Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

Converging Effects of Chronic Pain and Binge Alcohol Consumption on Anterior Insular Cortex Neurons Projecting to the Dorsolateral Striatum in Male Mice.

Chronic pain and alcohol use disorder (AUD) are highly comorbid, and patients with chronic pain are more likely to meet the criteria for AUD. Evidence suggests that both conditions alter similar brain pathways, yet this relationship remains poorly understood. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and AUD. However, circuit-specific changes elicited by the combination of pain and alcohol use remain understudied. The goal of this work was to elucidate the converging effects of binge alcohol consumption and chronic pain on AIC neurons that send projections to the dorsolateral striatum (DLS). Here, we used the Drinking-in-the-Dark (DID) paradigm to model binge-like alcohol drinking in mice that underwent spared nerve injury (SNI), after which whole-cell patch-clamp electrophysiological recordings were performed in acute brain slices to measure intrinsic and synaptic properties of AIC→DLS neurons. In male, but not female, mice, we found that SNI mice with no prior alcohol exposure consumed less alcohol compared with sham mice. Electrophysiological analyses showed that AIC→DLS neurons from SNI-alcohol male mice displayed increased neuronal excitability and increased frequency of miniature excitatory postsynaptic currents. However, mice exposed to alcohol prior to SNI consumed similar amounts of alcohol compared with sham mice following SNI. Together, our data suggest that the interaction of chronic pain and alcohol drinking have a direct effect on both intrinsic excitability and synaptic transmission onto AIC→DLS neurons in mice, which may be critical in understanding how chronic pain alters motivated behaviors associated with alcohol.

ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.

AIMS/HYPOTHESIS: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus. METHODS: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. RESULTS: Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis. CONCLUSIONS/INTERPRETATION: Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.

Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts.

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.

The Heel Complex: Anatomy, Imaging, Pathologic Conditions, and Treatment.

The differential diagnosis for heel pain is broad but primarily involves abnormalities of the Achilles tendon, calcaneus, and plantar fascia. Achilles tendon disorders include tendinosis, tendinitis, and partial or complete tears. Tendinosis refers to tendon degeneration, while tendinitis is inflammation after acute overload. Untreated tendinosis can progress to partial or complete tears. Tendon disorders can be accompanied by paratenonitis or inflammation of the loose sheath enclosing the tendon. Initial management involves rehabilitation and image-guided procedures. Operative management is reserved for tendon tears and includes direct repair, tendon transfer, and graft reconstruction. The calcaneus is the most commonly fractured tarsal bone. The majority of fractures are intra-articular; extra-articular fractures, stress or insufficiency fractures, medial process avulsion, and neuropathic avulsion can also occur. Posterosuperior calcaneal exostosis or Haglund deformity, retrocalcaneal bursitis, and insertional Achilles tendinosis form the characteristic triad of Haglund syndrome. It is initially managed with orthotics and physiotherapy. Operative management aims to correct osseous or soft-tissue derangements. The plantar fascia is a strong fibrous tissue that invests the sole of the foot and contributes to midfoot stability. Inflammation or plantar fasciitis is the most common cause of heel pain and can be related to overuse or mechanical causes. Acute rupture is less common but can occur in preexisting plantar fasciitis. Conservative treatment includes footwear modification, calf stretches, and percutaneous procedures. The main operative treatment is plantar fasciotomy. Plantar fibromatosis is a benign fibroblastic proliferation within the fascia that can be locally aggressive and is prone to recurrence. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

The effect of spanning external fixation on entrapped structures in tibial pilon fractures.

PURPOSE: Pilon fractures are often complex injuries involving severe soft tissue injury. Studies have shown pilon fractures may entrap soft tissue structures between fracture fragments. Staged fixation of pilon fractures with spanning external fixation (SEF) is important for soft tissue rest and plays an important role in the management of these injuries. While SEF has been shown to promote soft tissue rest prior to definitive fixation, no studies have shown the effect SEF has on entrapped structures (ES). The purpose of this study was to evaluate how SEF effects ES in pilon fractures. METHODS: A retrospective review of 212 pilon fractures treated at our institution between 2010 and 2022 was performed. Patients with a CT scan pre-SEF and post-SEF met inclusion criteria. CTs were reviewed to characterize ES in pre- and post-SEF imaging. RESULTS: Of the 19 patients with ES identified on CT pre-SEF, seven (36.8%) had full release of ES post-SEF and 12 (63.2%) had no release of ES. The posterior tibial tendon was the most commonly ES and remained entrapped in 62.5% of cases. Only 25% of 43-C3 fractures had release of ES post-SEF, while 100% of 43-C1 and 43-C2 fractures demonstrated complete release of ES post-SEF. CONCLUSION: Entrapped structures in pilon fractures are likely to remain entrapped post-SEF, with only one-third of our cohort demonstrating release. In 43-C3 patterns, if ES are identified on CT pre-SEF, surgeons should consider addressing these either through mini open versus open approaches at the time of SEF as they are likely to remain entrapped post-SEF.

Family size for women with primary ovarian insufficiency and their relatives.

STUDY QUESTION: How does the number of children in women with primary ovarian insufficiency (POI) compare to the number for control women across their reproductive lifespans? SUMMARY ANSWER: Approximately 14% fewer women with POI will have children, but for those able to have children the median number is 1 less than for age-matched controls. WHAT IS KNOWN ALREADY: Women with POI are often identified when presenting for fertility treatment, but some women with POI already have children and there remains a low chance for pregnancy after the diagnosis. Further, POI is heritable, but it is not known whether relatives of women with POI have a smaller family size than relatives of controls. STUDY DESIGN, SIZE, DURATION: The study was a retrospective case-control study of women with POI diagnosed from 1995 to 2021 (n = 393) and age-matched controls (n = 393). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with POI were identified using ICD9 and 10 codes in electronic medical records (1995-2021) from two major healthcare systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database. All POI cases (n = 393) were required to have genealogy information available for at least three generations of ancestors. Two sets of female controls were identified: one matched for birthplace (Utah or elsewhere) and 5-year birth cohort, and a second also matched for fertility status (children present). The number of children born and maternal age at each birth were ascertained by birth certificates (available from 1915 to 2020) for probands, controls, and their relatives. The Mann-Whitney U test was used for comparisons. A subset analysis was performed on women with POI and controls who delivered at least one child and on women who reached 45 years to capture reproductive lifespan. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 393 women with POI and controls, 211 women with POI (53.7%), and 266 controls (67.7%) had at least one child. There were fewer children born to women with POI versus controls (median (interquartile range) 1 (0-2) versus 2 (0-3); P = 3.33 × 10-6). There were no children born to women with POI and primary amenorrhea or those <25 years old before their diagnosis. When analyzing women with at least one child, women with POI had fewer children compared to controls overall (2 (1-3) versus 2 (2-4); P = 0.017) and when analyzing women who reached 45 years old (2 (1-3) versus 3 (2-4); P = 0.0073). Excluding known donor oocyte pregnancies, 7.1% of women with POI had children born after their diagnosis. There were no differences in the number of children born to relatives of women with POI, including those with familial POI. LIMITATIONS, REASONS FOR CAUTION: The data are limited based on inability to determine whether women were trying for pregnancy throughout their reproductive lifespan or were using contraception. Unassisted births after the diagnosis of POI may be slightly over-estimated based on incomplete data regarding use of donor oocytes. The results may not be generalizable to countries or states with late first births or lower birth rates. WIDER IMPLICATIONS OF THE FINDINGS: Approximately half of women with POI will bear children before diagnosis. Although women with POI had fewer children than age matched controls, the difference in number of children is one child per woman. The data suggest that fertility may not be compromised leading up to the diagnosis of POI for women diagnosed at 25 years or later and with secondary amenorrhea. However, the rate of pregnancy after the diagnosis is low and we confirm a birth rate of <10%. The smaller number of children did not extend to relatives when examined as a group, suggesting that it may be difficult to predict POI based on family history. STUDY FUNDING/COMPETING INTEREST(S): The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Shoulder and Elbow Injuries in Adult Overhead Throwers: Imaging Review.

Overhead throwing, particularly in baseball, subjects the shoulder and elbow to various unique injuries. Capsular contracture following repetitive external rotation shifts the humeral head posterosuperiorly, predisposing to glenohumeral internal rotation deficit (GIRD), Bennett, posterosuperior internal impingement (PSI), and superior labrum anterior-posterior (SLAP) lesions. GIRD represents loss of internal rotation at the expense of external rotation. Bennett lesion represents ossification of the posteroinferior glenohumeral ligament due to repetitive traction. PSI manifests with humeral head cysts and "kissing" tears of the posterosuperior cuff and labrum. Scapular dysfunction contributes to symptoms of PSI and predisposes to labral or rotator cuff disease. "Peel-back" or SLAP lesions occur when torsional forces detach the biceps-labral anchor from the glenoid. Finally, disorders of the anterior capsule, latissimus dorsi, teres major, and subscapularis are well recognized in overhead throwers. At the elbow, injuries typically involve the medial-sided structures. The ulnar collateral ligament (UCL) is the primary static restraint to valgus stress and can be thickened, attenuated, ossified, and/or partially or completely torn. Medial epicondylitis can occur with tendinosis, partial tear, or complete rupture of the flexor-pronator mass and can accompany UCL tears and ulnar neuropathy. Posteromedial impingement (PMI) and valgus extension overload syndrome are related entities that follow abundant valgus forces during late cocking or acceleration, and deceleration. These valgus stresses wedge the olecranon into the olecranon fossa, leading to PMI, osteophytes, and intra-articular bodies. Other osseous manifestations include olecranon stress fracture and cortical thickening of the humeral shaft. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Intravascular papillary hemangioendothelioma disguised as a peripheral sheath tumor of median nerve at the wrist: a case report and literature review.

BACKGROUND: Intravascular papillary hemangioendothelioma (IVPH) is a benign lesion previously reported in the nasal cavity, neck, upper extremities, and breast. Diagnosis with cross-sectional imaging can prove difficult, with histopathological examination necessary for diagnosis. IVPH resulting in carpal tunnel symptoms is quite rare. CASE PRESENTATION: We report the case of a 37-year-old woman who presented with a radial, volar right wrist mass enlarging over the span of 5 years. She noted numbness and tingling in her wrist and thumb, exacerbated by minor accidental collisions and wrist hyperextension. There was no antecedent trauma. On examination, a mildly tender, mobile mass was evident at the volar aspect of the right wrist. Magnetic resonance imaging (MRI) with contrast demonstrated a lobulated, predominantly T2 hyperintense, heterogeneously enhancing mass thought to be a peripheral nerve sheath tumor. The patient elected for surgical excision of the mass, and the histopathological examination showed organizing thrombi with prominent papillary endothelial hyperplasia. At the 2-month follow-up, the patient had full range of motion of her fingers and wrist, with subjectively normal sensation in the distribution of the median nerve. CONCLUSION: Carpal tunnel syndrome, in exceedingly rare occasions, can result from an IVPH. MRI findings may be confused with more common entities. Histopathological confirmation remains necessary for conclusive diagnosis.

Rumen-protected choline and methionine during the periparturient period affect choline metabolites, amino acids, and hepatic expression of genes associated with one-carbon and lipid metabolism.

Feeding supplemental choline and Met during the periparturient period can have positive effects on cow performance; however, the mechanisms by which these nutrients affect performance and metabolism are unclear. The objective of this experiment was to determine if providing rumen-protected choline, rumen-protected Met, or both during the periparturient period modifies the choline metabolitic profile of plasma and milk, plasma AA, and hepatic mRNA expression of genes associated with choline, Met, and lipid metabolism. Cows (25 primiparous, 29 multiparous) were blocked by expected calving date and parity and randomly assigned to 1 of 4 treatments: control (no rumen-protected choline or rumen-protected Met); CHO (13 g/d choline ion); MET (9 g/d DL-methionine prepartum; 13.5 g/d DL-methionine, postpartum); or CHO + MET. Treatments were applied daily as a top dress from ∼21 d prepartum through 35 d in milk (DIM). On the day of treatment enrollment (d -19 ± 2 relative to calving), blood samples were collected for covariate measurements. At 7 and 14 DIM, samples of blood and milk were collected for analysis of choline metabolites, including 16 species of phosphatidylcholine (PC) and 4 species of lysophosphatidylcholine (LPC). Blood was also analyzed for AA concentrations. Liver samples collected from multiparous cows on the day of treatment enrollment and at 7 DIM were used for gene expression analysis. There was no consistent effect of CHO or MET on milk or plasma free choline, betaine, sphingomyelin, or glycerophosphocholine. However, CHO increased milk secretion of total LPC irrespective of MET for multiparous cows and in absence of MET for primiparous cows. Furthermore, CHO increased or tended to increase milk secretion of LPC 16:0, LPC 18:1, and LPC 18:0 for primi- and multiparous cows, although the response varied with MET supplementation. Feeding CHO also increased plasma concentrations of LPC 16:0 and LPC 18:1 in absence of MET for multiparous cows. Although milk secretion of total PC was unaffected, CHO and MET increased secretion of 6 and 5 individual PC species for multiparous cows, respectively. Plasma concentrations of total PC and individual PC species were unaffected by CHO or MET for multiparous cows, but MET reduced total PC and 11 PC species during wk 2 postpartum for primiparous cows. Feeding MET consistently increased plasma Met concentrations for both primi- and multiparous cows. Additionally, MET decreased plasma serine concentrations during wk 2 postpartum and increased plasma phenylalanine in absence of CHO for multiparous cows. In absence of MET, CHO tended to increase hepatic mRNA levels of betaine-homocysteine methyltransferase and phosphate cytidylyltransferase 1 choline, α, but tended to decrease expression of 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and peroxisome proliferator activated receptor α irrespective of MET. Although shifts in the milk and plasma PC profile were subtle and inconsistent between primi- and multiparous cows, gene expression results suggest that supplemental choline plays a probable role in promoting the cytidine diphosphate-choline and betaine-homocysteine S-methyltransferase pathways. However, interactive effects suggest that this response depends on Met availability, which may explain the inconsistent results observed among studies when supplemental choline is fed.

Anthropometrics and body composition predict performance during a simulated direct-fire engagement.

This study determined anthropometric and body composition predictors of performance during a simulated direct-fire engagement. Healthy subjects (N = 33, age = 25.7 ± 7.0 yr) underwent anthropometric and body composition assessments before completing a simulated direct-fire engagement - consisting of marksmanship with cognitive workload assessment and a fire-and-move drill (16 × 6-m sprints) while wearing combat load. Susceptibility to enemy fire was modelled on sprint duration. Partial correlations and multiple linear regressions established the relationships between predictors and performance outcomes, controlling for age and sex. Significance was p ≤ 0.05. Higher percent body fat, fat mass, fight load index predicted greater susceptibility to enemy fire (r = 0.40 to 0.42) and lower cognitive performance (r= -0.45 to -0.49). Higher BMI also predicted lower cognitive performance (r= -0.49). Shorter stature/hand length predicted higher marksmanship accuracy (r= -0.40), while higher fat-free mass/fat-free mass index predicted slower reaction times (r = 0.36-0.41). These data suggest anthropometric and body composition measures modulate combat effectiveness and reinforce body composition standards in military organisations.Practitioner summary: This study identified field-expedient anthropometric and body composition predictors of a simulated direct-fire engagement that evaluated survivability (i.e. susceptibility to enemy fire) and lethality (i.e. marksmanship, cognitive performance) outcomes. Our findings suggest that anthropometric and body composition measures may play a role in soldier survivability and lethality during simulated direct-fire engagements.

HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum.

Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal-directed (via the dorsomedial striatum) and habitual (via the dorsolateral striatum, DLS) behaviours. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR-mediated long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD), depending on the input. In the DLS, MOR-LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR-STD occurs at thalamic inputs, suggesting input-specific MOR plasticity mechanisms. Here, we evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch-clamp electrophysiology. We found that cAMP/PKA signalling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of cannabinoid-mediated LTD in DLS. MOR-STD does not utilize these same mechanisms. We also demonstrated that cannabinoid-LTD occurs at AIC inputs to DLS. However, while cannabinoid-LTD requires mTOR signalling in DLS, MOR-LTD does not. We characterized the role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. These results suggest a mechanism in which MOR activation requires HCN1 to induce MOR-LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders. KEY POINTS: Mu opioid receptor-mediated long-term depression at anterior insular cortex inputs to dorsolateral striatum involves presynaptic cAMP/PKA signalling and protein translation, similar to known mechanisms of cannabinoid long-term depression. Dorsal striatal cannabinoid long-term depression also occurs at anterior insular cortex inputs to the dorsolateral striatum. Dorsal striatal cannabinoid long-term depression requires mTOR signalling, similar to hippocampal cannabinoid long-term depression, but dorsal striatal mu opioid long-term depression does not require mTOR signalling. Mu opioid long-term depression requires presynaptic HCN1 channels at anterior insular cortex inputs to dorsolateral striatum.

Transcriptome analysis of blastoderms exposed to prolonged egg storage and short periods of incubation during egg storage.

BACKGROUND: Cool temperature egg storage prior to incubation is a common practice in the broiler industry; however, prolonged egg storage causes increased embryonic mortality and decreased hatchability and growth in surviving chicks. Exposing eggs to short periods of incubation during egg storage (SPIDES) reduces the adverse consequences of prolonged storage. SPIDES increases blastodermal cell viability by reducing apoptosis, though the counteracting mechanisms are unclear. To define the impact of prolonged storage and SPIDES, transcriptome analysis compared gene expression from blastoderms isolated from eggs exposed to the following treatments: control (CR, stored at 17 °C for 4 days), prolonged storage (NSR, stored at 17 °C for 21 days), SPIDES (SR, stored at 17 °C for 21 days with SPIDES), and incubated control (C2, stored at 17 °C for 4 days followed by incubation to HH (Hamburger-Hamilton) stage 2, used as the ideal standard development) (n = 3/group). Data analysis was performed using the CLC Genomics Workbench platform. Functional annotation was performed using DAVID and QIAGEN Ingenuity Pathway Analysis. RESULTS: In total, 4726 DEGs (differentially expressed genes) were identified across all experimental group comparisons (q < 0.05, FPKM> 20, |fold change| > 1.5). DEGs common across experimental comparisons were involved in cellular homeostasis and cytoskeletal protein binding. The NSR group exhibited activation of ubiquitination, apoptotic, and cell senescence processes. The SR group showed activation of cell viability, division, and metabolic processes. Through comparison analysis, cellular respiration, tRNA charging, cell cycle control, and HMBG1 signaling pathways were significantly impacted by treatment and potential regulatory roles for ribosomal protein L23a (RPL23A) and MYC proto-oncogene, BHLH transcription factor (MYC) were identified. CONCLUSIONS: Prolonged egg storage (NSR) resulted in enriched cell stress and death pathways; while SPIDES (SR) resulted in enriched basic cell and anti-apoptotic pathways. New insights into DNA repair mechanisms, RNA processing, shifts in metabolism, and chromatin dynamics in relation to egg storage treatment were obtained through this study. Although egg storage protocols have been examined through targeted gene expression approaches, this study provided a global view of the extensive molecular networks affected by prolonged storage and SPIDES and helped to identify potential upstream regulators for future experiments to optimize egg storage parameters.

Interpretation of Cartilage Damage at Routine Clinical MRI: How to Match Arthroscopic Findings.

This review is intended to aid in the interpretation of damage to the articular cartilage at routine clinical MRI to improve clinical management. Relevant facets of the histologic and biochemical characteristics and clinical management of cartilage are discussed, as is MRI physics. Characterization of damage to the articular cartilage with MRI demands a detailed understanding of the normal and damaged appearance of the osteochondral unit in the context of different sequence parameters. Understanding the location of the subchondral bone plate is key to determining the depth of the cartilage lesion. Defining the bone plate at MRI is challenging because of the anisotropic fibrous organization of articular cartilage, which is susceptible to the "magic angle" phenomenon and chemical shift artifacts at the interface with the fat-containing medullary cavity. These artifacts may cause overestimation of the thickness of the subchondral bone plate and, therefore, overestimation of the depth of a cartilage lesion. In areas of normal cartilage morphology, isolated hyperintense and hypointense lesions often represent degeneration of cartilage at arthroscopy. Changes in the subchondral bone marrow at MRI also increase the likelihood that cartilage damage will be visualized at arthroscopy, even when a morphologic lesion cannot be resolved, and larger subchondral lesions are associated with higher grades at arthroscopy. The clinical significance of other secondary features of cartilage damage are also reviewed, including osteophytes, intra-articular bodies, and synovitis. Online supplemental material is available for this article. Work of the U.S. Government published under an exclusive license with the RSNA.

Prenatal opioid exposure reprograms the behavioural response to future alcohol reward.

As the opioid crisis has continued to grow, so has the number of infants exposed to opioids during the prenatal period. A growing concern is that prenatal exposure to opioids may induce persistent neurological changes that increase the propensity for future addictions. Although alcohol represents the most likely addictive substance that the growing population of prenatal opioid exposed will encounter as they mature, no studies to date have examined the effect of prenatal opioid exposure on future sensitivity to alcohol reward. Using a recently developed mouse model of prenatal methadone exposure (PME), we investigated the rewarding properties of alcohol and alcohol consumption in male and female adolescent PME and prenatal saline exposed (PSE) control animals. Conditioned place preference to alcohol was disrupted in PME offspring in a sex-dependent manner with PME males exhibiting resistance to the rewarding properties of alcohol. Repeated injections of alcohol revealed enhanced sensitivity to the locomotor-stimulating effects of alcohol specific to PME females. PME males consumed significantly more alcohol over 4 weeks of alcohol access relative to PSE males and exhibited increased resistance to quinine-adulterated alcohol. Further, a novel machine learning model was developed to employ measured differences in alcohol consumption and drinking microstructure to reliably predict prenatal exposure. These findings indicate that PME alters the sensitivity to alcohol reward in adolescent mice in a sex-specific manner and suggests prenatal opioid exposure may induce persistent effects on reward neurocircuitry that can reprogram offspring behavioural response to alcohol later in life.

Lower-body muscular power and exercise tolerance predict susceptibility to enemy fire during a tactical combat movement simulation.

This study examined if field-expedient physical fitness/performance assessments predicted performance during a simulated direct-fire engagement. Healthy subjects (n = 33, age = 25.7 ± 7.0 years) completed upper- and lower-body strength and power assessments and a 3-min all-out running test to determine critical velocity. Subjects completed a simulated direct-fire engagement that consisted of marksmanship with cognitive workload assessment and a fire-and-move drill (16 × 6-m sprints) while wearing a combat load. Susceptibility to enemy fire was modelled on average sprint duration during the fire-and-move drill. Stepwise linear regression identified predictors for the performance during the simulated direct-fire engagement. Critical velocity (ß = -0.30, p < 0.01) and standing broad jump (ß = -0.67, p < 0.001) predicted susceptibility to enemy fire (R2 = 0.74, p < 0.001). All predictors demonstrated poor relationships with marksmanship accuracy and cognitive performance. These data demonstrate the importance of exercise tolerance and lower-body power during simulated direct-fire engagements and provide potential targets for interventions to monitor and enhance performance and support soldier survivability. Practitioner Summary: This study identified field-expedient physical fitness/performance predictors of a simulated direct-fire engagement which evaluated susceptibility to enemy fire, marksmanship, and cognitive performance. Our findings suggest that high-intensity exercise tolerance and lower-body power are key determinants of performance that predicted susceptibility to enemy fire.

A multi-omic analysis of the dorsal striatum in an animal model of divergent genetic risk for alcohol use disorder.

The development of selectively bred high and low alcohol-preferring mice (HAP and LAP, respectively) has allowed for an assessment of the polygenetic risk for pathological alcohol consumption and phenotypes associated with alcohol use disorder (AUD). Accumulating evidence indicates that the dorsal striatum (DS) is a central node in the neurocircuitry underlying addictive processes. Therefore, knowledge of differential gene, protein, and phosphorylated protein expression in the DS of HAP and LAP mice may foster new insights into how aberrant DS functioning may contribute to AUD-related phenotypes. To begin to elucidate these basal differences, a complementary and integrated analysis of DS tissue from alcohol-naïve male and female HAP and LAP mice was performed using RNA sequencing, quantitative proteomics, and phosphoproteomics. These datasets were subjected to a thorough analysis of gene ontology, pathway enrichment, and hub gene assessment. Analyses identified 2,108, 390, and 521 significant differentially expressed genes, proteins, and phosphopeptides, respectively between the two lines. Network analyses revealed an enrichment in the differential expression of genes, proteins, and phosphorylated proteins connected to cellular organization, cytoskeletal protein binding, and pathways involved in synaptic transmission and functioning. These findings suggest that the selective breeding to generate HAP and LAP mice may lead to a rearrangement of synaptic architecture which could alter DS neurotransmission and plasticity differentially between mouse lines. These rich datasets will serve as an excellent resource to inform future studies on how inherited differences in gene, protein, and phosphorylated protein expression contribute to AUD-related phenotypes.

Mu opioid receptors on vGluT2-expressing glutamatergic neurons modulate opioid reward.

The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward.

Performance of the SSI development function compared with 33 other functions applied to 79 arthropod species' datasets.

The development rates of arthropods are temperature-dependent. Studies aiming to predict the dynamics of arachnid, crustacean, and insect populations in nature often require the derivation of development functions representing this phenomenon. A previous study (Quinn, B.K., 2017, J. Therm. Biol. 63, 65-77) identified 33 development functions commonly used in past studies on temperature-dependent development of arthropods, and illustrated that: (1) most of 99 past studies only applied one or few (2-5) development functions to their data without considering others; and (2) most of a subset of 79 studies' data were not fit with the actual best function for them, resulting in sometimes substantial differences in model performance and predictive ability. However, that study did not test the class of development functions based on theoretical enzyme thermodynamics, including the Sharpe-Schoolfield-Ikemoto (SSI) function. Herein, the meta-analyses done in that previous study were redone, after fitting all 79 reanalyzed datasets with the SSI function. Estimates of the intrinsic optimum temperature (TΦ) for development of each tested species were also derived using the SSI function and compared among taxa. Including the SSI function in analyses did not change the conclusions of the previous study concerning development function usage, choice, and consequences. Notably, the SSI function performed as well as or relatively better than other functions of comparable or lower complexity in terms of R2, AICC-based rankings, ΔAICC values, and prediction errors, which may recommend its more widespread use in future studies. Overall differences in TΦ were found among arthropod subphyla, as well as between most species pairs. Most TΦ estimates produced herein were novel, and could be used to make inferences about or comparisons among arthropod taxa in future studies.

High-Resolution MRI of the First Metatarsophalangeal Joint: Gross Anatomy and Injury Characterization.

The first metatarsophalangeal joint (MTPJ) is vital to the biomechanics of the foot and supports a weight up to eight times heavier than the body during athletic activities. The first MTPJ comprises osseous and cartilaginous surfaces along with a complex of supporting structures, including the dorsal extensor tendons, collateral ligaments, and a plantar plate complex. In contradistinction to the lesser MTPJ plantar plates, a single dominant fibrocartilaginous capsular thickening does not exist at the first MTPJ. Instead, the plantar plate complex comprises a fibrocartilaginous pad that invests the hallux sesamoids and is inseparable from the plantar capsule, the intersesamoid ligament, paired metatarsosesamoid and sesamoid phalangeal ligaments (SPLs), and the musculotendinous structures. Acute injury at the first MTPJ is typically secondary to forced hyperextension-turf toe-and can involve multiple structures. During hyperextension, the resulting forces primarily load the distal SPLs, making these structures more susceptible to injury. SPL injuries are best seen in the sagittal plane at MRI. Radiography can also aid in diagnosis of full-thickness SPL tears, demonstrating reduced sesamoid excursion at lateral dorsiflexed (stress) views. Hallux valgus is another common condition, resulting in progressive disabling deformity at the first MTPJ. Without appropriate treatment, first MTPJ injuries may progress to degenerative hallux rigidus. The authors detail the anatomy of the first MTPJ in cadaveric forefeet by using high-resolution 3-T and 11.7-T MRI and anatomic-pathologic correlation. Injuries to the plantar plate complex, collateral ligaments, and extensor mechanism are discussed using clinical case examples. Online supplemental material is available for this article. ©RSNA, 2020.