Cassini composite infrared spectrometer: correcting an offset error and refining the pointing parameters for the midinfrared detectors.

Based on preflight laboratory testing, an unexpectedly large positional offset between the two midinfrared (mid-IR) detector arrays in the Cassini composite infrared spectrometer (CIRS) instrument has been noted in the literature. A much smaller offset was measured in-flight. We investigate this discrepancy by estimating several spatial relationships among the detectors and comparing these results with three independent data sets. This enables us to infer the probable cause of this offset and to derive a new reduced value. We comment on the effect that this change could have on previously published results involving CIRS data. We also present a graphical display of the arrays projected on the sky as CIRS would see it.

Cassini composite infrared spectrometer: correcting an offset error and refining the pointing parameters for the midinfrared detectors: publisher's note.

This publisher's note serves to correct Appl. Opt.62, 5882 (2023).APOPAI0003-693510.1364/AO.491970.

Low-Magnitude Mechanical Signals Combined with Zoledronic Acid Reduce Musculoskeletal Weakness and Adiposity in Estrogen-Deprived Mice.

Combination treatment of Low-Intensity Vibration (LIV) with zoledronic acid (ZA) was hypothesized to preserve bone mass and muscle strength while reducing adipose tissue accrual associated with complete estrogen (E 2 )-deprivation in young and skeletally mature mice. Complete E 2 -deprivation (surgical-ovariectomy (OVX) and daily injection of aromatase inhibitor (AI) letrozole) were performed on 8-week-old C57BL/6 female mice for 4 weeks following commencement of LIV administration or control (no LIV), for 28 weeks. Additionally, 16-week-old C57BL/6 female E 2 -deprived mice were administered ±LIV twice daily and supplemented with ±ZA (2.5 ng/kg/week). By week 28, lean tissue mass quantified by dual-energy X-ray absorptiometry was increased in younger OVX/AI+LIV(y) mice, with increased myofiber cross-sectional area of quadratus femorii. Grip strength was greater in OVX/AI+LIV(y) mice than OVX/AI(y) mice. Fat mass remained lower in OVX/AI+LIV(y) mice throughout the experiment compared with OVX/AI(y) mice. OVX/AI+LIV(y) mice exhibited increased glucose tolerance and reduced leptin and free fatty acids than OVX/AI(y) mice. Trabecular bone volume fraction and connectivity density increased in the vertebrae of OVX/AI+LIV(y) mice compared to OVX/AI(y) mice; however, this effect was attenuated in the older cohort of E 2 -deprived mice, specifically in OVX/AI+ZA mice, requiring combined LIV with ZA to increase trabecular bone volume and strength. Similar improvements in cortical bone thickness and cross-sectional area of the femoral mid-diaphysis were observed in OVX/AI+LIV+ZA mice, resulting in greater fracture resistance. Our findings demonstrate that the combination of mechanical signals in the form of LIV and anti-resorptive therapy via ZA improve vertebral trabecular bone and femoral cortical bone, increase lean mass, and reduce adiposity in mice undergoing complete E 2 -deprivation. One Sentence Summary: Low-magnitude mechanical signals with zoledronic acid suppressed bone and muscle loss and adiposity in mice undergoing complete estrogen deprivation. Translational Relevance: Postmenopausal patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors to reduce tumor progression experience deleterious effects to bone and muscle subsequently develop muscle weakness, bone fragility, and adipose tissue accrual. Bisphosphonates (i.e., zoledronic acid) prescribed to inhibit osteoclast-mediated bone resorption are effective in preventing bone loss but may not address the non-skeletal effects of muscle weakness and fat accumulation that contribute to patient morbidity. Mechanical signals, typically delivered to the musculoskeletal system during exercise/physical activity, are integral for maintaining bone and muscle health; however, patients undergoing treatments for breast cancer often experience decreased physical activity which further accelerates musculoskeletal degeneration. Low-magnitude mechanical signals, in the form of low-intensity vibrations, generate dynamic loading forces similar to those derived from skeletal muscle contractility. As an adjuvant to existing treatment strategies, low-intensity vibrations may preserve or rescue diminished bone and muscle degraded by breast cancer treatment.

High Fat Diet Mediated Alterations in Serum Sphingolipid Profiles in An Experimental Mouse Model Measured by Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry.

Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic steatosis, a benign condition caused by accumulation of lipids in hepatocytes, which may progress to steatohepatitis and cirrhosis. Recent studies suggest that sphingolipids are involved in the development and severity of NAFLD. The goal of this study is to identify the circulating sphingolipid species that are altered by chronic high fat diet (HFD) feeding and correlate these abnormalities with hepatic sphingolipids. We utilized a previously established experimental model of NAFLD generated by HFD feeding of 8-week-old male mice for 16 weeks. Lipids were extracted from serum samples by Folch method and analyzed with matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in the positive and negative ion modes. MALDI-TOF detected a total of 47 serum sphingolipids including sphingomyelins, sulfatides, ceramides, phosphosphingolipids, and glycosphingolipids within the mass range of 600-2000 Da. Principle component analysis demonstrated clear separation of hepatic sphingolipids from low fat diet (LFD) and HFD groups and partial overlap of serum sphingolipids with a variance of 53.5% and 15.1%, and 11.7% in PC1, PC2, and PC3, respectively. Chronic HFD feeding significantly increased expression of SM (40:0), SM(42:2), ST(42:2), Hex(6)-Cer (40:1), and Hex(4)-HexNAc (2)-Cer (34:1) in both serum and liver. In addition, HFD mediated percent changes in hepatic sphingolipids correlate linearly with the percent changes in serum sphingolipids as determined by Pearson correlation (P = 0.0002). Elevated levels of serum and hepatic sphingomyelins and glycoceramides are key factors mediating NAFLD development and may serve as peripheral markers of hepatic steatosis.

Fluorodeoxyglucose positron emission tomography scans in patients with alcohol use disorder.

BACKGROUND: Diminished uptake of fluorodeoxyglucose (FDG) has been observed in patients with alcohol use disorder (AUD) but little statistical contrast of the regional brain deficits has been undertaken. This study examined prefrontal cortex inter-regional Brodmann area differences to delineate patterns associated with behavioral, neurotransmitter, and general toxicity hypotheses of cerebral involvement in AUD. METHODS: We obtained data from FDG positron emission tomography (PET) and anatomical magnetic resonance imaging (MRI) for 87 patients with AUD and 41 age- and sex-matched healthy volunteers. Patients were alcohol dependent and had negative breathalyzer tests at the time of imaging. They were assessed with the Beck Depression Inventory, Alcohol Urge Questionnaire, Obsessive Compulsive Drinking Scale, Spielberger State/Trait Anxiety Scale, Buss-Durkee Hostility Inventory, and the Drinker Inventory of Consequences (DrInC). PET images were co-registered to MRI and both voxel × voxel statistical mapping and stereotaxic regions of interest were obtained. RESULTS: Compared with healthy volunteers, patients with AUD had lower relative metabolic rates in the frontal, temporal, and parietal lobes, localizable most prominently to the dorsolateral and nearly all orbital prefrontal cortex, superior temporal gyrus, and inferior parietal lobule. In contrast, metabolic rates in the medial orbitofrontal and anterior cingulate cortex, and the subcortical structures (thalamus, cerebellum, ventral striatum, and the dorsal raphe nucleus) in patients were significantly greater. The severity of alcohol-related consequences as assessed by the DrInC scale was most highly associated with lower metabolism in the caudate, dorsolateral prefrontal, frontopolar, and anteroposterior cingulate cortex. CONCLUSIONS: Despite widespread metabolic abnormalities, decreases in AUD were most marked in frontal executive areas, consistent with diminished impulse control, and increases were most prominent in the striatum and cingulate areas, consistent with a suppressed reward system.

The Role of Muscle Ring Finger-1 (MuRF1), MuRF2, MuRF3, and Atrogin-1 on Bone Microarchitecture In Vivo.

Ubiquitin proteasome system was found to contribute to bone loss by regulating bone turnover and metabolism, by modulating osteoblast differentiation and bone formation as well as formation of osteoclasts that contribute to bone resorption. Muscle Ring Finger (MuRF) are novel ubiquitin ligases, which are muscle specific and have not been much implicated in the bone but have been implicated in several human diseases including heart failure and skeletal muscle atrophy. This study is aimed at understanding the role of MuRF1, MuRF2, MuRF3 and Atrogin which are distinct MuRF family proteins in bone homeostasis. Wildtype, heterozygous and homozygous mice of each of the isoforms were used and the bone microarchitecture and mechanical properties were assessed using microCT and biomechanics. MuRF1 depletion was found to alter cortical properties in both males and females, but only trabecular spacing in the females. MuRF2 depletion let to no changes in the cortical and trabecular properties but change in the strain to yield in the females. Depletion of MuRF3 led to decrease in the cortical properties in the females and increase in the trabecular properties in the males. Atrogin depletion was found to reduce cortical properties in both males and females, whereas some trabecular properties were found to be reduced in the females. Each muscle-specific ligase was found to alter the bone structure and mechanical properties in a distinct a sex-dependent manner.

Neurocognitive profile of adolescents with early-onset schizophrenia and their unaffected siblings.

BACKGROUND: We investigated the neurocognitive profiles of Early-Onset Schizophrenia (EOS; onset before age 18) and paired unaffected siblings and the little-studied effect of age-of-onset and duration of illness on cognitive performance. METHODS: 31 EOS probands, and 31 of their siblings, had four cognitive domains assessed: (a) Memory: California Verbal Learning Test, and the Wechsler Memory Scale-Revised; (b) Working memory: Digit Span; (c) Attention: Degraded-Stimulus Continuous Performance Test, Span of Apprehension (SPAN), and Trail Making Test (TMT) part A; (d) Executive function: Wisconsin card sorting task, and TMT part B. Diagnosis was confirmed using the structured clinical interview for DSM-IV. RESULTS: While EOS showed a generalised neurocognitive deficit (0.25-0.50 effect size) compared with siblings, across all cognitive domains, significantly greater patient deficits were observed with, working memory, attention, and executive function and minimal differences for digit span forward, block design and false alarms on the SPAN-12 confirmed by repeated measures MANOVA. Patients with earlier onset (12-15) showed greater deficits on false alarm and digits backward scores. Siblings showed individual cognitive task profiles similar to patients, confirming familial effects. EOS showed much more variable scores than siblings with more individual tasks showing 2 SD deficits than siblings. Long duration patients had greater z-score variability across tasks. CONCLUSIONS: Duration of illness was a more important characteristic in patients with onset 16 and over than in younger onset patients with comparable durations. Both the similarity of sibling pair profiles and greater patient variability across task provide further support for neurobiological heterogeneity in schizophrenia.

Four-modality imaging of unmedicated subjects with schizophrenia: 18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, and MRI.

Diminished prefrontal function, dopaminergic abnormalities in the striatum and thalamus, reductions in white matter integrity and frontotemporal gray matter deficits are the most replicated findings in schizophrenia. We used four imaging modalities (18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, structural MRI) in 19 healthy and 25 schizophrenia subjects to assess the relationship between functional (dopamine D2/D3 receptor binding potential, glucose metabolic rate) and structural (fractional anisotropy, MRI) correlates of schizophrenia and their additive diagnostic prediction potential. Multivariate ANOVA was used to compare structural and functional image sets for identification of schizophrenia. Integration of data from all four modalities yielded better predictive power than less inclusive combinations, specifically in the thalamus, left dorsolateral prefrontal and temporal regions. Among the modalities, fractional anisotropy showed highest discrimination in white matter whereas 18F-fallypride binding showed highest discrimination in gray matter. Structural and functional modalities displayed comparable discriminative power but different topography, with higher sensitivity of structural modalities in the left prefrontal region. Combination of functional and structural imaging modalities with inclusion of both gray and white matter appears most effective in diagnostic discrimination. The highest sensitivity of 18F-fallypride PET to gray matter changes in schizophrenia supports the primacy of dopaminergic abnormalities in its pathophysiology.

Chemokine-Based Therapeutics for the Treatment of Inflammatory and Fibrotic Convergent Pathways in COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 betacoronavirus and has taken over 761,426 American lives as of the date of publication and will likely result in long-term, if not permanent, tissue damage for countless patients. COVID-19 presents with diverse and multisystemic pathologic processes, including a hyperinflammatory response, acute respiratory distress syndrome (ARDS), vascular injury, microangiopathy, tissue fibrosis, angiogenesis, and widespread thrombosis across multiple organs, including the lungs, heart, kidney, liver, and brain. C-X-C chemokines contribute to these pathologies by attracting inflammatory mediators, the disruption of endothelial cell integrity and function, and the initiation and propagation of the cytokine storm. Among these, CXCL10 is recognized as a critical contributor to the hyperinflammatory state and poor prognosis in COVID-19. CXCL10 is also known to regulate growth factor-induced fibrosis, and recent evidence suggests the CXCL10-CXCR3 signaling system may be vital in targeting convergent pro-inflammatory and pro-fibrotic pathways. This review will explore the mechanistic role of CXCL10 and related chemokines in fibrotic complications associated with COVID-19 and the potential of CXCL10-targeted therapeutics for early intervention and long-term treatment of COVID-19-induced fibrosis.

Reading abilities and dopamine D2/D3 receptor availability: An inverted U-shaped association in subjects with schizophrenia.

Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used 18F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects' scores were positively and linearly associated with D2/D3 receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous. This relationship was weakened in schizophrenia subjects and in contrast to healthy participants followed an inverted U-shaped curve both in the cortex and dorsal striatum, indicating restricted optimal range of dopamine D2/D3 receptor availability for cognitive performance in schizophrenia.

Neural Correlates of Autobiographical Memory: Evidence From a Positron Emission Tomography Study in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

Background: Autobiographical memory (AM) changes are the hallmark of Alzheimer's disease (AD) and mild cognitive impairment (MCI). In recent neuroimaging studies, AM changes have been associated with numerous cerebral sites, such as the frontal cortices, the mesial temporal lobe, or the posterior cingulum. Regional glucose uptake in these sites was investigated for underlying subdimensions using factor analysis. Subsequently, the factors were examined with respect to AM performance in a subgroup of patients. Methods: Data from 109 memory clinic referrals, who presented with MCI (n = 60), mild AD (n = 49), or were cognitively intact, were analyzed. The glucose metabolic rates determined by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in 34 cerebral sites important for AM were investigated for underlying subdimensions by calculating factor analysis with varimax rotation. Subsequently, the respective factor scores were correlated with the episodic and semantic AM performance of 22 patients, which was measured with a semi-structured interview assessing episodic memories (characterized by event-related emotional, sensory, contextual, and spatial-temporal details) and personal semantic knowledge from three periods of life (primary school, early adulthood, and recent years). Results: Factor analysis identified seven factors explaining 69% of the variance. While patients with MCI and AD showed lower values than controls on the factors frontal cortex, mesial temporal substructures, and occipital cortex, patients with MCI presented with increased values on the factors posterior cingulum and left temporo-prefrontal areas. The factors anterior cingulum and right temporal cortex showed only minor, non-significant group differences. Solely, the factor mesial temporal substructures was significantly correlated with both episodic memories (r = 0.424, p < 0.05) and personal semantic knowledge (r = 0.547, p < 0.01) in patients with MCI/AD. Conclusions: The factor structure identified corresponds by large to the morphological and functional interrelations of the respective sites. While reduced glucose uptake on the factors frontal cortex, mesial temporal substructures, and occipital cortex in the patient group may correspond to neurodegenerative changes, increased values on the factors posterior cingulum and left temporo-prefrontal areas in MCI may result from compensatory efforts. Interestingly, changes of the mesial temporal substructures were correlated with both semantic and episodic AM. Our findings suggest that AM deficits do not only reflect neurodegenerative changes but also refer to compensatory mechanisms as they involve both quantitative losses of specific memories and qualitative changes with a semantization of memories.

Cardiomyocyte microRNA-150 confers cardiac protection and directly represses proapoptotic small proline-rich protein 1A.

MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by ß-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte-specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.

The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

Rapid Peak Alignment for MALDI-TOF Lipid Analysis.

The ability to measure structural and functional alterations in cellular and tissue lipids with small footprint, accessible instrumentation has sparked interest in their role in disease pathology. However, various lipidomic analytical tools tend to be cumbersome and time-consuming. A rapid, accurate, and straight forward peak alignment software routine would greatly facilitate the analysis of large datasets, such as those produced by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Herein, we describe a novel Rapid Peak Alignment Method (RPAM) which allows untargeted analysis of lipids expressed in brain white matter following chronic ethanol exposure in an established experimental model. The RPAM outputs data comparable to manual peak alignments but the processing time requires only 90 minutes instead of 8-10 hours. This method is readily adapted to a broad range of models, tissue types, and human diseases.

Clinical Characteristics and Risk Factors for Myocardial Injury and Arrhythmia in COVID-19 patients

The authors have withdrawn this manuscript because of a lack of novelty of results and, with that, a lack of intention to publish in a peer reviewed journal. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

ACVR2B antagonism as a countermeasure to multi-organ perturbations in metastatic colorectal cancer cachexia.

BACKGROUND: Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ co-morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. METHODS: NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham-operated animals received saline (n = 5-10 per group). Sham and tumour-bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. RESULTS: mHCT116 hosts displayed losses in fat mass ( - 79%, P < 0.0001), bone mass ( - 39%, P < 0.05), and SKM mass (quadriceps: - 22%, P < 0.001), in line with reduced muscle cross-sectional area ( - 24%, P < 0.01) and plantarflexion force ( - 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: - 16%, P < 0.0001; fractional shortening %: - 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass ( + 238%, P < 0.001), bone mass ( + 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross-sectional area: + 43%, P < 0.0001) and plantarflexion force ( + 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. CONCLUSIONS: Our metastatic CRC model recapitulates the multi-systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi-organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.

CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury.

Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.