Peutz-Jeghers syndrome (PJS). CONCLUSION: The findings in our patient were strikingly similar to those encountered in MAS. To our knowledge, our patient is the youngest ever reported to present with precocious puberty due to a Sertoli cell tumor in the setting of PJS.
Two isomeric pentacene dimers, each linked by a diamantane spacer, have been synthesized. These dimers are designed to provide experimental evidence to support quantum mechanical calculations, which predict the substitution pattern on the carbon-rich diethynyldiamantane spacer to be decisive in controlling the interpentacene coupling. Intramolecular singlet fission (i-SF) serves as a probe for the existence and strength of the electronic coupling between the two pentacenes, with transient absorption spectroscopy as the method of choice to characterize i-SF. 4,9-Substitution of diamantane provides a pentacene dimer (4,9-dimer) in which the two chromophores are completely decoupled and that, following photoexcitation, deactivates to the ground state analogous to a monomeric pentacene chromophore. Conversely, 1,6-substitution provides a pentacene dimer (1,6-dimer) that exhibits sufficiently strong coupling to drive i-SF, resulting in correlated triplet M(T1T1) yields close to unity and free triplet (T1 + T1) yields of ca. 50%. Thus, the diamantane spacer effectively switches "on" or "off" the coupling between the chromophores, based on the substitution pattern. The binary control of diamantane contrasts other known molecular spacers designed only to modulate the coupling strength between two pentacenes.
Neuromodulation trials for PTSD have yielded mixed results, and the optimal neuroanatomical target remains unclear. We analyzed three datasets to study brain circuitry causally linked to PTSD in military Veterans. After penetrating traumatic brain injury (n=193), lesions that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex (mPFC), amygdala, and anterolateral temporal lobe (cross-validation p=0.01). In Veterans without lesions (n=180), PTSD was specifically associated with connectivity within this circuit (p<0.01). Connectivity change within this circuit correlated with PTSD improvement after transcranial magnetic stimulation (TMS) (n=20) (p<0.01), even though the circuit was not directly targeted. Finally, we directly targeted this circuit with fMRI-guided accelerated TMS, leading to rapid resolution of symptoms in a patient with severe lifelong PTSD. All results were independent of depression severity. This lesion-based PTSD circuit may serve as a neuromodulation target for Veterans with PTSD.
The frustrated Lewis pair (FLP) adducts PB{ECl2} (PB = iPr2P(C6H4)BCy2; Cy = cyclohexyl; E = Si, Ge) were used to access a bis(alkynyl)-functionalized silylene and a germylene; the goal behind preparing these species was to obtain new unsaturated main group polymers [E(CîCSiMe3)2]n upon heating. While the silylene adduct PB{Si(CîCSiMe3)2} was stable up to 150 °C, the heavier element congener PB{Ge(CîCSiMe3)2} underwent a complicated rearrangement process accompanied by Cy-group migration and Ge(II)-alkyne coordination. Density functional theory computations were performed to understand the mechanistic pathway for the unusual rearrangement of PB{Ge(CîCSiMe3)2}.
The solid-state reaction of the active pharmaceutical ingredient theophylline with citric acid is a well-established example of a mechanochemical reaction, leading to a model pharmaceutical cocrystal. Here, classical force field molecular dynamics was employed to investigate the molecular mixing and structural distortion that take place on the mechanically driven indentation of a citric acid nanoparticle on a slab of crystalline theophylline. Through non-equilibrium molecular dynamics simulations, a 6 nm diameter nanoparticle of citric acid was introduced onto an open (001) surface of a theophylline crystal, varying both the angle of incidence of the nanoparticle between 15° and 90° and the indentation speed between 1 m s-1 and 16 m s-1. This theoretical study enabled the evaluation of how these two parameters promote molecular mixing and overall structural deformation upon the mechanical contraction of theophylline and citric acid, both of which are important parameters underlying mechanochemical cocrystallisation. The results show that the angle of incidence plays a key role in the molecular transfer ability between the two species and in the structural disruption of the initially spherical nanoparticles. Changing the indentation speed, however, did not lead to a discernible trend in molecular mixing, highlighting the importance of the incident angle in mechanochemical events in the context of supramolecular chemistry, such as the disruption of the crystal structure and molecular transfer between molecular crystals.
Music is a universal human attribute. The study of amusia, a neurologic music processing deficit, has increasingly elaborated our view on the neural organization of the musical brain. However, lesions causing amusia occur in multiple brain locations and often also cause aphasia, leaving the distinct neural networks for amusia unclear. Here, we utilized lesion network mapping to identify these networks. A systematic literature search was carried out to identify all published case reports of lesion-induced amusia. The reproducibility and specificity of the identified amusia network were then tested in an independent prospective cohort of 97 stroke patients (46 female and 51 male) with repeated structural brain imaging, specifically assessed for both music perception and language abilities. Lesion locations in the case reports were heterogeneous but connected to common brain regions, including bilateral temporoparietal and insular cortices, precentral gyrus, and cingulum. In the prospective cohort, lesions causing amusia mapped to a common brain network, centering on the right superior temporal cortex and clearly distinct from the network causally associated with aphasia. Lesion-induced longitudinal structural effects in the amusia circuit were confirmed as reduction of both gray and white matter volume, which correlated with the severity of amusia. We demonstrate that despite the heterogeneity of lesion locations disrupting music processing, there is a common brain network that is distinct from the language network. These results provide evidence for the distinct neural substrate of music processing, differentiating music-related functions from language, providing a testable target for noninvasive brain stimulation to treat amusia.
Aphasia , Auditory Perceptual Disorders , Music , Humans , Male , Female , Auditory Perceptual Disorders/etiology , Prospective Studies , Reproducibility of Results , Brain , Aphasia/etiology , Aphasia/complications
The Vietnam Head Injury Study has been curated by Dr Jordan Grafman since the 1980s in an effort to study patients with penetrating traumatic brain injuries suffered during the Vietnam War. Unlike many datasets of ischemic stroke lesions, the VHIS collected extraordinarily deep phenotyping and was able to sample lesion locations that are not constrained to typical vascular territories. For decades, this dataset has helped researchers draw causal links between neuroanatomical regions and neuropsychiatric symptoms. The value of the VHIS has only increased over time as techniques for analyzing the dataset have developed and evolved. Tools such as voxel lesion symptom mapping allowed one to relate symptoms to individual brain voxels. With the advent of the human connectome, tools such as lesion network mapping allow one to relate symptoms to connected brain networks by combining lesion datasets with new atlases of human brain connectivity. In a series of recent studies, lesion network mapping has been combined with the Vietnam Head Injury dataset to identify brain networks associated with spirituality, religiosity, consciousness, memory, emotion regulation, addiction, depression, and even transdiagnostic mental illness. These findings are enhancing our ability to make diagnoses, identify potential treatment targets for focal brain stimulation, and understand the human brain generally. Our techniques for studying brain lesions will continue to improve, as will our tools for modulating brain circuits. As these advances occur, the value of well characterized lesion datasets such as the Vietnam Head Injury Study will continue to grow. This study aims to review the history of the Vietnam Head Injury Study and contextualize its role in modern-day localization of neurological symptoms.
Brain Injuries, Traumatic , Connectome , Humans , Vietnam , Brain/pathology , Connectome/methods
OBJECTIVE: Spontaneous confabulation is a symptom in which false memories are conveyed by the patient as true. The purpose of the study was to identify the neuroanatomical substrate of this complex symptom and evaluate the relationship to related symptoms, such as delusions and amnesia. METHODS: Twenty-five lesion locations associated with spontaneous confabulation were identified in a systematic literature search. The network of brain regions functionally connected to each lesion location was identified with a large connectome database (N=1,000) and compared with networks derived from lesions associated with nonspecific (i.e., variable) symptoms (N=135), delusions (N=32), or amnesia (N=53). RESULTS: Lesions associated with spontaneous confabulation occurred in multiple brain locations, but they were all part of a single functionally connected brain network. Specifically, 100% of lesions were connected to the mammillary bodies (familywise error rate [FWE]-corrected p<0.05). This connectivity was specific for lesions associated with confabulation compared with lesions associated with nonspecific symptoms or delusions (FWE-corrected p<0.05). Lesions associated with confabulation were more connected to the orbitofrontal cortex than those associated with amnesia (FWE-corrected p<0.05). CONCLUSIONS: Spontaneous confabulation maps to a common functionally connected brain network that partially overlaps, but is distinct from, networks associated with delusions or amnesia. These findings lend new insight into the neuroanatomical bases of spontaneous confabulation.
Connectome , Memory Disorders , Humans , Amnesia/diagnostic imaging , Brain/diagnostic imaging , Brain/pathology , Prefrontal Cortex/pathology , Datasets as Topic
There is disagreement regarding the major components of the brain network supporting spatial cognition. To address this issue, we applied a lesion mapping approach to the clinical phenomenon of topographical disorientation. Topographical disorientation is the inability to maintain accurate knowledge about the physical environment and use it for navigation. A review of published topographical disorientation cases identified 65 different lesion sites. Our lesion mapping analysis yielded a topographical disorientation brain map encompassing the classic regions of the navigation network: medial parietal, medial temporal, and temporo-parietal cortices. We also identified a ventromedial region of the prefrontal cortex, which has been absent from prior descriptions of this network. Moreover, we revealed that the regions mapped are correlated with the Default Mode Network sub-network C. Taken together, this study provides causal evidence for the distribution of the spatial cognitive system, demarking the major components and identifying novel regions.
Orientation, Spatial , Orientation , Humans , Brain/pathology , Brain Mapping , Confusion/etiology , Confusion/pathology , Magnetic Resonance Imaging
The synthesis and characterization of platinum(II) and palladium(II) complexes bearing two (dimers Pt(Lpc)2Cl2 and Pd(Lpc)2Cl2), one (monomers Pt(Lpc)(Lref)Cl2 and Pd(Lpc)(Lref)Cl2), or no (reference compounds Pt(Lref)2Cl2 and Pd(Lref)2Cl2) pentacene-based pyridyl ligands are presented. Photophysical properties of the dimers are probed by means of steady-state and time-resolved transient absorption measurements in comparison to the monomer and model compounds. Our results document that despite enhanced spin-orbit coupling from the presence of heavy atoms, intramolecular singlet fission (iSF) is not challenged by intersystem crossing. iSF thus yields correlated triplet pairs and even uncorrelated triplet excited states upon decoherence. Importantly, significant separation of the two pentacenyl groups facilitates decoupling of the two chromophores. Furthermore, the mechanism of iSF is altered depending on the respective metal center, that is, Pt(II) versus Pd(II). The dimer based on Pt(II), Pt(Lpc)2Cl2, exhibits a direct pathway for the iSF and forms a correlated triplet pair with singlet-quintet spin-mixing within 10 ns in variable solvents. On the other hand, the dimer based on Pd(II), Pd(Lpc)2Cl2, leads to charge transfer mixing during the population of the correlated triplet pair that is dependent on solvent polarity. Moreover, Pd(Lpc)2Cl2 gives rise to a stable equilibrium between singlet and quintet correlated triplet pairs with lifetimes of up to 170 ns. Inherent differences in the size and polarizability, when contrasting platinum(II) with palladium(II), are the most likely rationale for the underlying trends.
A comparative experimental and computational study examining the interplay of the ancillary ligand structure and Ni oxidation state in the Ni-catalyzed C(sp2)-O cross-coupling of (hetero)aryl chlorides and primary or secondary aliphatic alcohols is presented, focusing on PAd-DalPhos (L1)-, CyPAd-DalPhos (L2)-, PAd2-DalPhos (L3)-, and DPPF (L4)-ligated [(L)NiCl]n (n = 1 or 2) and (L)Ni(o-tol)Cl precatalysts. Both L1 and L2 were found to outperform the other ligands examined, with the latter proving to be superior overall. While Ni(II) precatalysts generally outperformed Ni(I) species, in some instances the catalytic abilities of Ni(I) precatalysts were competitive with those of Ni(II). Density-functional theory calculations indicate the favorability of a Ni(0)/Ni(II) catalytic cycle featuring turnover-limiting C-O bond reductive elimination over a Ni(I)/Ni(III) cycle involving turnover-limiting C-Cl oxidative addition.
In the target article, Bowers et al. dispute deep artificial neural network (ANN) models as the currently leading models of human vision without producing alternatives. They eschew the use of public benchmarking platforms to compare vision models with the brain and behavior, and they advocate for a fragmented, phenomenon-specific modeling approach. These are unconstructive to scientific progress. We outline how the Brain-Score community is moving forward to add new model-to-human comparisons to its community-transparent suite of benchmarks.
Brain , Neural Networks, Computer , Humans
Precision oncology is defined as the selection of an effective treatment for a cancer patient based upon genomic profiling of the patient's tumor to identify targetable alterations. The application of precision oncology toward pediatric cancer patients has moved forward more slowly than with adults but is gaining momentum. Clinical and pharmaceutical advances developed over the past decade for adult cancer indications have begun to move into pediatric oncology, expanding treatment options for young high-risk and refractory patients. As a result, the FDA has approved 23 targeted drugs for pediatric cancer indications, moving targeted drugs into the standard of care. Our precision oncology program is in a medium sized children's hospital, lacking internal sequencing capabilities and bioinformatics. We have developed methods, medical and business partnerships to provide state-of-the-art tumor characterization and targeted treatment options for our patients. We present here a streamlined and practical protocol designed to enable any oncologist to implement precision oncology options for their patients.
Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.
Aging , Genome-Wide Association Study , Multimorbidity , Longevity , Phenotype , Aging/genetics , Humans
BACKGROUND: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. METHODS: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. RESULTS: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. CONCLUSIONS: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.
Multiple Sclerosis , Stroke , Humans , Female , Middle Aged , Male , Multiple Sclerosis/complications , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Cross-Sectional Studies , Magnetic Resonance Imaging/methods , Memory, Short-Term , Stroke/complications , Brain/pathology
Photon energy conversion can be accomplished in many different ways, including the two opposing manners, down-conversion (i.e., singlet fission, SF) and up-conversion (i.e., triplet-triplet annihilation up-conversion, TTA-UC). Both processes have the potential to help overcome the detailed balance limit of single-junction solar cells. Tetracene, in which the energies of the lowest singlet excited state and twice the triplet excited state are comparable, exhibits both down- and up-conversion. Here, we have designed meta-diethynylphenylene- and 1,3-diethynyladamantyl-linked tetracene dimers, which feature different electronic coupling, to characterize the interplay between intramolecular SF (intra-SF) and intramolecular TTA-UC (intra-TTA-UC) via steady-state and time-resolved absorption and fluorescence spectroscopy. Furthermore, we have used Pd-phthalocyanine as a sensitizer to enable intra-TTA-UC in the two dimers via indirect photoexcitation in the near-infrared part of the solar spectrum. The work is rounded off by temperature-dependent measurements, which outline key aspects of how thermal effects impact intra-SF and intra-TTA-UC in different dimers.
IMPORTANCE: Biofilms are the communal way of life that microbes adopt to increase survival. Key to our ability to systematically promote or ablate biofilm formation is a detailed understanding of the biofilm matrix macromolecules. Here, we identify the first two essential steps in the Bacillus subtilis biofilm matrix exopolysaccharide (EPS) synthesis pathway. Together, our studies and approaches provide the foundation for the sequential characterization of the steps in EPS biosynthesis, using prior steps to enable chemoenzymatic synthesis of the undecaprenyl diphosphate-linked glycan substrates.
Bacillus subtilis , Biofilms , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Extracellular Polymeric Substance Matrix/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism
Previous work has shown that the TbFUT1 and LmjFUT1 genes encode essential fucosyltransferases located inside the single mitochondria of the protozoan parasites Trypanosoma brucei and Leishmania major, respectively. However, nothing was known about the orthologous gene TcFUT1 or its gene product in Trypanosoma cruzi, aetiological agent of Chagas disease. In this study, we describe the overexpression of TcFUT1 with a C-terminal 6xMyc epitope tag in T. cruzi epimastigote cells. Overexpressed and immunoprecipitated TcFUT1-6xMyc was used to demonstrate enzymatic activity and to explore substrate specificity. This defined TcFUT1 as a GDP-Fuc : ßGal α1-2 fucosyltransferase with a strict requirement for acceptor glycans with non-reducing terminal Galß1-3GlcNAc structures. This differs from the specificity of the T. brucei orthologue TbFUT1, which can also tolerate non-reducing terminal Galß1-4GlcNAc and Galß1-4Glc acceptor sites. Immunofluorescence microscopy using α-Myc tag antibodies also showed a mitochondrial location for TcFUT1 in T. cruzi epimastigote cells. Collectively, these results are like those described for TbFUT1 and LmjFUT1 from T. brucei and L. major, suggesting that FUT1 gene products have conserved function for across the trypanosomatids and may share therapeutic target potential.
Chagas Disease , Leishmania major , Trypanosoma cruzi , Humans , Trypanosoma cruzi/genetics , Fucosyltransferases/genetics , Leishmania major/genetics , Mitochondria
