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We present a rare case with gossypiboma following cesarean section which led to uterine wound dehiscence. A 30-year-old woman had been submitted to an emergency cesarean section 4 months previously at another hospital. Clinical and ultrasound findings revealed a large intra-abdominal mass and diffuse peritonitis. At laparotomy, a gossypiboma causing an abscess and uterine wound dehiscence with necrosis of the margins was detected. We performed repetitive wound debridements under broad-spectrum antibiotic cover and eventually resutured the incision. Although hysterectomy has so far been the choice of treatment in the literature once a uterine wound dehiscence had occurred, it was possible in this case to preserve the uterus.

Background: To evaluate the efficacy of the preoperative ultrasonographic sliding sign in predicting intra-abdominal adhesions. Methods: This was a single-center, double-blinded, prospective observational study undertaken from March and September 2021 on 110 patients with a history of previous abdominal surgery. All patients who were scheduled for laparoscopy underwent slide test in 5 zones of abdomen: right lower quadrant, left lower quadrant, previous operation site, vesicouterine pouch, and rectovaginal pouch. Adhesions were assessed by the same gynecologic surgeon using ultrasonography before the surgery and by gynecological surgeons during surgery, and by a third gynecologic surgeon to compare the preoperative slide test findings and laparoscopic findings after the surgery. Results: Seventy-three (66.4%) patients underwent laparoscopic surgery, and 37 (33.6%) patients underwent laparotomy. The mean age of patients was 46.9 ± 1.0 years. Sensitivity, specificity, and positive and negative predictive values of preoperative ultrasonography in predicting adhesions were 89.5%, 91.7%, 97.5%, and 71.0%, respectively. The accuracy of the slide test was calculated as 90.0%. It was found that as the total number of cesarean sections increased the estimates of vesicouterine adhesions and actual adhesions increased (P =.008). Also, the prediction of intra-abdominal adhesions and actual adhesions significantly increased as the total number of surgical operations increased (P =.002). Conclusions: Intra-abdominal adhesions can be detected with the slide test, which is a non-invasive and well-tolerated procedure. Slide test can guide the physician before the elective operation in patients with previous abdominal surgery and may assist in counseling patients. [ABSTRACT FROM AUTHOR]

Abstract Background The initiation of migraine headaches and the involvement of neuroinflammatory signaling between parenchymal and meningeal cells remain unclear. Experimental evidence suggests that a cascade of inflammatory signaling originating from neurons may extend to the meninges, thereby inducing neurogenic inflammation and headache. This review explores the role of parenchymal inflammatory signaling in migraine headaches, drawing upon recent advancements. Body Studies in rodents have demonstrated that sterile meningeal inflammation can stimulate and sensitize meningeal nociceptors, culminating in headaches. The efficacy of relatively blood-brain barrier-impermeable anti-calcitonin gene-related peptide antibodies and triptans in treating migraine attacks, both with and without aura, supports the concept of migraine pain originating in meninges. Additionally, PET studies utilizing inflammation markers have revealed meningeal inflammatory activity in patients experiencing migraine with aura, particularly over the occipital cortex generating visual auras. The parenchymal neuroinflammatory signaling involving neurons, astrocytes, and microglia, which eventually extends to the meninges, can link non-homeostatic perturbations in the insensate brain to pain-sensitive meninges. Recent experimental research has brought deeper insight into parenchymal signaling mechanisms: Neuronal pannexin-1 channels act as stress sensors, initiating the inflammatory signaling by inflammasome formation and high-mobility group box-1 release in response to transient perturbations such as cortical spreading depolarization (CSD) or synaptic metabolic insufficiency caused by transcriptional changes induced by migraine triggers like sleep deprivation and stress. After a single CSD, astrocytes respond by upregulating the transcription of proinflammatory enzymes and mediators, while microglia are involved in restoring neuronal structural integrity; however, repeated CSDs may prompt microglia to adopt a pro-inflammatory state. Transcriptional changes from pro- to anti-inflammatory within 24 h may serve to dampen the inflammatory signaling. The extensive coverage of brain surface and perivascular areas by astrocyte endfeet suggests their role as an interface for transporting inflammatory mediators to the cerebrospinal fluid to contribute to meningeal nociception. Conclusion We propose that neuronal stress induced by CSD or synaptic activity-energy mismatch may initiate a parenchymal inflammatory signaling cascade, transmitted to the meninges, thereby triggering lasting headaches characteristic of migraine, with or without aura. This neuroinflammatory interplay between parenchymal and meningeal cells points to the potential for novel targets for migraine treatment and prophylaxis.

Abstract The role of high mobility group box 1 (HMGB1) in inflammation is well characterized in the immune system and in response to tissue injury. More recently, HMGB1 was also shown to initiate an “inflammatory signaling cascade” in the brain parenchyma after a mild and brief disturbance, such as cortical spreading depolarization (CSD), leading to headache. Despite substantial evidence implying a role for inflammatory signaling in prevalent neuropsychiatric disorders such as migraine and depression, how HMGB1 is released from healthy neurons and how inflammatory signaling is initiated in the absence of apparent cell injury are not well characterized. We triggered a single cortical spreading depolarization by optogenetic stimulation or pinprick in naïve Swiss albino or transgenic Thy1-ChR2-YFP and hGFAP-GFP adult mice. We evaluated HMGB1 release in brain tissue sections prepared from these mice by immunofluorescent labeling and immunoelectron microscopy. EzColocalization and Costes thresholding algorithms were used to assess the colocalization of small extracellular vesicles (sEVs) carrying HMGB1 with astrocyte or microglia processes. sEVs were also isolated from the brain after CSD, and neuron-derived sEVs were captured by CD171 (L1CAM). sEVs were characterized with flow cytometry, scanning electron microscopy, nanoparticle tracking analysis, and Western blotting. We found that HMGB1 is released mainly within sEVs from the soma of stressed neurons, which are taken up by surrounding astrocyte processes. This creates conditions for selective communication between neurons and astrocytes bypassing microglia, as evidenced by activation of the proinflammatory transcription factor NF-ĸB p65 in astrocytes but not in microglia. Transmission immunoelectron microscopy data illustrated that HMGB1 was incorporated into sEVs through endosomal mechanisms. In conclusion, proinflammatory mediators released within sEVs can induce cell-specific inflammatory signaling in the brain without activating transmembrane receptors on other cells and causing overt inflammation.

Objective To investigate the efficacy of new endometriosis biomarkers in diagnosis and treatment.Methods Thirty women with Stage III-IV endometriosis who were given an indication for surgery and 49 control patients were compared. Preoperative and postoperative serum levels of Annexin A5 (ANXA5), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble vascular cell adhesion molecule-1 (sVCAM-1), vascular endothelial growth factors (VEGF) and Ca-125 measurements were compared.Results AUCs of ANXA5, sICAM-1, IL-6, TNF-α, VCAM-1, VEGF biomarkers were not found to be significant in diagnosing endometriosis when evaluated alone (p > 0.05). Only the AUC of the Ca-125 biomarker values were found to be significant with 73% sensitivity and 98% specificity (p

Functional neuroimaging, which measures hemodynamic responses to brain activity, has great potential for monitoring recovery in stroke patients and guiding rehabilitation during recovery. However, hemodynamic responses after stroke are almost always altered relative to responses in healthy subjects and it is still unclear if these alterations reflect the underlying brain physiology or if the alterations are purely due to vascular injury. In other words, we do not know the effect of stroke on neurovascular coupling and are therefore limited in our ability to use functional neuroimaging to accurately interpret stroke pathophysiology. To address this challenge, we simultaneously captured neural activity, through fluorescence calcium imaging, and hemodynamics, through intrinsic optical signal imaging, during longitudinal stroke recovery. Our data suggest that neurovascular coupling was preserved in the chronic phase of recovery (2 weeks and 4 weeks post-stoke) and resembled pre-stroke neurovascular coupling. This indicates that functional neuroimaging faithfully represents the underlying neural activity in chronic stroke. Further, neurovascular coupling in the sub-acute phase of stroke recovery was predictive of long-term behavioral outcomes. Stroke also resulted in increases in global brain oscillations, which showed distinct patterns between neural activity and hemodynamics. Increased neural excitability in the contralesional hemisphere was associated with increased contralesional intrahemispheric connectivity. Additionally, sub-acute increases in hemodynamic oscillations were associated with improved sensorimotor outcomes. Collectively, these results support the use of hemodynamic measures of brain activity post-stroke for predicting functional and behavioral outcomes.

Abstract Background Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments. Body Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura. Conclusion Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine.

OBJECTIVE: A considerable fraction of ischemic stroke cases remain cryptogenic and there is increasing data suggesting the role of missed paroxysmal atrial fibrillations (pAF) in at least a number of these cases. Since electrophysiological identification of pAFs can be challenging, there has been an accumulation of proposed predictors and biomarkers for pAFs. The predictive values of these is varying and sometimes conflicting among studies. Therefore, we aimed to verify a fraction of previously reported parameters for pAF detection by investigating an independent clinical sample. METHODS: Using a publicly available data downloaded from the MIMIC-3 intensive care unit database, we tested the predictive role of particular risk factors and biomarkers for pAF detection after ischemic stroke in 124 patients with ischemic stroke admitted within 24 hours of stroke onset. RESULTS: Our evaluation revealed a strong association of older age in women, as well as admission National Institutes of Health Stroke Scale (NIHSS) and discharge modified Rankin Scores (mRS) in both sexes for pAFs, in patients that were in sinus rhythm on admission. We also detected a trend for lower gender-adjusted hemoglobin in patients with pAF, although the difference was insignificant. On the other hand, we did not find any significant association of pAF detection with some other previously reported biomarkers: serum magnesium level, leukocyte count, neutrophil/lymphocyte ratio or left atrial dilatation. CONCLUSION: Even though our analysis did not reveal a strong and specific biomarker to predict pAFs after stroke, it identified key risk factors. It may be necessary to consider the possibility of pAFs and perform rigorous evaluation to prevent further events of embolic stroke in female patients older than 75 years, with more severe neurological deficits on admission, higher disability on discharge and also with relatively lower hemoglobin level. This first study from Turkey using clinical data from the MIMIC-3 database also demonstrates the value of publicized clinical data for confirmatory studies on various medical fields across the World.

Purpose: We investigated the optimal cut-off level for urinary neutrophil gelatinase-associated lipocalin (NGAL) in preeclamptic patients to confirm the diagnosis. Methods: Urinary NGAL concentrations were measured by specific enzyme-linked immunosorbent assay (ELISA). Results: Patients with preeclampsia had significantly higher urinary NGAL concentrations than controls (mean: 387 ng/ml vs. 188 ng/ml, respectively; P< 0.001). Using a cutoff value 252 ng/ml for urinary NGAL to confirm diagnosis of preeclampsia, sensitivity, and specificity were 92% and 91%, respectively. Conclusion: Urinary NGAL concentrations were significantly elevated in women with preeclampsia versus normotensive controls.

Ischemic stroke leads to a reduction or complete loss of blood supply causing injury to brain tissue, which ultimately leads to behavioral impairment. Optical techniques are widely used to study the structural and functional changes that result as a consequence of ischemic stroke both in the acute and chronic phases of stroke recovery. It is currently a challenge to accurately estimate the spatial extent of the infarct without the use of histological parameters however, and in order to follow recovery mechanisms longitudinally at the mesoscopic scale it is essential to know the spatial extent of the stroke core. In this paper we first establish optical coherence tomography (OCT) as a reliable indicator of the stroke core by analyzing signal attenuation and spatially correlating it with the infarct, determined by staining with triphenyl-tetrazolium chloride (TTC). We then introduce spatial frequency domain imaging (SFDI) as a mesoscopic optical technique that can be used to accurately measure the infarct spatial extent by exploiting changes in optical scattering that occur as a consequence of ischemic stroke. Additionally, we follow the progression of ischemia through the acute and sub-acute phases of stroke recovery using both OCT and SFDI and show a consistently high spatial overlap in estimating infarct location. The use of SFDI in assessing infarct location will allow longitudinal studies targeted at following functional recovery mechanisms on a mesoscopic level without having to sacrifice the mouse acutely.

Chronic cranial windows allow for longitudinal brain imaging experiments in awake, behaving mice. Different imaging technologies have their unique advantages and combining multiple imaging modalities offers measurements of a wide spectrum of neuronal, glial, vascular, and metabolic parameters needed for comprehensive investigation of physiological and pathophysiological mechanisms. Here, we detail a suite of surgical techniques for installation of different cranial windows targeted for specific imaging technologies and their combination. Following these techniques and practices will yield higher experimental success and reproducibility of results.

Abstract A high‐speed, contrast‐free, quantitative ultrasound velocimetry (vUS) for blood flow velocity imaging throughout the rodent brain is developed based on the normalized first‐order temporal autocorrelation function of the ultrasound field signal. vUS is able to quantify blood flow velocity in both transverse and axial directions, and is validated with numerical simulation, phantom experiments, and in vivo measurements. The functional imaging ability of vUS is demonstrated by monitoring the blood flow velocity changes during whisker stimulation in awake mice. Compared to existing Power‐Doppler‐ and Color‐Doppler‐based functional ultrasound imaging techniques, vUS shows quantitative accuracy in estimating both axial and transverse flow speeds and resistance to acoustic attenuation and high‐frequency noise.

The cerebral microcirculation holds a critical position to match the high metabolic demand by neuronal activity. Functionally, microcirculation is virtually inseparable from other nervous system cells under both physiological and pathological conditions. For successful bench-to-bedside translation of neuroprotection research, the role of microcirculation in acute and chronic neurodegenerative disorders appears to be under-recognized, which may have contributed to clinical trial failures with some neuroprotectants. Increasing data over the last decade suggest that microcirculatory impairments such as endothelial or pericyte dysfunction, morphological irregularities in capillaries or frequent dynamic stalls in blood cell flux resulting in excessive heterogeneity in capillary transit may significantly compromise tissue oxygen availability. We now know that ischemia-induced persistent abnormalities in capillary flow negatively impact restoration of reperfusion after recanalization of occluded cerebral arteries. Similarly, microcirculatory impairments can accompany or even precede neural loss in animal models of several neurodegenerative disorders including Alzheimer's disease. Macrovessels are relatively easy to evaluate with radiological or experimental imaging methods but they cannot faithfully reflect the downstream microcirculatory disturbances, which may be quite heterogeneous across the tissue at microscopic scale and/or happen fast and transiently. The complexity and size of the elements of microcirculation, therefore, require utilization of cutting-edge imaging techniques with high spatiotemporal resolution as well as multidisciplinary team effort to disclose microvascular-neurodegenerative connection and to test treatment approaches to advance the field. Developments in two photon microscopy, ultrafast ultrasound, and optical coherence tomography provide valuable experimental tools to reveal those microscopic events with high resolution. Here, we review the up-to-date advances in understanding of the primary microcirculatory abnormalities that can result in neurodegenerative processes and the combined neurovascular protection approaches that can prevent acute as well as chronic neurodegeneration.

We evaluated the reversible electrophysiologic abnormalities of two cases of hypokalemia paralysis (HypoPP) because of its similar findings in acute motor axonal neuropathy (AMAN). Nerve conduction studies (NCS), repetitive nerve stimulation, and exercise tests were performed in both patients. Adding a 15 minute-exercise test to routine NCS may help distinguish AMAN from HypoPP

Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy is characterized by asymmetric multifocal motor and sensory loss and conduction blocks in peripheral nerves. Peripheral demyelinating diseases may be accompanied by demyelination in central nervous system (CNS). In this report, a MADSAM patient with a solitary tumefactive demyelinating lesion in brain is presented. Neuroimaging due to a visual field defect revealed a right parietooccipital lesion, which was initially misdiagnosed as a tumor. Pathological examination showed that it was demyelinating in nature. Peripheral nervous symptoms of the patient developed two years later and she was then diagnosed with MADSAM. There was prominent clinical and electrophysiological response to steroid treatment. Tumefactive brain involvement was not previously reported for MADSAM neuropathy, although it was documented in a single case with typical chronic inflammatory demyelinating polyneuropathy (CIDP). CNS involvement should therefore be considered in MADSAM patients.

Ischemic cell death is a complex process and the initial distinction between apoptosis and necrosis appears to be an oversimplification. We previously reported that in ischemic neurons with disrupted plasmalemma, apoptotic mechanisms were also active. In the present study, we investigated cellular co-localization of another necrotic feature, lysosomal rupture, with apoptotic mechanisms in the mouse brain and assessed the potential interactions between cysteine proteases. The lysosomal enzymes were spilled into the cytoplasm 1–4 h after ischemia/reperfusion, suggesting that lysosomal membrane integrity was rapidly lost, as occurs in necrosis. The same neurons also exhibited caspase-3 and Bid cleavage, and cytochrome-c release. Caspase-3 activity preceded cathepsin-B leakage in most neurons, and declined by 12 h, while lysosomal leakage continued to increase. Concurrent inhibition of cathepsin-B and caspase-3 provided significantly better neuroprotection than obtained with separate use of each inhibitor. These data suggest that necrotic and apoptotic mechanisms may act both in concert as well as independently within the same cell beginning at the onset of ischemia to ensure the demise of damaged neurons. Therefore, combined inhibition of cysteine proteases may abrogate potential shifts between alternative death pathways and improve the success of stroke treatments.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities., (© 2024. The Author(s).)

Despite perinatal damage to the cerebellum being one of the highest risk factors for later being diagnosed with autism spectrum disorder (ASD), it is not yet clear how the cerebellum might influence the development of cerebral cortex and whether this co-developmental process is distinct between neurotypical and ASD children. Leveraging a large structural brain MRI dataset of neurotypical children and those diagnosed with ASD, we examined whether structural variation in cerebellar tissue across individuals was correlated with neocortical variation during development, including the thalamus as a coupling factor. We found that the thalamus plays a distinct role in moderating cerebro-cerebellar structural coordination in ASD. Notably, structural coupling between cerebellum, thalamus, and neocortex was strongest in younger childhood and waned by early adolescence, mirroring a previously undescribed trajectory of behavioral development between ASD and neurotypical children. Complementary functional connectivity analyses likewise revealed atypical connectivity between cerebellum and neocortex in ASD. This relationship was particularly prominent in a model of cerebellar structure predicting functional connectivity, where ASD and neurotypical children showed divergent patterns. Interestingly, these functional-structural relationships became more prominent with age, while structural effects were most prominent earlier in childhood, and showed significant lateralization. This pattern may suggest a developmental sequence where early uncoordinated structural growth amongst regions is followed by increasingly atypical functional synchronization. These findings provide multimodal evidence in the living brain for a cerebellar diaschisis model of autism, where both increased cerebellar-cerebral structural coupling and altered functional connectivity in cerebro-cerebellar pathways contribute to the ontogeny of this neurodevelopmental disorder., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Insight into how the immune system recognizes and responds to pathogens had led to landmark advances in biology and medicine in the last decades. This year's Albert Lasker Award for Basic Medical Research honors Zhijian "James" Chen for the discovery of cGAS, the enzyme that senses foreign and "pathogenic" self-DNA-self-DNA aberrantly located in intracellular compartments. The definition of the cGAS-STING pathway opens new horizons for the understanding and treatment of human disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: 3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described., Methods: We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants ( n = 24)., Results: We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects ( n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes., Conclusions: Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. HSPCs expressing H1.0 from a doxycycline (dox) inducible transgene favor the lymphoid fate, display strengthened nucleosome organization and reduced chromatin accessibility at genomic regions hosting key myeloid fate drivers. The transcription factor Hlf is located in one of such regions, where chromatin accessibility and gene expression is reduced in H1.0 high HSPCs. Furthermore, H1.0 protein in HSPCs decreases in an aspartyl protease dependent manner, a process enhanced in response to interferon alpha (IFNα) signaling. Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work uncovers a point of intervention to mitigate myeloid skewed hematopoiesis.

The Aedes aegypti mosquito is a vector of many infectious agents, including flaviviruses such as Zika virus. Components of mosquito saliva have pleomorphic effects on the vertebrate host to enhance blood feeding, and these changes also create a favorable niche for pathogen replication and dissemination. Here, we demonstrate that human CD47, which is known to be involved in various immune processes, interacts with a 34-kilodalton mosquito salivary protein named Nest1. Nest1 is up-regulated in blood-fed female A. aegypti and facilitates Zika virus dissemination in human skin explants. Nest1 has a stronger affinity for CD47 than its natural ligand, signal regulatory protein α, competing for binding at the same interface. The interaction between Nest1 with CD47 suppresses phagocytosis by human macrophages and inhibits proinflammatory responses by white blood cells, thereby suppressing antiviral responses in the skin. This interaction elucidates how an arthropod protein alters the human response to promote arbovirus infectivity.

The 3q29 deletion (3q29Del) is a copy number variant (CNV) with one of the highest effect sizes for psychosis-risk (>40-fold). Systematic research offers avenues for elucidating mechanism; however, compared to CNVs like 22q11.2Del, 3q29Del remains understudied. Emerging findings indicate that posterior fossa abnormalities are common among carriers, but their clinical relevance is unclear. We report the first in-depth evaluation of psychotic symptoms in participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes, and compare this profile to 22q11.2Del (N=31) and healthy controls (N=279). We also explore correlations between psychotic symptoms and posterior fossa abnormalities. Cumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder or attenuated positive symptoms, with a subset meeting criteria for clinical high-risk. 3q29Del had more severe ratings than controls on all domains and only exhibited less severe ratings than 22q11.2Del in negative symptoms; ratings demonstrated select sex differences but no domain-wise correlations with IQ. An inverse relationship was identified between positive symptoms and cerebellar cortex volume in 3q29Del, documenting the first clinically-relevant neuroanatomical connection in this syndrome. Our findings characterize the profile of psychotic symptoms in the largest 3q29Del sample reported to date, contrast with another high-impact CNV, and highlight cerebellar involvement in psychosis-risk., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Single-cell RNA sequencing has been widely used to investigate cell state transitions and gene dynamics of biological processes. Current strategies to infer the sequential dynamics of genes in a process typically rely on constructing cell pseudotime through cell trajectory inference. However, the presence of concurrent gene processes in the same group of cells and technical noise can obscure the true progression of the processes studied. To address this challenge, we present GeneTrajectory, an approach that identifies trajectories of genes rather than trajectories of cells. Specifically, optimal transport distances are calculated between gene distributions across the cell-cell graph to extract gene programs and define their gene pseudotemporal order. Here we demonstrate that GeneTrajectory accurately extracts progressive gene dynamics in myeloid lineage maturation. Moreover, we show that GeneTrajectory deconvolves key gene programs underlying mouse skin hair follicle dermal condensate differentiation that could not be resolved by cell trajectory approaches. GeneTrajectory facilitates the discovery of gene programs that control the changes and activities of biological processes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Erectile dysfunction (ED) is a worldwide health problem. Oral phosphodiesterase type 5 inhibitors (PDE5I) are used in its first-line treatment. This study aimed to compare the effects of hyperbaric oxygen (HBO) treatment with PDE5I treatment and determine the patient-dependent factors affecting the efficacy of the HBO treatment and duration of action of HBO treatment., Methods: Adult male patients who presented to the HBO unit for HBO treatment with non-urological indications and had ED based on the International Index for Erectile Function (IIEF-5) constituted the target population of this study. Participants were given HBO treatment (Group 1), no treatment (Group 2), or daily oral tadalafil 5 mg treatment (Group 3). The treatment duration was 1 month. Patients were assessed by IIEF-5 both initially and after the completion of 1 month., Results: There were significant increases in the mean IIEF-5 scores of the patients in Group 1 and Group 3 (p < 0.001, p < 0.001). However, there was no significant improvement in Group 2 (p = 0.496). Also, the post-treatment IIEF-5 scores of Group 1 and Group 3 were significantly higher than Group 2 (p < 0.001). There was no significant difference between the IIEF-5 scores and ∆IIEF-5 values of Group 1 and Group 3 (p = 0.166, p = 0.093). Evaluation regarding comorbidities revealed that patients with the peripheral vascular disease did not improve with HBO treatment (p = 0.285)., Conclusion: HBO can improve erectile functions, and it can be a reasonable alternative for patients who cannot use PDE5Is due to comorbidities or treatment side effects., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Regulatory T cells (T reg cells) are key players in ensuring a peaceful coexistence with microorganisms and food antigens at intestinal borders. Startling new information has appeared in recent years on their diversity, the importance of the transcription factor FOXP3, how T cell receptors influence their fate and the unexpected and varied cellular partners that influence T reg cell homeostatic setpoints. We also revisit some tenets, maintained by the echo chambers of Reviews, that rest on uncertain foundations or are a subject of debate., (© 2023. Springer Nature Limited.)

Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC. We identified that scleroderma skin grafts contained both skin and bone marrow-derived human CD4 and CD8 T cells along with human endothelial cells and pericytes. Unlike healthy skin, fibroblasts in scleroderma skin were depleted and replaced by mouse fibroblasts. Furthermore, HSC engraftment alleviated multiple signatures of fibrosis, including expression of collagen and interferon genes, and proliferation and activation of human T cells. Fibrosis improvement correlated with reduced markers of T cell activation and expression of human IL-6 by mesenchymal cells. Mechanistic studies supported a model whereby IL-6 trans-signaling driven by CD4 T cell-derived soluble IL-6 receptor complexed with fibroblast-derived IL-6 promoted excess extracellular matrix gene expression. Thus, MISTRG6 mice transplanted with scleroderma skin demonstrated multiple fibrotic responses centered around human IL-6 signaling, which was improved by the presence of healthy bone marrow-derived immune cells. Our results highlight the importance of IL-6 trans-signaling in pathogenesis of scleroderma and the ability of healthy bone marrow-derived immune cells to mitigate disease.

Reduced hippocampal volume (HV) is an established brain morphological feature of psychiatric conditions. HV is associated with brain connectivity in humans and non-human animals and altered connectivity is associated with risk for psychiatric illness. Associations between HV and connectivity remain poorly characterized in humans, and especially in phases of psychiatric illness that precede disease onset. This study examined associations between HV and hippocampal functional connectivity (FC) during rest in 141 healthy controls and 248 individuals at-risk for psychosis. Significant inverse associations between HV and hippocampal FC with the inferior parietal lobe (IPL) and thalamus were observed. Select associations between hippocampal FC and HV were moderated by diagnostic group. Significant moderation results shifted from implicating the IPL to the temporal pole after excluding participants on antipsychotic medication. Considered together, this work implicates hippocampal FC with the temporoparietal junction, within a specialized subsystem of the default mode network, as sensitive to HV., Competing Interests: Conflicts of Interest The authors declare that there were no conflicts of interest with respect to the authorship or the publication of this article.

Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects., Competing Interests: Declaration of interests R.A.F. is an advisor to Glaxo Smith Kline, Celsius, and is the recipient of a grant from Genetech/Roche., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.

Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7R hi tumor-specific CD8 + population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8 + population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypomethylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7R hi and antigen-specific T cells allows for enrichment of a potent functional CD8 + population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell-based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents.

Regulatory T (T reg ) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating T reg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver T reg -expressed non-protein-coding RNA), which was specifically expressed in the nucleus of T reg cells and increased with aging. T reg -specific deletion of Altre did not affect T reg homeostasis and function in young mice but caused T reg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice. Depletion of Altre reduced T reg mitochondrial integrity and respiratory capacity, and induced reactive oxygen species accumulation, thus increasing intrahepatic T reg apoptosis in aged mice. Moreover, lipidomic analysis identified a specific lipid species driving T reg aging and apoptosis in the aging liver microenvironment. Mechanistically, Altre interacts with Yin Yang 1 to orchestrate its occupation on chromatin, thereby regulating the expression of a group of mitochondrial genes, and maintaining optimal mitochondrial function and T reg fitness in the liver of aged mice. In conclusion, the T reg -specific nuclear long noncoding RNA Altre maintains the immune-metabolic homeostasis of the aged liver through Yin Yang 1-regulated optimal mitochondrial function and the T reg -sustained liver immune microenvironment. Thus, Altre is a potential therapeutic target for the treatment of liver diseases affecting older adults., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors., Method: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor., Results: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth., Conclusions: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing., Competing Interests: Competing interests: HHMI lab heads have previously granted a non-exclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication. RF is an advisor to GlaxoSmithKline, EvolveImmune, and Ventus Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Rationale: Drug- and alcohol-related motor vehicle accidents are a leading cause of morbidity and mortality worldwide. Compared to alcohol, less is known about the effects of cannabis on driving and even less about their combined effects., Objective: To characterize the combined and separate effects of ethanol and tetrahydrocannabinol (THC) on perceived ability to drive, subjective effects, and simulated driving., Methods: In a within-subject (crossover), randomized, placebo-controlled, double-blind, 2 × 2 design, the effects of oral THC (10 mg [dronabinol] or placebo) and low-dose intravenous ethanol (clamped at BAC 0.04% or placebo) on perceived ability to drive, simulated driving (standard deviation of lateral position [SDLP]), subjective effects (e.g., "high"), and physiological effects (e.g., heart rate) were studied in healthy humans (n = 18)., Results: Subjects reported reductions in perceived ability to drive (THC < ethanol < combination) which persisted for ~ 6 h (placebo = ethanol, THC < combination). Ethanol and THC produced synergistic effects on heart rate, significant differences compared to either drug alone on perceived ability to drive and feeling states of intoxication (e.g., high), as well increases in SDLP compared to placebo., Conclusions: Perceived ability to drive is reduced under the influence of THC against the backdrop of blood alcohol levels that are below the legal limit. People should be aware that the effects of oral THC on driving may persist for up to six hours from administration. Findings are relevant to the increasingly common practice of combining alcohol and cannabinoids and the effects on driving., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)